CN104321141B - Digital micro-fluid system with interconvertible PCB - Google Patents

Digital micro-fluid system with interconvertible PCB Download PDF

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Publication number
CN104321141B
CN104321141B CN201380011785.6A CN201380011785A CN104321141B CN 104321141 B CN104321141 B CN 104321141B CN 201380011785 A CN201380011785 A CN 201380011785A CN 104321141 B CN104321141 B CN 104321141B
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China
Prior art keywords
interconvertible
battery lead
box
array
electrod
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CN201380011785.6A
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Chinese (zh)
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CN104321141A (en
Inventor
M·N·费格林
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Tecan Trading AG
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Tecan Trading AG
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B01L3/502792—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0672—Integrated piercing tool
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/089—Virtual walls for guiding liquids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0427—Electrowetting

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

Disclose a kind of digital micro-fluid system (1) for being used to manipulate sample drop in disposable cassette (2), disposable cassette (2) includes bottom (3), top layer (4) and the gap (6) between bottom and top layer (3,4).The digital micro-fluid system (1) includes the base unit (7) with box receiving station (8)；And central control unit (14), it is used for the selection for the single electrode (10) for controlling (multiple) electrod-array (9), and for providing a mean for each voltage pulse that electrowetting manipulates drop in box (2) for these electrodes (10).The digital micro-fluid system (1) also includes plate receiving station (40), plate receiving station (40) is located at box receiving station (8) place of base unit (7) and can receive interconvertible battery lead plate (41), and interconvertible battery lead plate (41) includes electrod-array (9) and is separately connected to the electric plates contact element (42) of the electrode (10) of electrod-array (9).Each plate receiving station (40) includes electrical base unit contact element (43), and electrical base unit contact element (43) is connected to central control unit (14) and is configured to the electric plates contact element (42) of the interconvertible battery lead plate (41) with being placed in plate receiving station (40) place and engages.Also disclose a series of disposable cassettes (2), interconvertible battery lead plate (41) and the method for manipulating the sample drop (23) for adhering to hydrophobic surface (17).

Description

Digital micro-fluid system with interconvertible PCB
Technical field
The present invention relates to digital micro-fluid system or device, for manipulate wherein sample drop it is one or more once Property box can be inserted into the system or device.The digital micro-fluid system includes：Electrod-array, it is supported by substrate；And in Control unit is entreated, it is used for the selection for the single electrode for controlling the electrod-array, and is used for for being provided for these electrodes Each voltage pulse of drop is manipulated by electrowetting.Therefore, the invention further relates to the molecule skill for being conducive to droplet to activate The droplet actuator devices of art.The technical field relates generally to the control of the liquid of small size (being usually micron order or nanoscale) And manipulation.
Background technology
Such as derived from the applicant (Tecan Trading AG, Seestrasse 103, CH-8708 meldurf,Switzerlands) FreedomThe automatic fluid processing system of robot workstation is generally known in the art.The device allows Automatic fluid processing in free-standing instrument or in the automation with analysis system is connected.These automated systems are not It is designed to portable and usually requires the large volume of liquid of processing (microlitre to milliliter).In digital micro-fluid, limit Voltage be applied to the electrode of electrod-array, so as to handle (electrowetting) each droplet., please on the general introduction of electrowetting method Referring to Washizu, IEEE commercial Applications transactions (IEEE Transactions on Industry Applications), 1998 Year, volume 34, No. 4, the chip lab magazine (Lab chip) of 1998 and Pollack et al., volume 2002,2,96- 101.In brief, electrowetting refers to the method for moving drop using the microelectrode array preferably covered by hydrophobic layer.Pass through The voltage of restriction is applied to the electrode of electrod-array, causes the change of the surface tension of drop present on handled electrode Change.This causes the significant changes of the contact angle of the droplet on handled electrode, so as to cause the movement of droplet.For such For electrowetting program, it is known that the basic mode of two kinds of arrangement electrodes：It is small to cause using the single surface with electrod-array The movement of drop, or addition second surface, it is relative with similar electrod-array and provides at least one grounding electrode.Electrowetting The major advantage of technology is, it is only necessary to the liquid of small size, such as single droplet.Therefore, liquid handling can be significantly more Carried out in the short time.In addition, the control of liquid movement can be carried out under electronic control completely, this causes the automation of sample Processing.
It is known a kind of for by using the single surface (electricity with electrod-array from United States Patent (USP) No.5,486,337 Pole monoplane arrangement) electrowetting manipulate drop device.All electrodes are placed on the surface of carrier substrate, drop to base In plate, or covered by non-wettable surface.Voltage source is connected to electrode.Moved by applying a voltage to subsequent electrode Droplet, so as to guide the movement of the drop above electrode according to the order of the voltage application to electrode.
From US 6, a kind of Electrowetting device for the micron order control moved for drop known to 565,727, it uses relative Surface there is the electrod-array biplane of electrode (arrangement) of at least one grounding electrode.Each surface of the device may include Multiple electrodes.Two relative array formation gaps.Surface towards the electrod-array in gap is hydrophobic preferably by what is be electrically insulated Layer covering.Drop is positioned in gap and many on the relative station in gap by being continually applied to be positioned at by multiple electric fields Individual electrode and moved in nonpolar filler stream body.
It is used to manipulate the container in the polymer film of sample drop thereon from known to the A1 of WO 2010/069977 having： A kind of Biosample processing system includes being used for the container that large volume handles and flat with lower surface and hydrophobic top surface Polymer film.Flat polymer film is kept at a distance by the back side of projection and container., should be away from when container is positioned on film From at least one gap of restriction.Droplet manipulation instrument includes at least one electrod-array for being used to cause drop to move.It is also disclosed Support the substrate of at least one electrod-array and the control unit for droplet manipulation instrument.Container and film are reversibly attached It is connected to droplet manipulation instrument.Thus the system allows at least one drop to be moved by the passage of container from least one described well is recessed Put on the hydrophobic top surface of flat polymer film and higher than at least one described electrod-array.Droplet manipulation instrument is by reality It is now that the drop being moved by guiding on the hydrophobic top surface of flat polymer film is controlled by electrowetting, and There processing Biosample.
It is used for the use for manipulating such Electrowetting device of drop under the background of processing Biosample also from being disclosed as It is known in the A2 of WO 2011/002957 international patent application.A kind of droplet actuator is disclosed in that patent, and it is generally wrapped Include the bottom substrate with the coordination electrode (electrowetting electrode) by dielectric insulation, conductive top substrate and be coated on Hydrophobic coating on bottom and head substrate.The invention also discloses one or more parts for replacing droplet actuator The droplet actuator devices of (that is, disposable unit).From have known to the international application (for example, PCB) fixed bottom substrate, Droplet actuator with electrowetting electrode and with removable or interchangeable head substrate.Self-contained box can be such as Including buffer solution, reagent and filler fluid.Pouch in box can be used as fluid reservoir and can be punctured with by fluid (example Such as, reagent or oil) discharge into box gap.Box may include the grounding electrode that can be replaced by hydrophobic layer and for sample to be loaded into Opening in the gap of box.The adhesion of box can be provided and arrive electrod-array by interface material (for example, liquid, glue or grease).
Disclosed in the A1 of WO 2006/125767 (translator of English is referring to the A1 of US 2009/0298059) for for entering Microfluidic process and the disposable cassette of analysis in the automated system of row molecule diagnostic analysis.Box is configured as flat chamber device (size with about cheque card) simultaneously can be inserted into system.Sample can be pipetted in box by port.
The content of the invention
The purpose of the present invention is to propose to a kind of alternative digital micro-fluid system or digital micro-fluid device, it is configured to Adapt to one or more disposable cassettes for manipulating sample drop wherein.The purpose is used in disposable cassette due to proposing It is interior manipulate sample drop digital micro-fluid system and realize.Such disposable cassette preferably includes bottom, top layer, Yi Ji Gap between bottom and top layer.
Included according to the digital micro-fluid system of the present invention：
(a) base unit, it has at least one the box receiving station for being configured to receive disposable cassette；
(b) at least one electrod-array, it substantially extends and including multiple single electrodes in this first plane, described At least one electrod-array is supported by bottom substrate；And
(c) central control unit, its be used to controlling the selection of the single electrode of at least one electrod-array and For providing a mean for each voltage pulse that electrowetting manipulates the drop in the box for these electrodes.
