CN105899294A

CN105899294A - Multi-well plates and methods of use thereof

Info

Publication number: CN105899294A
Application number: CN201480063117.2A
Authority: CN
Inventors: 什洛莫·图尔格曼; 本·锡安·拉维; 埃坦·谢费尔
Original assignee: Idea Machine Development Design and Production Ltd
Current assignee: Idea Machine Development Design and Production Ltd
Priority date: 2013-11-19
Filing date: 2014-11-19
Publication date: 2016-08-24
Anticipated expiration: 2034-11-19
Also published as: CA2931068A1; CA2931068C; JP6553071B2; EP3071332A2; WO2015075653A2; WO2015075653A3; JP2016538573A; CN105899294B

Abstract

There is provided a plate specifically a multi-well plate equipped with a mechanism to facilitate determination of the amount of a fluid added to or removed from a well in the plate. Specifically it foresees a balance integrated in the frame of the plate and capable of determining the difference in mass before and after filling the wells. Other embodiments foresee also a heating and cooling device to be associated with the plate and the plate to have removable wells. Other embodiments are also described.

Description

Porous plate and using method thereof

Related application

The application requires priority and the foundation of following U.S. Provisional Application according to Paris Convention 35U.S.C. § 120 requires the rights and interests of following U.S. Provisional Application: on November 19th, 2013 submits to No. 61/905865, No. 61/929086 and March 7 in 2014 of submission January 19 in 2014 No. 61/949272 U.S. Provisional Application that day submits to.By way of reference by aforementioned provisional application Content be incorporated herein.

Background technology

Contain the plate of multiple hole as is generally known in the art, this plate for contain for observe chemical example, Cell or other biological material.Generally, such plate has the length-width ratio of 3:2 and thus includes 24 (4 × 6), 96 (8 × l2), 384 (16 × 24) or 1536 (32 × 48) individual hole；Typically 96 orifice plates are 128mm length, 86mm width, and at ANSI/SBS 1-2004 and ANSI/SBS 3-2004 respectively describes the area occupied (footprint) for 96 orifice plates and bottom outward flange Standard.

Such porous plate (depends on the capacity in hole, otherwise referred to as microwell plate or microtitration plate) Generally made by plastics (such as polystyrene, polypropylene or Merlon or the combination of these materials) Become, the most also glass is combined in the base section of plate.In numerous applications, hole Bottom is transparent for being used for observing the frequency of the light of sample.Hole in the degree of depth, highly, always Size and the shape of the bottom in the shape in hole and hole in terms of volume become according to the special-purpose of this plate Change.

The example of the supplier of such plate is:

Perkin-Elmer is (see http://www.perkinelmer.com/CMSResources/Images/44 -73879SPC_MicroplateDimensionsSummaryChart.pdf)；

Sigma-Aldrich is (see http://www.sigmaaldrich.com/labware/labware-produc ts.html？TablePage=9576216)；With

Thermo-Scientific is (see http://www.thermoscientific.com/ecomm/servlet/p roductscatalog_11152_81996_-1_4)。

It is for test to compound in drug development that a field of such plate is widely used High flux screening, Binding experiment etc. to antigen.

Generally, in high flux screening and other application, use automatic machinery by a certain amount of liquid Body be simultaneously dispensed into a some holes or institute porose in, such as by fluid is simultaneously dispensed in 96 orifice plates In the hole of 8 hole rows or be assigned to 384 orifice plates institute porose in.But, if added in particular bore The amount of liquid incorrect, then may be until whole experiment complete just to will recognize that this fact；And, Go out to be added into the particular bore of fluid of incorrect amount if unidentified, then may must give up whole plate Result.

Summary of the invention

Provide a kind of plate according to one embodiment of present invention, comprising: the first substantially flat surface, It has and is limited at least one first aperture therein；Substantially parallel with the first substantially flat surface Second substantially flat surface, the second substantially flat surface is spaced with the first substantially flat；At plate At least one hole of interior restriction, at least one hole described has and at least one the first aperture Aperture correspondence and the second aperture of alignment, at least one hole described has sidewall and bottom, and described At least one hole extends towards the second substantially flat surface from the first substantially flat surface, and described at least one Individual hole can be away from described first substantially flat surface displacement；Functionally with at least one hole phase described At least one signal provider of association, described signal provider can be in response at least one hole described Signal is produced away from the displacement of first surface.