It is characterised by according to the digital micro-fluid system of the present invention, it also includes at least one plate receiving station, and it is located at At one in the box receiving station of base unit；Each plate receiving station is configured to receive interconvertible battery lead plate, and this can The battery lead plate of exchange includes electrod-array and is electrically connected to multiple electric plates contact elements of the single electrode of the electrod-array Part；Each plate receiving station includes being electrically connected to multiple electrical base unit contact elements of the central control unit, electric base Seat unit contact element is configured to and is placed on the electric plates contact element of the interconvertible battery lead plate at the plate receiving station Engagement.
Preferably, at least one plate receiving station be located at base unit the box receiving station in a lower section and by with It is set to the interconvertible battery lead plate in the base unit for receiving insertion digital micro-fluid system.It is also disclosed according to the present invention Digital micro-fluid system additional preferred embodiment.
Preferably, digital micro-fluid system is configured to receive one in the base unit of pluggable digital micro-fluid system Individual or multiple disposable cassettes.It may further be preferable that digital micro-fluid system includes being used to use digital micro-fluid system or dress Put at least one disposable cassette for manipulating sample drop.It may further be preferable that the bottom and top layer of box are included exposed to box The hydrophobic surface in gap, and box does not have conductive layer.
Preferably, digital micro-fluid system includes at least one cover plate with head substrate, at least one cover plate position At (multiple) described box receiving station.At least one cover plate also includes conductive material, and it extends and basic in the second plane On parallel to the box receiving station assigned by least one cover plate electrod-array.The conductive material of at least one cover plate not with The source connection of potential.Preferably, the conductive material of cover plate is attached to the conductive foil of box.
According to the first advantageous variant of box receiving station, cover plate is configured to the electrod-array relative to corresponding box receiving station It is removable.According to the second advantageous variant, box receiving station is arranged to receive the disposable cassette being slidably inserted into, the disposable cassette It may move in the electrod-array essentially parallel directions relative to corresponding box receiving station.
Preferably, digital micro-fluid system includes at least one interconvertible battery lead plate, and it includes being supported by bottom substrate Electrod-array and including the multiple electric plates contact elements for the single electrode for being electrically connected to the electrod-array.
The additional purpose of the present invention is to propose that one kind is different for being carried out inside disposable cassette for technically adjusting Measure alternative digital micro-fluid system means, the disposable cassette is used to manipulate using digital micro-fluid system or device Sample drop.The additional purpose by propose to be configured to be placed at the plate receiving station of digital micro-fluid system at least one can The battery lead plate of exchange is realized.At least one interconvertible battery lead plate includes the electrod-array supported by bottom substrate and is electrically connected It is connected to multiple electric plates contact elements of the single electrode of the electrod-array.At least one interconvertible battery lead plate by with It is set at one in the plate receiving station for being placed on digital micro-fluid system；Electric plates contact element is configured to and is electrically connected It is connected to the electrical base unit contact element engagement of the base unit of the central control unit of the digital micro-fluid system.
Preferably, the bottom substrate of support electrod-array is configured as printed circuit board (PCB) (PCB), and electric plates contact element Part is positioned and close to PCB one or more borders in groups.Preferably, the single electrode of the electrod-array is arranged Drop is manipulated in box and for specifically being determined with electrowetting is configured to.In particular it is preferred that interchangeable At least electrod-array of battery lead plate covered by dielectric layer.
A further object of the present invention is to propose to be used in digital micro-fluid system or device manipulate the standby of sample drop Choosing method.Another purpose is realized due to proposing for manipulating the method for the sample drop for adhering to hydrophobic surface.
Comprised the following steps according to the first method of the present invention：
(a) the digital micro-fluid system according to the present invention is provided；
(b) box as described herein is provided；And
(c) interconvertible battery lead plate as described herein is provided,
Wherein, interconvertible battery lead plate includes electrod-array, and the electrod-array is arranged to carry out in the gap of box Specific to determine, during the measure, the sample drop for adhering to hydrophobic surface is manipulated by electrowetting in gap.
Comprised the following steps according to the second method of the present invention：
(a) digital micro-fluid system as described herein is provided；
(b) box as described herein is provided；And
(c) the interconvertible battery lead plate according to the present invention is selected,
Wherein, interconvertible battery lead plate includes electrod-array, and the electrod-array is arranged to carry out in the gap of box Specific to determine, during the measure, the sample drop for adhering to hydrophobic surface is manipulated by electrowetting in gap.
Digital micro-fluid system, interconvertible battery lead plate and for manipulate sample drop method it is additional and creative Feature and preferred embodiment and modification drawn from specification and dependent claims.
Advantages of the present invention includes：
Interconvertible battery lead plate is provided so that digital micro-fluid system is relative to can be placed in such interconvertible electricity For the different measure carried out in disposable cassette above pole plate extremely flexibly, because each interconvertible battery lead plate can be specific For carrying out, one kind is specific to be determined for ground design.Therefore, it is necessary to for a large amount of purposes electrod-array it is complicated and expensive Design can be avoided by providing interconvertible battery lead plate simply too much with affordable price.
Instrument with interconvertible battery lead plate is carried compared to disposable digital micro-fluid box of the design with integrated PCB For greater flexibility and lower cost.By being set on interconvertible PCB rather than in disposable cassette because of measure Different feature, can be utilized for the general simpler box of many measure.Increased simplicity (by removing PCB) and manufacture Both abilities (because they are general for being used in many different measure) of greater amount of box allow lower manufacture Cost.The flexibility for carrying out many measure is provided by the ability of staggered poles plate.
Interconvertible battery lead plate damage or non-functional can be easily replaced, and without using any specific purpose tool, And also without any maintenance expert.
There is provided and created with the digital micro-fluid system for being used at least one the plate receiving station for receiving interconvertible battery lead plate Make for utilizing the possibility for carrying out the still undeveloped following same numbers microfluid system determined.
The electrod-array for covering at least interconvertible battery lead plate with dielectric layer provides for the sensing surface of electrod-array For oxidation or the supplementary protection of fingerprint.
Disposable cassette can be configured as simple running stores, its provide working lining and between them and for progress by The gap for the measure that interconvertible battery lead plate is limited.The working lining of box prevents interconvertible battery lead plate and whole digital micro-fluid system System is contaminated.
" interconvertible PCB " concept is, is retained in for the general expensive components of many biochemical measurements in instrument.Example Such as, digital micro-fluid system includes the following：
O is designed for one group of interconvertible PCB for specifically determining (for example, molecular biology), and it is included for example：
O top layers, it has the electrode pattern for limiting measure ability,
The o second layers, it has the trace for being used for powering for each electrode,
O third layer, it has the thin trace that heating is provided in designated area,
The 4th layer of o, it has the integrated thermal electric for being used to measuring and controlling the temperature of designated area even, and
O substrates, it carries all layers and its electric contact；
High-voltage power relay module, for controlling switching on and off for PCB electrodes；
Power supply, for being powered for whole system；
Optical module (for example, for fluoroscopic examination)；
Clamp and/or vacuum module, for box to be kept in place on PCB；
Magnetic actuator, its make permanent magnet toward and away from PCB bottom movement (permanent magnet than electromagnet provide more Concentrate and stronger magnetic field)；
Analog/digital I/O modules, for controlling numeral output (that is, magnetic actuator, heater, vacuum etc.) and input (thermocouple etc.)；
Power model, for providing power for system；And
For the embeded processor of runtime, the processor includes：
O softwares and user interface.
According to the present invention, digital micro-fluid system proposes to be " instrument platform ", and it is solid comprising above-mentioned all expensive bands The item of round dot bullets and available for nearly all biochemical applications.By only changing or changing band soft dot bullets Item, can produce " different instruments " for carrying out entirely different application or even " new instrument ".
The concept provides two remarkable advantages：
1. because quantity is big, manufacturer can produce substantial amounts of instrument platform or digital miniflow respectively with significantly reduced cost System is united (referring to the above-mentioned item with black circle bullets).For limited number of instrument platform addition in stock it is selected can Variable (that is, a series of items with soft dot bullets, see above) will cause the various numbers that are exclusively used in special-purpose Word microfluid system.Selected variable item (that is, a series of band soft dots are changed in some in the instrument platform produced The item of bullets, sees above) a variety of new digital micro-fluid systems will be caused, and each system can be exclusively used in New special-purpose.
2. the commercially available single instrument platform for being exclusively used in special-purpose of user is (for example, as measuring the spy in blood sample Determine the instrument of analyte).If user determines the different experiment of progress or measure, he can simply change corresponding variable (that is, a series of items with soft dot bullets, see above), this will cause to be exclusively used in new special-purpose (for example, Be used as the instrument for analyzing the gene in blood sample) new digital micro-fluid system.In order to for example carry out ELISA measure, PCB It can be exchanged and software is updated, so that instrument turns into immunoassay system.
In these cases, PCB may be designed such that software is actually included on the chip on PCB, so that in PCB Automatic software update when being exchanged.
According to the present invention, digital micro-fluid system is proposed as multi-level " instrument platform ".On the first level, digital miniflow The base unit of system system is for being identical using all applications of electrowetting technology.Therefore, all purpose instrument is created, wherein Expensive but general module is retained in the base unit of instrument, and wherein by such as can be inserted into PCB and pluggable box Plug-in package provides larger flexibility.On the second level, PCB is can be replaced by manufacturer or end user replaceable Element.The PCB of replacement electrod-array is joined by contact site and base unit so that in the box being placed on PCB top Internal droplet movement is controlled very closely.Preferably, the contact site on PCB and in base unit is standardization. In third level, using the different box types for being preloaded with different reagent sets.For same measured, it can be used The box of same type, but introduce different samples.
Brief description of the drawings
By means of accompanying schematic figure explain according to the present invention digital micro-fluid system, a series of interconvertible battery lead plates, The selected and exemplary embodiment of the present invention is shown in self-contained disposable cassette and the method for manipulating sample, figure, without Reduce scope and spirit of the present invention.In the accompanying drawings：
Fig. 1 shows the general view of digital micro-fluid system, and it is furnished with central control unit and base unit, four box receiving station With four plate receiving station for receiving the interconvertible battery lead plate including electrod-array；
Fig. 2 shows wherein to accommodate the sectional view of a box receiving station of the disposable cassette according to first embodiment；Electrode Array is located on fixed bottom substrate；
Fig. 3 shows wherein to accommodate the sectional view of a box receiving station of the disposable cassette according to second embodiment；Electrode Array is located on fixed bottom substrate；
Fig. 4 shows the general view of digital micro-fluid system, and it is equipped with central control unit and base unit, including fixation 12 box receiving station of cover plate and 12 plate receiving station for receiving the interconvertible battery lead plate including electrod-array；
Fig. 5 shows wherein to accommodate the sectional view of a box receiving station of the disposable cassette according to 3rd embodiment, wherein：
Fig. 5 A show that the top for inserting substantially vertical box receiving station enters box, and it has substantially vertical electrode array Row and cover plate, and
Fig. 5 B show that the top from the section B indicated in fig. 5 enters box；
Fig. 6 shows the general view of interconvertible battery lead plate, and it can be inserted into digital micro-fluid system；The interconvertible battery lead plate Bottom substrate be configured as printed circuit board (PCB) (PCB)；
Fig. 7 shows the cross-sectional view according to Fig. 2；Here, electrod-array is located at adjustable according to the first embodiment of electrical contact On the battery lead plate changed；
Fig. 8 shows the cross-sectional view according to Fig. 3；Here, electrod-array is located at adjustable according to the second embodiment of electrical contact On the battery lead plate changed；
Fig. 9 shows the schematic diagram of general multi-level " instrument platform ", and it includes the standardization with all general modules Base unit；" instrument platform " also includes the interchangeable PCB and interchangeable box suitable for particular experiment or measure.
Embodiment
Fig. 1 shows the general view of exemplary digital micro-fluid system 1, and digital micro-fluid system 1 is furnished with central control unit 14 and base unit 7, respective four box receiving station 8 including electrod-array 9 and cover plate 12.Digital micro-fluid system 1 is configured For manipulating sample drop 23 in the disposable cassette 2, disposable cassette 2 includes bottom 3, top layer 4 and finally distance piece 5, interval Part 5 is limited to the gap 6 between bottom 3 and top layer 4.Therefore, sample drop 23 is manipulated in the gap 6 of disposable cassette 2.Root Four plate receiving station 40 for also including being used to receive interconvertible battery lead plate 41 according to the digital micro-fluid system 1 of the present invention.
Digital micro-fluid system 1 includes base unit 7, and it has at least one box for being configured to receive disposable cassette 2 Receiving station 8.Digital micro-fluid system 1 can be stand alone type and stationary unit, and multiple operators operate them to carry thereon Box 2.Therefore digital micro-fluid system 1 may include multiple box receiving station 8 and multiple electrodes array 9, and wherein at least some is located at On interconvertible battery lead plate 41 so that multiple boxes 2 can be operated simultaneously and/or concurrently.Box receiving station 8 and plate receiving station 40 Number can be 1 or be at such as 1 and 100 or even more many between any number；The number is for example single by center control The disposal ability limitation of member 14.
It may be preferred that digital micro-fluid system 1 is integrated into liquid handling work station or FreedomMachine In device people's work station so that Yi Xi robots can be used to the sample by liquid portion and/or comprising liquid and be transferred to box 2 and from box 2 produce.Alternatively, system 1 can be configured as handheld unit, and it only includes and can be with a small amount of for example single disposable cassette 2 work together.It is each it should be understood to the one skilled in the art that within the spirit of the invention, between two extreme versions having just mentioned Middle scheme also can run and work.
According to the present invention, digital micro-fluid system 1 also includes at least one plate for being used to receive interconvertible battery lead plate 41 Receiving station 40, interconvertible battery lead plate 41 includes substantially extending and including the electricity of multiple single electrodes 10 in this first plane Pole array 9.Such interconvertible battery lead plate 41 be preferably located in each in the box receiving station 8 of base unit 7 at. Preferably, each electrod-array 9 is supported by bottom substrate 11.It should be pointed out that expression " electrod-array ", " electrode lay-out " and " print Printed circuit board (PCB) " is used herein as synonym.
Digital micro-fluid system 1 may also comprise at least one cover plate 12 with head substrate 13；Although setting such Cover plate 12 is particularly preferred, but at least some in cover plate are saved or can replaced by alternative covering, the covering Part is used to inside the base unit of microfluid system 1 keep disposable cassette 2 in place.Therefore, at least one cover plate 12 can position At one in the box receiving station 8.The head substrate 13 of cover plate 12 and the bottom substrate 11 with electrod-array 9 or PCB Space or box receiving station 8 are limited respectively.(referring to two box receiving station 8 at the middle part of base unit 7) in the first modification, box Receiving station 8 is arranged to receive the disposable cassette 2 being slidably inserted into, and disposable cassette 2 can be relative to corresponding box receiving station 8 The essentially parallel directions of electrod-array 9 on move.Loading or top-loaded can be supported by pulling in automechanism before such, This pulls in automechanism and box 2 is transported into its final purpose in box receiving station 8 after the partial insertion of disposable cassette 2 Ground, herein, box 2 is by critically seating.Preferably, these box receiving station 8 do not include moveable cover plate 12.To test liquid Drop is carried out after all expected manipulations, and used box 2 can be ejected by pulling in automechanism and be transported to analysis station or discarding.
(referring to two box receiving station 8 on the right side and left side of base unit 7) in the second modification, box receiving station 8 is wrapped Cover plate 12 is included, it is configured to move relative to the electrod-array 9 of corresponding box receiving station 8.Cover plate 12 is preferably configured Into can be moved up around one or more hinges 16 and/or in the side substantially perpendicular to electrod-array 9.
Plate receiving is inserted similar to the possibility for inserting disposable cassette 2 in box receiving station 8, by interconvertible battery lead plate 41 The possibility stood in 40 includes following alternative：
(a) interconvertible battery lead plate 41 is vertically descended through into corresponding box receiving station 8 and entered in plate receiving station 40；
(b) interconvertible battery lead plate 41 is essentially horizontally slided below corresponding box receiving station 8 and enters plate and held Receive station 40 in；
(c) interconvertible battery lead plate 41 is essentially horizontally slided and substantially erected below corresponding box receiving station 8 Directly lifted in plate receiving station 40.
In Fig. 1, only draw an interconvertible battery lead plate 41, it can be by the second box receiving station 8 (from left-hand digit) Load and be slidably inserted into before lower section.All possible position for location-plate receiving station 40 is all indicated and referred to by dotted arrow Go out.