In certain embodiments, have in described first surface and be limited to therein have multiple first hole Mouthful, and in described plate, defining multiple hole, each hole has and limit in described first surface First aperture in fixed the plurality of first aperture is corresponding and the second aperture of alignment, every in described hole Individual hole all has sidewall and bottom, and each hole is the most flat towards second from the first substantially flat surface Smooth surface extends.In certain embodiments, each hole in the plurality of hole can be away from the first base This flat surfaces shifts.

Provide a kind of porous plate according to one embodiment of present invention, including: the first substantially flat table Face, it has multiple first apertures defined wherein wherein；With described first substantially flat table The second substantially flat surface that face is substantially parallel, described second substantially flat surface is first basic with described Flat surfaces is spaced apart；The multiple holes limited in described plate, each hole has and at described first table Aperture in the first aperture limited in face is corresponding and the second aperture of alignment, every in described hole Individual hole all has sidewall and bottom, and each hole is the most flat towards second from the first substantially flat surface Smooth surface extends, and each hole in described hole can be away from the first substantially flat surface displacement； At least one signal provider being functionally associated with the plurality of hole, described signal provider energy Enough produce signal in response to hole at least one described away from the displacement of first surface.

In certain embodiments, described first surface and described second surface are by described first surface And multiple sidewalls of extending between described second surface and spaced apart.

In certain embodiments, the movement in all described holes all couples so that described signal provider energy Enough provide individual signals in response to any one in described hole or more displacements.Real at some Executing in example, the movement of some in described hole is both coupled to two or more groups, and described at least One signal provider includes each to provide signal in response to the displacement of in described group Multiple signal provider.In certain embodiments, the movement of a some holes coupled to two or more In group, and signal provider can provide single signal in response to each displacement of group.

In certain embodiments, at least one signal provider described include each with in multiple holes One associated plurality of signal provider in hole, each hole in the plurality of hole can be the most remote Shift from described first surface, and in the plurality of signal provider each can in response to The displacement of that it is associated, described Kong Zhongyi and signal is provided.

In certain embodiments, at least one signal provider can be placed in response to by following material Hole provides signal: the material of 300 milligrams, the material of 250 milligrams, the material of 200 milligrams, 150 The material of milligram, the material of 100 milligrams, the material of 75 milligrams, the material of 50 milligrams, 45 milligrams Material, the material of 40 milligrams, the material of 35 milligrams, the material of 30 milligrams, the material of 25 milligrams, The material of 20 milligrams, the material of 15 milligrams, the material of 10 milligrams, the material of 5 milligrams, 4 milligrams Material, the material of 3 milligrams, the material of 2 milligrams, or the material of 1 milligram, 500 micrograms (μ g) Material, the material of 300 μ g, the material of 200 μ g or the material of 100 μ g.

In certain embodiments, described signal provider can be described in response to being placed into by following fluid Hole provides signal: the fluid of 300 microlitres (μ l), the fluid of 250 μ l, the fluid of 200 μ l, The fluid of 150 μ l, the fluid of 100 μ l, the fluid of 75 μ l, the fluid of 50 μ l, the fluid of 45 μ l, 40 μ l Fluid, the fluid of 35 μ l, the fluid of 30 μ l, the fluid of 25 μ l, the fluid of 20 μ l, the stream of 15 μ l Body, the fluid of 10 μ l, the fluid of 5 μ l, the fluid of 4 μ l, the fluid of 3 μ l, the fluid of 2 μ l, 1 μ l Fluid, the fluid of 0.5 μ l, the fluid of 0.3 μ l, the fluid of 0.5 μ l or the fluid of 0.1 μ l.

In certain embodiments, described signal provider can be in response to hole at least one described towards institute State the displacement of first surface and signal is provided.

In certain embodiments, at least one signal provider described can in response to by following material from Described hole removes and signal is provided: the material of 300 milligrams, the material of 250 milligrams, 200 milligrams Material, the material of 150 milligrams, the material of 100 milligrams, the material of 75 milligrams, the material of 50 milligrams, The material of 45 milligrams, the material of 40 milligrams, the material of 35 milligrams, the material of 30 milligrams, 25 milligrams Material, the material of 20 milligrams, the material of 15 milligrams, the material of 10 milligrams, the material of 5 milligrams, The material of 4 milligrams, the material of 3 milligrams, the material of 2 milligrams, or the material of 1 milligram, 500 micro- Gram material of (μ g), the material of 300 μ g, the material of 200 μ g or the material of 100 μ g.