Digital micro-fluid system 1 also includes central control unit 14, and it is used to control at least one electrod-array 9 The selection of single electrode 10, and drop is manipulated in the box 2 for providing a mean for electrowetting for these electrodes 10 Each voltage pulse.As partly indicated in Fig. 1, each single absolute electrode 10 is operably connected to central control Unit 14 processed and therefore it can be independently processed from by the central control unit 14, it is suitable that the central control unit 14 also includes Source, for forming and providing necessary potential in a manner known in the art.
At least one cover plate 12 preferably includes conductive material 15, and conductive material 15 extends and basic in the second plane On parallel to the box receiving station 8 assigned by least one cover plate 12 electrod-array 9.It is particularly preferred that cover plate 12 The conductive material 15 is configured to be not connected to the source of ground potential.If applicant of the present invention is it has surprisingly been found that in cover plate Connection is not present between any source of 12 conductive material 15 and some potential (such as ground potential), conductive material 15 is also contributed to The electrowetting movement of the drop manipulated in digital micro-fluid system 1.Therefore, cover plate 12 is configured in any random side Move up, and select cover plate 12 it is particularly preferred mobile when, it is not necessary to consider electric contact.Therefore, cover plate 12 can by with Being set to can also move up in the side for being arranged essentially parallel to electrod-array 9, and for the corresponding electricity relative to base unit 7 Pole array 9 carries out linear, circular or any random movement.
Fig. 2 shows wherein to accommodate the section view of an exemplary cartridge receiving station 8 of the disposable cassette 2 according to first embodiment Figure.Cover plate 12 is mechanically connected via hinge 16 and the base unit 7 of digital micro-fluid system 1；Therefore, cover plate 12 is swingable beats Open, and disposable cassette 2 can be placed in box receiving station 8 (referring to Fig. 1) by top into loading.The conductive material of cover plate 12 15 are configured to attach to the sheet metal or metal foil of head substrate 13.Alternatively, the conductive material 15 of cover plate 12 is configured For the metal level being deposited on head substrate 13.This deposition of conductive material 15 can pass through chemically or physically gas known per se Phase deposition technique is carried out.
Cover plate 12 is configured to exert a force to the disposable cassette 2 being contained at the box receiving station 8 of base unit 7.The power Disposable cassette 2 is promoted against electrod-array 9, so as to which the bottom 3 of box is positioned to as close to the surface of electrod-array 9.Should Puncture facility 18 of the power also by disposable cassette 2 relative to cover plate 12 is pushed into the perfect position on electrod-array 9.The puncture facility 18 are arranged to introduce sample droplet in the gap 6 of box 2.Puncture facility 18 and be configured as through hole 19, it is across whole lid Plate 12, which is guided and enabled, punctures the top layer 4 that liquid relief pipe end 20 was pushed over and pierced through box 2.Puncturing liquid relief pipe end 20 can be A part for hand-held pipette (not shown) or the part for aspirating robot (not shown).
In the case of shown in Fig. 2, electrod-array 9 is covered by dielectric layer 24.Electrod-array 9 is fixed to bottom substrate 11, And each individually electrode 10 electrically and is operatively connected with central control unit 14 and (only draws 10 electrodes 10 here In 3 connection).Electrod-array 9 is located on immovably fixed bottom substrate 11.Digital micro-fluid system 1 is configured For manipulating sample drop 23 in the disposable cassette 2 comprising gap 6.Therefore, sample drop 23 is in the gap 6 of disposable cassette 2 In be manipulated.Disposable cassette 2 includes bottom 3, top layer 4 and the distance piece 5 in the gap 6 being limited between bottom 3 and top layer 4, For manipulating sample drop 23 in the gap 6.Bottom 3 and top layer 4 include the hydrophobic surface exposed to the gap 6 of box 2 17.The bottom 3 and top layer 4 of box 2 are entirely hydrophobic film or at least include the hydrophobic surface exposed to the gap 6 of box 2.From this Fig. 2 can be seen that box 2 does not have conductive layer.The distance piece 5 of box 2 is configured as including being used to apply here at least in part To the main body of the compartment 21 of the reagent needed for the measure of the sample droplet in gap 6.
Fig. 3 shows wherein to accommodate the section view of an exemplary cartridge receiving station 8 of the disposable cassette 2 according to second embodiment Figure.Different from previous embodiment, cover plate 12 and the base unit 7 of digital micro-fluid system 1 are mechanically connected and irremovable Ground is fixed.The conductive material 15 of cover plate 12 is configured to attach to the thick sheet metal of head substrate 13.Here, cover plate 12 not by with It is set to the disposable cassette 2 for exerting a force to and being contained at the box receiving station 8 of base unit 7；Therefore, the retention position of cover plate 12, and And disposable cassette 2 can be placed in box receiving station 8 via loading is advanced into.It is such to advance into loading and generally include disposable cassette 2 movement on the direction parallel to electrod-array 9 (referring to Fig. 1).In order to allow the correct of disposable cassette 2 to pull in and box is whole Receiving station 8 is positioned at together, and base unit 7 is preferably fitted with inserting guider 25.These insertion guiders 25 are preferably by all As the self-lubricating plastic of tetrafluoroethene is made, and preferably leaves between them and be just enough slidably inserted into disposable cassette 2 space.Alternatively, the conductive material 15 of cover plate 12 is configured as metallic plate, the gold being clipped between the material of head substrate 13 Belong to paper tinsel or metal level (referring to Fig. 5 A).
Fig. 3 disposable cassette 2 includes the interval in bottom 3, top layer 4 and the gap 6 being limited between bottom 3 and top layer 4 Part, for manipulating sample drop 23 in the gap 6.Bottom 3 and top layer 4 include the hydrophobicity table exposed to the gap 6 of box 2 Face 17.The bottom 3 and top layer 4 of box 2 are entirely hydrophobic film or at least include the hydrophobic surface exposed to the gap 6 of box 2.Make For with describing such difference in Fig. 2, the box 2 has the dielectric layer 24 for the part for being attached to bottom 3 or forming bottom 3.Cause This, bottom 3 is covered by dielectric layer 24, or bottom 3 itself is made up of dielectric substance.Therefore, electrod-array 9 need not have this The dielectric layer 24 of sample.The sample that the distance piece 5 of box 2 is configured as including being used to be applied in gap 6 here at least in part is small The main body of the compartment 21 of reagent needed for the measure of drop.In this case, electrod-array 9 is covered by dielectric layer 24.
Electrod-array 9 is fixed to bottom substrate 11, and each individually electrode 10 and central control unit 14 are electrically And be operatively connected and (only draw 3 connections in 10 electrodes 10 here).Electrod-array 9 is located at immovably fixed On bottom substrate 11.Digital micro-fluid system 1 is arranged in the disposable cassette 2 comprising gap 6 manipulate sample drop 23. Therefore, sample drop 23 is manipulated in the gap 6 of disposable cassette 2.
Cover plate 12 also includes puncturing facility 18, and it is arranged to sample droplet being introduced into the gap 6 of box 2.Puncture is set Apply 18 and be configured as through hole 19, it guides across whole cover plate 12 and enables puncture liquid relief pipe end 20 to be pushed over and pierce through The top layer 4 of box 2.Puncturing liquid relief pipe end 20 can be a part for hand-held pipette (not shown) or aspirate robot (not shown) A part.Cover plate 12 includes additional puncture facility 22 here, and puncture cover plate 12 is pushed through for that will puncture liquid relief pipe end 20 Through hole 19, to pierce through the top layer 4 of box 2 and extract reagent portion out from compartment 21, and for the reagent portion to be introduced into box 2 In gap 6.Here, compartment 21 is configured as the otch in the main body of distance piece 5, and the otch is closed by bottom 3 and top layer 4.
Equally, in the first and second embodiments introduced, disposable cassette 2 includes bottom 3, top layer 4 and is limited to The distance piece 5 in the gap 6 between bottom 3 and top layer 4, for manipulating sample drop 23 in the gap 6.Bottom 3 and top layer 4 Including the hydrophobic surface 17 exposed to the gap 6 of box 2.First hydrophobic surface 17 ' is located on the inside of bottom 3, and the Two hydrophobic surfaces 17 " are located on the inside of top layer 4.The bottom 3 and top layer 4 of box 2 are entirely hydrophobic film or at least included sudden and violent It is exposed to the hydrophobic surface in the gap 6 of box 2.It can be seen that from the Fig. 2, box 2 does not have conductive layer.The distance piece 5 of box 2 is here It is not necessarily configured to include the master of the compartment 21 for the reagent needed for the measure for the sample droplet being applied in gap 6 Body because these reagents can using hand-held pipette or using aspirate robot (seeing above) by it is conventional aspirate be added between Gap 6.
Equally, in the first and second embodiments introduced, disposable cassette 2 includes bottom 3, top layer 4 and is limited to The distance piece 5 in the gap 6 between bottom 3 and top layer 4, for manipulating sample drop 23 in the gap 6.Bottom 3 and top layer 4 Including the hydrophobic surface 17 exposed to the gap 6 of box 2.First hydrophobic surface 17 ' is located on the inside of bottom 3, and the Two hydrophobic surfaces 17 " are located on the inside of top layer 4.The bottom 3 and top layer 4 of box 2 are entirely hydrophobic film or at least included sudden and violent It is exposed to the hydrophobic surface in the gap 6 of box 2.It can be seen that from the Fig. 2, box 2 does not have conductive layer.The distance piece 5 of box 2 is here It is not necessarily configured to include the master of the compartment 21 for the reagent needed for the measure for the sample droplet being applied in gap 6 Body because these reagents can using hand-held pipette or using aspirate robot (seeing above) by it is conventional aspirate be added between Gap 6.
Fig. 4 shows the general view of digital micro-fluid system 1, and digital micro-fluid system 1 is furnished with central control unit 14 and pedestal Unit 7, the 12 box receiving station 8 that each may include fixed cover plate 12.The base unit 7 is particularly suitable for receiving according to the 6th The box 2 of embodiment, and be adapted to these boxes being loaded into substantially erecting with substantially vertical electrod-array 9 and cover plate 12 (referring to Fig. 5) in straight box receiving station 8.Such loading is preferably by the roboticized of liquid handling work station (not shown) Clamping device is carried out.
According to the present invention, the digital micro-fluid system 1 also includes 12 plate receiving station 40, includes electrode for receiving The interconvertible battery lead plate 41 of array 9.In Fig. 4 exemplary embodiment, all box receiving station 8 and plate receiving station 40 into To packet, plate receiving station 40 is located at the underface of box receiving station 8.These paired box receiving station 8 and plate receiving station 40 are herein It is arranged to the row of four row three；Box receiving station 8 above right row is without disposable cassette 2, and it is shown outside the right side of base unit 7 Portion.In addition, middleboxes receiving station 8 and plate receiving station 40 are also without disposable cassette 2 and interconvertible battery lead plate 41, it equally shows In the right hand external of base unit 7.
Fig. 5 (referring to Fig. 5 A and Fig. 5 B) shows wherein to accommodate the digital micro-fluid of the disposable cassette 2 according to sixth embodiment The sectional view of one exemplary box receiving station 8 of the base unit 7 of system 1.Open-and-shut from Fig. 5 A is that top enters box 2 are inserted into the substantially vertical box receiving station 8 with substantially vertical electrod-array 9 and cover plate 12.The disposable cassette 2 Distance piece 5 including bottom 3 and top layer 4 and the gap 6 being limited between bottom 3 and top layer 4, in the gap 6 Manipulate sample drop 23.Bottom 3 and top layer 4 include the hydrophobic surface 17 ', 17 " exposed to the gap 6 of box 2.The bottom 3 of box 2 It is entirely hydrophobic film with top layer 4 or at least includes the hydrophobic surface exposed to the gap 6 of box 2.Similar to describing that in Fig. 2 Sample, the box 2 does not have the dielectric layer for the part for being attached to bottom 3 or forming bottom 3.Therefore, electrod-array 9 needs have this The dielectric layer 24 of sample.The box 2 is preferably filled with silicone oil.
Electrod-array 9 is fixed to bottom substrate 11 (inside for itself being non-removably secured to base unit 7), and Each individually electrode 10 electrically and is operatively connected with central control unit 14 and (only draws 14 electrodes 10 here Four connections).Digital micro-fluid system 1 is arranged in the disposable cassette 2 comprising gap 6 manipulate sample drop 23.Cause This, sample drop 23 is manipulated in the gap 6 of disposable cassette 2.
Cover plate 12 is mechanically connected and is fully integratible into the base unit 7 of digital micro-fluid system 1, and not removable It is dynamic.Therefore, disposable cassette 2 can be advanced into the case of being carried in Fig. 5 A and 5B via advancing into loading insertion box receiving station 8 Actually it is referred to as top and enters loading (comparing Fig. 4).Here, the conductive material 15 of cover plate 12 is made up simultaneously of conductive metal material And be sandwiched between the material of head substrate 13.Alternatively, instead of the material or in addition of the (not shown) of head substrate 13, lid The conductive material 15 of plate 12 can be covered by ductile bed.
Distance piece 5 also includes puncturing facility 18, and it is arranged to sample droplet being introduced into the gap 6 of box 2.Puncture is set Apply 18 amplifier sections for being configured as distance piece 5.The spacer portion of the amplification is preferably fitted with pierceable self-sealing membrane 31, It allows to push through puncture liquid relief pipe end 20.Puncture a part or suction that liquid relief pipe end 20 can be hand-held pipette (not shown) Move a part for robot (not shown).Liquid automates the extraction of delivering or liquid from the gap 6 of box 2 to the gap 6 of box 2 Simplified by the relatively large penetrating area that the spacer portion of the amplification by box 2 is provided.Assuming that gap width is about 1-3mm, then the width of the penetrating area be preferably about 5-10mm and therefore with about 96 hole microplates hole size, this It can be easily attained by the automation pipettor of liquid processing system or liquid handling work station.Space is being provided for compartment 21 While (referring also to Fig. 5 B), the spacer portion of the amplification of box 2 is also provided for the robot clasper by automating (not Show) grasping surface that grasps, the clasper is preferably used for handling the box of the outside of digital micro-fluid system 1 and is used to insert Box 2 and box 2 is extracted out from its receiving station 8.In addition, the spacer portion of the amplification of box 2 provides abutment surface, the abutment surface exists Box 2 is properly accommodated in the surface that base unit 7 is abutted when in receiving station 8.
It is interconvertible similar to disposable cassette 2 to the insertion of corresponding box receiving station 8 and from withdrawing from box receiving station 8 Battery lead plate 41 can be inserted into corresponding plate receiving station 40 and withdraw from therefrom.Additionally, it is important that it should be noted that being similar to or phase The spatial orientation for showing and discussing so far different from them, these receiving station 8,40 can be determined with any random spatial orientation To, if box receiving station 8 and plate receiving station 40 be positioned to each other very close to so that inserting disposable cassette 2 in its receiving station 8 will Surface (that is, the surface of electrod-array 9 or in corresponding interconvertible electricity of its bottom 3 and corresponding interconvertible battery lead plate 41 The surface of dielectric layer 24 on the top of the electrod-array 9 of pole plate 41) operationally contact.
Preferably, electrod-array 9 extends to the front position on the surface relative to base unit 7, so as to make liquid The diverse location that drop 23 is moved on printed circuit board (PCB) (PCB) or electrod-array 9 from compartment 21.Equally, drop 23 is made in phase In the reverse direction from the reaction station on electrod-array 9 be moved to compartment 21 be it is highly preferred, especially will be in reaction product The outside of digital micro-fluid system 1 and also in the case of the external analysis of box 2.
Fig. 5 B show that the top of Fig. 5 A from the section B indicated in fig. 5 enters box 2.Between the section is extended through Gap 6 and between the bottom 3 and top layer 4 of self-contained disposable cassette 2.The section is also across distance piece 5, the U-shaped portion of distance piece 5 Divide and be located between bottom 3 and top layer 4, and the spacer portion amplified is arranged on around U-shaped portion point and bottom 3 and top layer 4. Preferably, the U-shaped portion of distance piece 5 is divided into plastic material (being preferably molded) and glued or be fused to bottom 3 and top layer 4.It is excellent Choosing, the spacer portion of amplification is prepared also by injection；This makes it possible to provide isolating bar 32, and the one side of isolating bar 32 exists The compartment 21 formed below of pierceable film 31, on the other hand makes the stabilization of pierceable film 31.Such stabilization will be preferably by that will isolate The spacer portion back side of bar 32 and amplification is molded into pierceable film 31 and provided.Preferably, the spacer portion of amplification is then It is applied in the U-shaped portion of the distance piece 5 with bottom 3 and top layer 4 point.