In certain embodiments, described signal provider can in response to by following fluid from described hole Remove and signal be provided: the fluid of 300 microlitres (μ l), the fluid of 250 μ l, the fluid of 200 μ l, The fluid of 150 μ l, the fluid of 100 μ l, the fluid of 75 μ l, the fluid of 50 μ l, the fluid of 45 μ l, 40 μ l Fluid, the fluid of 35 μ l, the fluid of 30 μ l, the fluid of 25 μ l, the fluid of 20 μ l, the stream of 15 μ l Body, the fluid of 10 μ l, the fluid of 5 μ l, the fluid of 4 μ l, the fluid of 3 μ l, the fluid of 2 μ l, 1 μ l Fluid, the fluid of 0.5 μ l, the fluid of 0.3 μ l, the fluid of 0.2 μ l or the fluid of 0.1 μ l.

In certain embodiments, at least one hole in described plate is can to remove from described plate.

In certain embodiments, described plate includes at least be associated with at least one in described hole Individual temperature sensor.In certain embodiments, a hole during described temperature sensor is positioned at described hole Among or on.In certain embodiments, at least one temperature sensor is configured to provide for representing at least The signal of in one hole or near at least one hole temperature.In some such embodiments, At least one temperature sensor is configured to detect the temperature at least one hole constantly and periodically carry For representing the signal of temperature.

In certain embodiments, plate also includes that electronic storage element, described electronic storage element are used for depositing Store up and provided at least by least one at least one signal provider and at least one temperature sensor One signal.

In certain embodiments, at least one temperature sensor is configured to the one group of hole detecting in multiple hole In temperature.

In certain embodiments, at least one temperature sensor include being configured to detection porose in The single temperature sensor of temperature.

In certain embodiments, at least one temperature sensor include each with in multiple holes Associated plurality of temperature sensor, described temperature sensor is used for detecting in multiple hole associated with it A hole in temperature.

In certain embodiments, plate also includes at least one heater block being associated with at least one hole, At least one heater block described is located close enough at least one hole described with at least one hole described Or being internally heated of at least one hole described.In certain embodiments, at least one heating part Part includes that multiple heater block, each heater block are associated and position with a hole in multiple holes In sufficiently close together one hole associated there not heat other of the plurality of hole In the case of hole, one hole or one hole are internally heated.In some embodiments In, at least one heater block includes heating coil.In certain embodiments, at least one heating part Part can also cool down at least one hole.In certain embodiments, heater block includes peltier device.

In certain embodiments, at least one hole in plate is will not can be removed with at least one The hole heater block that is associated remove from it in the case of plate removes.In certain embodiments, At least one hole in plate can remove from it, and is associated with at least one removable hole Heater block be attached at least one hole described or integral formed and be can be with one Rise and remove.

In certain embodiments, plate also include functionally with at least one signal provider and at least one The electric port that at least one in temperature sensor is associated.In certain embodiments, plate also includes merit It is associated also with at least one at least one signal provider and at least one temperature sensor on energy And be configured to pass and be connected to the chargeable electric supply installation that power supply charges.In some embodiments In, rechargeable device is configured to the charging when electricity port is electrically connected to power supply.

Also providing for a kind of data reader according to one embodiment of present invention, it is configured to according to this The plate of inventive embodiment is contained therein, and described data reader includes: pedestal, for putting for plate Put thereon；With for the electric port corresponding with the electric port of the plate of its electric interlock；Functionally with electricity end The processor that mouth is associated, for processing by electricity port from signal provider and temperature sensor At least one signal obtained.In certain embodiments, processor is configured to directly from signal provider Signal is obtained with at least one in temperature sensor.In certain embodiments, processor be configured to from Electronic memory component obtains signal, and described electronic memory component is for storing by signal provider and temperature At least one at least one signal provided in sensor.