As indicated above, distance piece 5 preferably also includes the puncture facility 18 for being configured to the amplifier section of distance piece 5.This is put Big spacer portion is preferably fitted with pierceable self-sealing membrane 31, and it allows to push through puncture liquid relief pipe end 20.Puncture and inhale Liquid relief end 20 can be a part for hand-held pipette (not shown) or the part for aspirating robot (not shown).Distance piece 2 Here additional puncture facility 22 is included, liquid relief pipe end 20 pushes through self-sealing membrane 31 and gap 6 from box 2 is extracted out for that will puncture Such as silicone oil.In the box 2 of Fig. 5 B, drop 23 (for example, sample) in the puncture liquid relief pipe end 20 for puncturing facility 18 by drawing Enter, be then moved to physical location on the hydrophobic surface 17 ' of bottom 3.With drop 23 is introduced into compartment 21 and in gap 6 Meanwhile, the silicone oil (or any other chemically inert liquid that will not be reacted with drop 23) of similar quantity is worn from additional Corresponding compartment 21 at thorn facility 22 is extracted out.Balanced while instead of such in gap 6 of liquid, it is contemplated that amount it is oily or lazy Property liquid removal can insertion drop 23 before or after carry out soon.Compartment 21 also acts as reservoir, for storing More liquid needed for than preparing moveable drop 23 from the liquid；Therefore, once being introduced at least one in compartment 21 It is interior, so that it may to prepare multiple such droplets 23 from single liquid volume.However, can it is suggested that reserve a compartment 21 for Tapped oil or inert fluid, and reserve another compartment 21 to extract reagent manufacture out.
According to alternative and very simple embodiment (not shown), disposable cassette 2 can be installed on PCB and moistened for electricity Wet, disposable cassette 2 includes bottom 3 and top layer 4 with the hydrophobic surface 17 ', 17 " for being directed to gap 6, regardless of whether PCB is It is no be configured as it is interconvertible.Instead of using the cover plate 12 equipped with conductive material 15, conducting film (for example, aluminium foil) could attach to top The outer surface of layer 4.As a result show, such conducting film even also allows electrowetting when the conducting film is earth-free.Instead of will not The conducting film of ground connection is attached to box, and top layer 4 can have film coating on its outer surface；The film coating can be any metal And deposited by chemically or physically evaporation coating technique.The conductive film on the outer surface of top layer 4 can be even electrically-conducting paint.Cause This, it is proposed that provide in the second plane and be arranged essentially parallel to the conductive material 15 of the extension of electrod-array 9, the conductive material 15 The source of different potentials is not connected on the top layer 4 of box 2 and during sample drop 23 is manipulated.
Fig. 6 shows can be inserted into the general view of the interconvertible battery lead plate 41 in the plate receiving station 40 of digital micro-fluid system 1.Should The bottom substrate 11 of interconvertible battery lead plate 41 is configured as printed circuit board (PCB) (PCB).This top view show electrod-array 9 Similar layout, just as in patent application No.US 13/188, the printing for being used for the system that liquid droplets the are manipulated electricity disclosed in 584 Like that, US 2013/ is submitted and be published as to the patent application to road plate (PCB) by the applicant on July 22nd, 2011 0020202 A1.The special electrodes array 9 of system 40 is arranged to receive disposable cassette 2 on top of this.The electrode array Row 9 are particularly configured as being suitable for the cracking of cell material, extraction and PCR amplifications for DNA fragmentation, for gene point Type hybrid experiment, and for optical detection.However, different from the PCB disclosed in the A1 of US 2013/0020202, the electrode The bottom substrate 11 of array 9 is fixed to the base unit 7 of digital micro-fluid system 1 not non-removablely.Here, bottom substrate 11 and electrod-array 9 be the interconvertible battery lead plate that can be removably inserted into the plate receiving station 40 of digital micro-fluid system 1 41 part.
When all experiments and measurement are all completed, box 2 (together with sample therein and waste) is safely disposed, so that Anyone for making in lab assistant is not endangered by its content.It is then possible to determine to utilize similar or other examinations Sample carries out similar measure, but utilizes the interconvertible battery lead plate 41 of identical with its electrode special array 9.In such case Under, next disposable cassette 2 is forced on electrod-array 9, and can carry out next experiment.It is alternatively possible to determine into The not particularly suitable other experiments of of the invention interconvertible battery lead plate 41 of the row with its electrode special array 9.It is alternative at this In situation, selection is with another the interconvertible electrode for being more suitable for the different electrod-arrays 9 by the experiment of progress or measure Plate 41.Therefore, the interconvertible battery lead plate 41 currently selected includes electrod-array 9, and it is arranged in the gap 6 of box 2 Carry out special alternative measure or test, during the measure or experiment, the sample drop 23 for adhering to hydrophobic surface 17 leads to Cross electrowetting and be manipulated in gap 6.
In figure 6 (referring on the top of the figure and bottom), it can be seen that substantial amounts of contact point, i.e. electric plates contact element Part 42.Single electric wire (not shown to make accompanying drawing more clear here) makes each single electrode 10 be connect with these electric plates Touch a contact in element 42.In addition, the heater in the bottom substrate 11 of interconvertible battery lead plate 41 is also connected to Some in these electric plates contact elements 42.All electric plates contact elements 42 all by with appropriate number of electrical base list The physical contact of the central control unit 14 of first contact element 43 and digital microfluid system 1 and connect, the central control unit 14 control such as heater, puncture facility 18 and needs electrodes 10 all potentials be necessary activate.In electricity Single contact point is additionally provided with every side of pole array 9 and close to PCB 11 border 44, for single with center control The ground potential source contact of member 14.Plate contact element 42 can be positioned close to PCB 11 one or more borders 44, specifically be depended on In the method for the plate receiving station 40 that physics needs and makes interconvertible battery lead plate 41 enter its digital micro-fluid system 1.
Shown interconvertible battery lead plate 41 is configured to one be placed in the plate receiving station 40 of digital micro-fluid system 1 Place, for example, as shown in Fig. 1 or 4.In each case, the electric plates contact element 42 of interconvertible battery lead plate 41 is configured to Engaged with the electrical base unit contact element 43 of base unit 7, it is micro- that electrical base unit contact element 43 is electrically connected to numeral The central control unit 14 of fluid system 1.Preferably, the bottom substrate 11 of support electrod-array 9 is configured as printed circuit board (PCB) (PCB), electric plates contact element 42 is positioned and close to PCB one or more borders 44 in groups.In particular it is preferred that electrode The single electrode 10 of array 9 is arranged and configured to manipulate liquid droplets in box 2 by electrowetting and for carrying out It is specific to determine or test.
Fig. 7 shows the cross-sectional view according to Fig. 2；However, herein, electrod-array 9 is according to the first embodiment of electrical contact On interconvertible battery lead plate 41, accordingly, electric plates contact element 42 is configured as rigid plate or cima, its perpendicular to Extend on the direction of first plane substantially at least one border 44 of bottom substrate 11, interconvertible battery lead plate 41 is extremely A few electrod-array 9 substantially extends in this first plane.Preferably, in order to receive such interconvertible battery lead plate 41, The multiple electrical base unit contact elements 43 for being electrically connected to the central control unit 14 of digital micro-fluid system 1 are configured as plate Spring, the flat spring substantially perpendicularly extends and is in the horizontal direction with resilience, so as to safely and individually Engagement is electrically connected to multiple electric plates contact elements 42 of the interconvertible battery lead plate 41 of single electrode 10.
Fig. 8 shows the cross-sectional view according to Fig. 3；However, herein, electrod-array 9 is according to the second embodiment of electrical contact On interconvertible battery lead plate 41, accordingly, electric plates contact element 42 is configured as rigid plate or cima, its parallel to Extend on the direction of first plane substantially on downside and close to the border 44 of bottom substrate 11, at least one electrod-array 9 Substantially extend in this first plane.Preferably, in order to receive such interconvertible battery lead plate 41, it is electrically connected to digital miniflow Multiple electrical base unit contact elements 43 of the central control unit 14 of system system 1 are configured as with resilience or flexibly The pin of support, it substantially perpendicularly extends and in the vertical direction is with resilience, to connect safely and individually Close the multiple electric plates contact elements 42 for the interconvertible battery lead plate 41 for being electrically connected to single electrode 10.As illustrated, common (being vertically provided here) or individually (flatly arranging here) insertion guider can be conducive to disposable cassette 2 And/or safe and exact insertion of the interconvertible battery lead plate 41 into corresponding receiving station 8,40 and from corresponding receiving station 8th, 40 convenient removal.