In certain embodiments, data reader also includes the display being functionally associated with processor, Described display is configured to provide a user with the information from treated signal acquisition.In some embodiments In, described information includes the instruction at least one in the following: (i) is in special time plate The amount of fluid；(ii) amount of the fluid at least one hole of special time；(iii) fluid in plate Amount change over a period；(iv) amount of the fluid at least one hole is over a period Change；The temperature at special time in (v) at least one hole；(vi) temperature at least one hole Change over a period.In certain embodiments, processor is configured to process in real time signal, and And display is configured to provide in real time described information to user.

Additionally provide a kind of plate according to one embodiment of present invention, including: the first substantially flat surface, It has and is limited at least one first aperture therein；Substantially parallel with the first substantially flat surface Second substantially flat surface, the second substantially flat surface is spaced with the first substantially flat；At plate At least one hole of interior restriction, at least one hole described has and at least limited in first surface An aperture correspondence in individual first aperture and the second aperture of alignment, at least one hole described has side Wall and bottom, and at least one hole described from the first substantially flat surface towards the second substantially flat table Face extends；And at least one heater block being associated with at least one hole described, it is positioned at and enough leans on Nearly at least one hole described is with heating at least one hole described or the inside at least one hole described.One In a little embodiments, in first surface, define multiple first aperture；At least one hole described is included in The multiple holes limited in plate, each hole has and multiple first apertures limited in first surface One first aperture correspondence and the second aperture of alignment, each hole in described hole has sidewall and the end Portion, and each hole extends towards the second substantially flat surface from the first substantially flat surface；At least One heater block includes multiple heater block so that each hole in described hole has the plurality of A heater block associated there in heater block, each heater block in heater block is positioned at The hole that sufficiently close together and described heater block is associated, with right in the case of not heating other holes Being internally heated of described hole or described hole.In certain embodiments, heater block includes heating Coil.In certain embodiments, heater block can also Cooling Holes.In certain embodiments, heating Parts include peltier device.In certain embodiments, at least one hole in plate is can to move from it Remove, and the heater block being associated with at least one removable hole described is not removed from plate.? In some embodiments, at least one hole in plate can remove from it, and with described at least one The heater block that individual removable hole is associated is attached at least one hole described or landform integrated therewith Become, and can therewith remove.

Provide according to one embodiment of present invention a kind of for measure be added into according to the present invention appoint The method of the amount of the fluid in the plate of one embodiment, described method includes: record is carried by signal provider The initial signal of confession；And when fluid being added at least one hole in plate, it is thus achieved that by signal The secondary signal that provider produces in response to the addition of fluid, wherein, based on initial signal and second Difference between signal, it is possible to calculate the amount of the fluid being added at least one hole.Implement at some In example, after recording initial signal and before obtaining secondary signal, also include adding fluid In plate.In certain embodiments, described method also includes based between initial signal and secondary signal Difference, calculate the amount of the fluid added at least one hole.In certain embodiments, described in calculating Amount includes the volume calculating the fluid adding at least one hole.In certain embodiments, described amount is calculated Including the quality calculating the fluid adding at least one hole.In certain embodiments, described amount bag is calculated Include volume and the quality calculating the fluid adding at least one hole.

Additionally provide a kind of for measuring the arbitrary reality according to the present invention according to one embodiment of present invention Executing the amount of the fluid lost in the plate of example, plate has the primary quantity at least one hole being arranged on plate Fluid, described method includes: the initial signal that record is provided in the very first time by signal provider；? The second time being later than the very first time obtains signal from signal provider；With based on initial signal and second Difference between signal, the amount of the fluid that at least one hole of computing board loses.In certain embodiments, Calculate described amount and include calculating the volume of the fluid that at least one hole loses.In certain embodiments, meter Calculate described amount and include calculating the quality of the fluid that at least one hole loses.In certain embodiments, calculate Described amount includes volume and the quality calculating the fluid that at least one hole loses.In certain embodiments, Described method also includes: be repeated cyclically the step obtaining signal；With based on two, place different time Between difference between the signal that obtains, calculate in persistent period between two different times from least The amount of the fluid that one hole loses.

Additionally provide a kind of method according to one embodiment of present invention, comprising: obtain in porous plate The displacement datum measurement result at least one hole, be provided with displacement measurement assembly, institute in the hole Displacement measurement assembly for measure at least one hole in plate, in response at least one hole described The change of amount of fluid and the displacement that produces, described reference measurement is obtained by displacement measurement assembly； Time after acquisition reference measurement result, it is thus achieved that the second measurement of the displacement at least one hole described Result；With based on the second displacement measurement, calculate the change of the amount of fluid at least one hole described Change.