Fig. 9 shows the schematic diagram of general multi-level " instrument platform ", i.e. the numeral of the base unit 7 including standardization Microfluid system 1, it has all general modules needed all the time when manipulating liquid droplets by electrowetting.Such module For example including digital-to-analog (D/A) plate 45, high-voltage relay module 46, for box 2 to be fixed on interconvertible PCB 41 In box clamp module 47 or vacuum mechanism 49 (there is O-ring 53), the control unit 14 being preferably loaded into base unit 7 Embedded software 51 and the graphical user interface (GUI) 52 for being preferably configured to touch-screen.
Such as to contain analysis (such as fluorescence or the transmission optics detection of absorbance of the sample in liquid droplets 23 Unilateral optical detection) optical module 48 or for attracting the optional module of the magnetic actuator module 50 of magnetic bead to be integrated into It is in all digital micro-fluid systems 1 or integrated according only to needing.For carrying out as a series of specific experiments or measure " instrument platform " is preferably configured as free-standing instrument, and it also includes a set of replaceable suitable for what is tested or determine accordingly PCB and interchangeable box.
The difference of electric plates contact element 42 and electrical base unit contact element 43 is arranged in the technology read and applied In the selection of personnel.
A kind of method for being used to manipulate the sample drop 23 for adhering to hydrophobic surface 17 may include at the bottom of disposable cassette 2 The step of the first hydrophobic surface 17 ' being provided on layer 3.The bottom 3 is positioned on the electrod-array 9 of digital micro-fluid system 1 Side is substantially parallel.The electrod-array 9 substantially extends and including multiple single electrodes 10, these electrodes in this first plane 10 are supported by the bottom substrate 11 of the base unit 7 of digital micro-fluid system 1.The electrod-array 9 is connected to digital micro-fluid The central control unit 14 of system 1, for the selection for the single electrode 10 for controlling the electrod-array 9, and for being These electrodes 10 provide a mean for each voltage that electrowetting manipulates the drop 23 on first hydrophobic surface 17 ' Pulse.The step of this method may also comprise the second hydrophobic surface 17 " of offer, the second hydrophobic surface 17 " is arranged essentially parallel to First hydrophobic surface 17 ' and from first hydrophobic surface 17 ' with a certain distance from.So, in the first hydrophobic surface 17 ' and second form gap 6 between hydrophobic surface 17 ".Preferably, such gap 6 is limited by distance piece 5, including first The bottom 3 of hydrophobic surface 17 ' and top layer 4 including the second hydrophobic surface 17 " are attached to distance piece 5.This method can also be wrapped Include and provide head substrate 13 for cover plate 12.Cover plate 12 also includes conductive material 15, and it is in the second plane and is arranged essentially parallel to Electrod-array 9 extends.In particular it is preferred that the conductive material 15 of cover plate 12 is not connected to difference during sample drop 23 is manipulated The source of potential.
In all embodiments that are shown or discussing, it is preferred that the gap 6 of disposable cassette 2 is substantially filled out with silicone oil Fill.Equally it is preferably all the time, the bottom 3 and top layer 4 of box 2 are entirely hydrophobic film or including exposed to the gap 6 of box 2 Hydrophobic surface 17 ', 17 ".With the electrowetting of gap 6 of disposable cassette 2 and manipulate at least one drop 23 after, manipulate or survey Fixed result can be evaluated, while disposable cassette 2 is still at box receiving station 8, i.e. micro- using digital micro-fluid system 1 or numeral The analysis system for the work station that fluid system 1 is integrated into.Alternatively, disposable cassette 2 can be taken out to the base of digital micro-fluid system 1 Seat unit 7 is simultaneously analyzed elsewhere.
After an analysis, disposable cassette 2 can be dropped, and electrod-array 9 is reusable.Due to digital micro-fluid system 1 part is never contacted when being worked together with the first or second embodiments of box 2 with any sample or reagent, with it is other once Property box 2 this reuse can be immediately, and cleaning in the middle of any.Due to the lid of digital micro-fluid system 1 The through hole 19 of plate 12 can be contacted when working together with the 3rd or fourth embodiment with box 2 with sample and reagent, with it is other once Property box 2 this reuse can be cleaned in the middle of certain after or carry out after the replacing it of cover plate 12.
It is an object of the invention to provide removable and disposable film, it will during drop 23 is manipulated by electrowetting Drop 23 is separated with electrod-array 9 and top plate 12.Six differences of the self-contained disposable cassette 2 such as proposed in description above Embodiment shown in, removable and disposable film is provided preferably as the bottom 3 and top layer 4 of box 2.
In a preferred embodiment, the bottom 3 of box 2 passes through vacuum attraction to PCB.Small evacuation holes in PCB connect Vavuum pump is connected to for this purpose.By such vacuum attraction be applied to bottom 3 make it possible to avoid using any liquid or Adhesive is so that the bottom 3 of box 2 better contacts with the surface of electrod-array 9.
Seem any combinations of feature of the not be the same as Example of rational box 2 disclosed herein for technical staff all Within the spirit and scope of the present invention.
Even if they are not specifically described in each case, reference shown in accompanying drawing also refers to the numeral of the present invention The similar component of microfluid system 1 and the similar component of interchangeable battery lead plate 2.
Reference：
1 digital micro-fluid system
2 disposable cassettes
3 bottoms
4 top layers
5 distance pieces
Gap between 63 and 4
7 base units
8 box receiving station
9 electrod-arrays
10 single electrodes
11 bottom substrates, PCB
12 cover plates
13 head substrates
14 central control units
15 conductive materials
16 hinges
17 hydrophobic surfaces
17 ' first hydrophobic surfaces
17 " second hydrophobic surfaces
18 puncture facility
19 through holes
20 puncture liquid relief pipe end
21 compartments
22 additional puncture facilities
23 drops
24 dielectric layers
25 insertion guiders
26 disposable liquid relief pipe ends
27 puncture pin
31 pierceable films
32 isolating bars
40 plate receiving station
41 interconvertible battery lead plates
42 electric plates contact elements
43 electrical base unit contact elements
44 PCB borders
45 D/A I/O plates
46 HV relay module
47 box clamp modules
48 optical modules
49 vacuum mechanisms
50 magnetic actuator modules
51 embedded softwares
52 GUI
53 O-rings

Claims (21)

1. one kind is used for the digital micro-fluid system (1) that sample drop is manipulated in disposable cassette (2), the disposable cassette (2) Gap (6) including bottom (3), top layer (4) and between the bottom (3) and top layer (4)；The digital micro-fluid system System (1) includes：
(a) base unit (7), it has at least one the box receiving station (8) for being configured to receive disposable cassette (2)；
(b) at least one electrod-array (9), it extends and including multiple single electrodes (10) in this first plane, it is described extremely A few electrod-array (9) is supported by bottom substrate (11)；And
(c) central control unit (14), it is used for the single electrode (10) for controlling at least one electrod-array (9) Selection, and for providing a mean for each electricity that electrowetting manipulates drop in the box (2) for these electrodes (10) Press pulse,
Characterized in that, the digital micro-fluid system (1) also includes at least one plate receiving station (40), at least one described plate Receiving station (40) is located at one in the box receiving station (8) of the base unit (7)；Each plate receiving station (40) by with It is set to and receives interconvertible battery lead plate (41) independently and separately from disposable cassette (2)；In each case, the box receiving station (8) and plate receiving station (40) be positioned to each other so close to so that the disposable cassette (2) of insertion with the bottom (3) with it is described The surface of the interconvertible battery lead plate (41) inserted accordingly is operationally contacted, and each interconvertible battery lead plate (41) includes electricity Pole array (9) and be electrically connected to the electrod-array (9) the single electrode (10) multiple electric plates contact elements (42)；Each plate receiving station (40) includes being electrically connected to multiple electrical base unit contact elements of the central control unit (14) Part (43), the electrical base unit contact element (43) is configured to and is placed on the interchangeable at plate receiving station (40) place Battery lead plate (41) the electric plates contact element (42) engagement.
2. digital micro-fluid system (1) according to claim 1, it is characterised in that at least one described plate receiving station (40) lower section, top or the side in the box receiving station (8) of the base unit (7), and being configured to Reception is individually inserted into the interconvertible battery lead plate (41) in the base unit (7) of the digital micro-fluid system (1).