Additionally provide a kind of method according to one embodiment of present invention, comprising: in the very first time, The displacement datum measurement result at least one hole in acquisition porous plate, is provided with displacement in the hole Measure assembly, displacement measurement assembly for measure at least one hole in plate, in response to described at least The change of the amount of the fluid in one hole and the displacement that produces, described reference measurement passes through displacement measurement group Part obtains；In the second time being later than the very first time, measure the displacement at least one hole described；With Based on the change in the displacement between the described very first time and the second time, calculate at least one hole described In the change of amount of fluid, wherein at least one time in the very first time and the second time, Described hole exists the fluid of detectable amount.In certain embodiments, described method also includes: the cycle Property repeat in the step of the displacement at least one hole described in the second measure of time；Survey with based on two displacements The change in displacement between amount result, the amount of the fluid in calculating at least one hole described is two positions The change during time period between shift measurement result.In certain embodiments, the change of the amount of fluid Produce owing to fluid is added at least one hole described.In certain embodiments, the amount of fluid Change produce owing at least one hole described loses fluid.

In some embodiments of preceding method, plate is the plate of any embodiment according to the present invention.

In some embodiments of preceding method, signal provider is the sensitiveest to detect at least one The following change in volume of the fluid in hole: 300 microlitres (μ l), 250 μ l, 200 μ l, 150 μ l, 100 μ l, 75μl、50μl、45μl、40μl、35μl、30μl、25μl、20μl、15μl、10μl、5μl、4μl、 3 μ l, 2 μ l, 1 μ l, the fluid of 0.5 μ l, the fluid of 0.3 μ l, the fluid of 0.2 μ l or the stream of 0.1 μ l Body.

In some embodiments of preceding method, signal provider is the sensitiveest to detect at least one hole In the following mass change of fluid: 300 milligrams (mg), 250mg, 200mg, 150mg, 100mg, 75mg、50mg、45mg、40mg、35mg、30mg、25mg、20mg、15mg、10mg、 5mg, 4mg, 3mg, 2mg, 1mg, 500 micrograms (μ g), 300 μ g, 200 μ g or 100 μ g.

In some embodiments of preceding method, described method also includes detecting the temperature at least one hole Degree.In certain embodiments, described method is additionally included in described in the detection of two different time points at least one Described temperature in individual hole.In certain embodiments, described method also includes coming in response to detection temperature Regulate the temperature in single hole.

In some embodiments of preceding method, at least one hole in described porous plate is can be from it Remove.

Unless otherwise defined, all technology the most used herein and scientific terminology all have and this The meaning equivalent in meaning that bright those skilled in the art is generally understood that.In the case of a conflict, say Bright book (including definition) will be preferential.

As used in this article, term " include ", " comprising ", " having " and phraseological modification thereof It is considered to specify described feature, integer, step or composition, but is not excluded for adding one or more Individual other feature, integer, step, composition or a combination thereof.These terms comprise term " include ", " substantially include ".

As used in this article, indefinite article " ", " a kind of " refer to " at least one ", " one Individual or more ", unless expressly stated otherwise in context.

The method of the present invention and/or the embodiment of device can include with manual, automatic or its combination Mode performs or completes required task.Some embodiments of the present invention use include hardware, software, Implement in the case of firmware or its parts combined.In certain embodiments, some parts are general Parts, such as general purpose computer or display.In certain embodiments, some parts are special or fixed Parts processed, such as circuit, integrated circuit or software.

Such as, in certain embodiments, some in embodiment are implemented as by data processor (example A most general or part for customized computer) multiple software instructions of performing.In certain embodiments, Data processor or computer include for store instruction and/or the volatile memory of data and/or For storing instruction and/or the nonvolatile memory (such as hard disc and/or removable medium) of data. In certain embodiments, implement to include that network connects.In certain embodiments, implement to include user circle Face, it is and defeated that described user interface generally includes input equipment (such as allowing input order and/or parameter) Go out in device (such as allow reporting operations parameter and result) one or more.