3. digital micro-fluid system (1) according to claim 2, it is characterised in that be electrically connected to the digital micro-fluid The multiple electrical base unit contact element (43) of the central control unit (14) of system (1) is configured as plate bullet Spring, the flat spring vertically extends and is with resilience in the horizontal direction, to engage safely and individually electricity It is connected to multiple electric plates contact elements (42) of the interconvertible battery lead plate (41) of the single electrode (10).
4. digital micro-fluid system (1) according to claim 2, it is characterised in that be electrically connected to the digital micro-fluid The multiple electrical base unit contact element (43) of the central control unit (14) of system (1) has been configured as resilience The pin of power or the pin being elastically supported, the pin vertically extends and in the vertical direction is with resilience, so as to safety Ground and individually engagement are electrically connected to the multiple electric plates of the interconvertible battery lead plate (41) of the single electrode (10) Contact element (42).
5. digital micro-fluid system (1) according to claim 2, it is characterised in that at least one described plate receiving station (40) it is configured to receive independently and separately from disposable cassette (2) and inserts the digital micro-fluid system in the following manner (1) the interconvertible battery lead plate (41) in the base unit (7)：
(a) the interconvertible battery lead plate (41) is vertically descended through into corresponding box receiving station (8) and enters described In plate receiving station (40)；Or
(b) the interconvertible battery lead plate (41) is slided in corresponding box receiving station (8) lower horizontal and enters institute State in plate receiving station (40)；Or
(c) the interconvertible battery lead plate (41) slided in corresponding box receiving station (8) lower horizontal and vertically Lifted in the plate receiving station (40).
6. digital micro-fluid system (1) according to claim 1, it is characterised in that also including for manipulating sample drop Disposable cassette (2), it is characterised in that the bottom (3) and the top layer (4) include exposed to the box (2) it is described between The hydrophobic surface (17) of gap (6).
7. digital micro-fluid system (1) according to claim 6, it is characterised in that the box (2) also includes distance piece (5), the distance piece (5) is configured as including at least in part the survey of the sample droplet for being applied in the gap (6) The main body of the compartment (21) of reagent needed for fixed.
8. digital micro-fluid system (1) according to claim 6, it is characterised in that the box (2) also includes distance piece (5), the distance piece (5) is configured as including at least in part the reality of the sample droplet for being applied in the gap (6) The main body of the compartment (21) of reagent needed for testing.
9. digital micro-fluid system (1) according to claim 6, it is characterised in that the bottom (3) of the box (2) Covered by dielectric layer (24), or the bottom (3) itself is made up of dielectric substance.
10. digital micro-fluid system (1) according to claim 1, it is characterised in that also including with head substrate (13) At least one cover plate (12), at least one described cover plate (12) be located at box receiving station (8) place, at least one described cover plate (12) conductive material (15) is also included, the conductive material (15) extends parallel at least one described lid in the second plane The electrod-array (9) of the box receiving station (8) assigned by plate (12), and the conductive material (15) not with potential Source connection.
11. digital micro-fluid system (1) according to claim 1, it is characterised in that also interconvertible including at least one Battery lead plate (41), at least one described interconvertible battery lead plate (41) includes the electrod-array (9) supported by bottom substrate (11) And including the multiple electric plates contact elements (42) for the single electrode (10) for being electrically connected to the electrod-array (9), The interconvertible battery lead plate (41) is configured to be placed on the digital micro-fluid system independently and separately from disposable cassette (2) Plate receiving station (40) place of system (1)；It is micro- that the electric plates contact element (42) is configured to and be electrically connected to the numeral The electrical base unit contact element of the base unit (7) of the central control unit (14) of fluid system (1) (43) engage.
12. a kind of interconvertible battery lead plate (41), including electrod-array (9) and the bottom substrate of the support electrod-array (9) (11), and including the multiple electric plates contact elements (42) for the single electrode (10) for being electrically connected to the electrod-array (9), Characterized in that, the interconvertible battery lead plate (41) be configured to independently and separately from disposable cassette (2) be placed in right will Ask 1 the digital micro-fluid system (1) the plate receiving station (40) in one at；The interconvertible battery lead plate (41) The electric plates contact element (42) be configured to and be electrically connected to the digital micro-fluid system (1) it is described center control The electrical base unit contact element (43) engagement of the base unit (7) of unit (14).
13. interchangeable battery lead plate (41) according to claim 12, it is characterised in that the support electrod-array (9) The bottom substrate (11) is configured as printed circuit board (PCB) (PCB), the electric plates contact element (42) position in groups and Close to one or more borders (44) of the PCB, wherein, the single electrode (10) of the electrod-array (9) is by cloth Put and be configured to electrowetting and drop is manipulated in box (2) and for specifically being determined or being tested.
14. interchangeable battery lead plate (41) according to claim 12, it is characterised in that the electric plates contact element (42) Rigid plate or cima are configured as, the rigid plate or cima are on the direction perpendicular to first plane at the bottom Extend at least one border (44) of portion's substrate (11), at least one described electrode array of the interconvertible battery lead plate (41) (9) are arranged in first plane to extend.
15. interchangeable battery lead plate (41) according to claim 12, it is characterised in that the electric plates contact element (42) Rigid plate or cima are configured as, the rigid plate or cima prolong along the direction parallel to first plane on downside Stretch and close to the border (44) of the bottom substrate (11), at least one described electrod-array (9) prolongs in first plane Stretch.
16. interchangeable battery lead plate (41) according to claim 12, it is characterised in that it includes being used to carry out particular experiment Or the electronic chip and special-purpose software determined, wherein, the chip and special-purpose software of the interconvertible battery lead plate (41) by with Putting is used for when the interconvertible battery lead plate (41) is inserted in the base unit (7) of the digital micro-fluid system (1) certainly The software included in the base unit (7) of digital micro-fluid system (1) is updated dynamicly.
17. interchangeable battery lead plate (41) according to claim 12, it is characterised in that at least described electrod-array (9) by Dielectric layer (24) is covered.
18. the method that one kind adheres to the sample drop (23) of hydrophobic surface (17) for manipulation, methods described includes following Step：
(a) digital micro-fluid system (1) according to claim 1 is provided；
(b) box according to claim 6 (2) is provided separately；And
(c) interconvertible battery lead plate (41) according to claim 11 is provided separately,
Characterized in that, the interconvertible battery lead plate (41) includes electrod-array (9), the electrod-array (9) is configured to use Specifically determined in the gap (6) of the box (2), during the measure, adhere to hydrophobic surface (17) sample drop (23) is manipulated by electrowetting in the gap (6).
19. the method that one kind adheres to the sample drop (23) of hydrophobic surface (17) for manipulation, methods described includes following Step：
(a) digital micro-fluid system (1) according to claim 1 is provided；
(b) box according to claim 6 (2) is provided separately；And
(c) interconvertible battery lead plate (41) according to claim 11 is provided separately,
Characterized in that, the interconvertible battery lead plate (41) includes electrod-array (9), the electrod-array (9) is configured to use Specifically tested in the gap (6) of the box (2), during the experiment, adhere to hydrophobic surface (17) sample drop (23) is manipulated by electrowetting in the gap (6).
20. the method that one kind adheres to the sample drop (23) of hydrophobic surface (17) for manipulation, methods described includes following Step：
(a) digital micro-fluid system (1) according to claim 1 is provided；
(b) box according to claim 6 (2) is provided separately；And
(c) interconvertible battery lead plate (41) according to claim 12 is individually chosen,
Characterized in that, the interconvertible battery lead plate (41) includes electrod-array (9), the electrod-array (9) is configured to use Specifically determined in the gap (6) of the box (2), during the measure, adhere to hydrophobic surface (17) sample drop (23) is manipulated by electrowetting in the gap (6).
21. the method that one kind adheres to the sample drop (23) of hydrophobic surface (17) for manipulation, methods described includes following Step：
(a) digital micro-fluid system (1) according to claim 1 is provided；
(b) box according to claim 6 (2) is provided separately；And
(c) interconvertible battery lead plate (41) according to claim 12 is individually chosen,
Characterized in that, the interconvertible battery lead plate (41) includes electrod-array (9), the electrod-array (9) is configured to use Specifically tested in the gap (6) of the box (2), during the experiment, adhere to hydrophobic surface (17) sample drop (23) is manipulated by electrowetting in the gap (6).
CN201380011785.6A 2013-05-23 2013-05-23 Digital micro-fluid system with interconvertible PCB Active CN104321141B (en)

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