Accompanying drawing explanation

Herein in reference to accompanying drawing, some embodiments of the present invention are described.Description makes this area together with accompanying drawing Those of ordinary skill understands how can implement some embodiments of the present invention.Accompanying drawing is used for exemplary opinion State and be not intended to illustrate in greater detail embodiment than details necessary to the basic comprehension of the present invention CONSTRUCTED SPECIFICATION.For the sake of clarity, some objects described in accompanying drawing can not be proportional.

In the drawings:

Fig. 1 is the axonometric chart of the porous plate of prior art；

Fig. 2 A is the axonometric chart being construction and operation of porous plate according to embodiments of the invention；

Fig. 2 B is the exploded view of the porous plate of Fig. 2 A；

That Fig. 2 C and 2D obtains respectively along hatching IIC-IIC and IID-IID in Fig. 2 A, The three-dimensional cutaway view of the porous plate of Fig. 2 A and 2B；

Fig. 3 A and 3B is the solid being construction and operation of porous plate according to another embodiment of the present invention Figure；

Fig. 3 C is the exploded view of the porous plate of Fig. 3 A and 3B；

Fig. 3 D is the amplification of the support member of a part for the porous plate of pie graph 3A and 3B, arm and block Axonometric chart；

Fig. 3 E, 3F and 3G are along hatching IIIE-IIIE, IIIF-IIIF and the IIIG-IIIG in Fig. 3 A The sectional view of porous plate that obtain, Fig. 3 A to 3C；

Fig. 4 A is the axonometric chart being construction and operation of porous plate according to another embodiment of the present invention；

Fig. 4 B is the exploded view of the porous plate of Fig. 4 A；

Fig. 4 C is along the hatching IVC-IVC acquirement in Fig. 4 A, the porous of Fig. 4 A and 4B The sectional view of plate；

Fig. 5 A to 5D be a diagram that the sectional drawing of graphic user interface, and this graphic user interface is for online (in real time) monitoring fluid is added into the porous plate of the teaching according to embodiment herein；

Fig. 6 A and 6B be a diagram that the sectional drawing of graphic user interface, and this graphic user interface is used for off-line Monitoring is according to the volume of the fluid in the porous plate of the teaching of embodiment herein；

Fig. 7 be a diagram that the sectional drawing of graphic user interface, and this graphic user interface is used for off-line monitoring root Temperature according to the fluid in the porous plate of the embodiment of the present invention；

Fig. 8 is that the teaching according to embodiment herein is construction and operation of data reader and plate pedestal Axonometric chart, this data reader is for receiving the signal from the porous plate according to teaching herein； With

Fig. 9 A and 9B be for from porous plate remove hole receiving element or hole limit element and/or for By the axonometric chart of such component placement device in porous plate, this device is according to enforcement herein The teaching of example and construct and operate.

Detailed description of the invention

Principle herein, the teaching that use and implement be may be better understood with reference to specification and drawings. After reading specification and drawings presented herein, those skilled in the art can exert without too much The present invention is implemented in the case of power or experiment.

Before at least one embodiment of the present invention is explained in detail it should be understood that the present invention does not limits Propose in it is applied to description below and/or shown in accompanying drawing and/or example, the details of structure and Parts and/or the layout of method.The present invention can implement with other embodiments and can be with various sides Formula is practiced or carried out.It will also be appreciated that wording used herein and term are the mesh for describing , and it is not construed as restrictive.

It it is the axonometric chart of the porous plate of prior art referring now to Fig. 1, Fig. 1.Fig. 1 shows such as this Typical 96 orifice plates 10 known to field.Plate 10 has upper surface 12, lower surface 14 and upper table Multiple sides 16 between face 12 and lower surface 14.Multiple holes 17 are prolonged between surface 12 and 14 Stretching, 96 such holes are arranged as 8 row, often 12 holes of row altogether.Each hole has and is formed at Aperture 18 in surface 12, to contribute in sample fluid hand-hole.Plate 10 can be by plastics (example Combination such as polystyrene, Merlon or these materials) make；In some cases, plate 10 Can have Glass base.Generally, the sample being placed in hole will seen by lower surface 14 with it It is transparent under the most a certain characteristic frequency examined or frequency range, but for some purposes, so Transparent be not likely to be necessary.The side 20 in hole 17 can be or can not be transparent, this Depend on character and the type of pending observation of sample.

This some holes has circular cross section and substantially cylindrical the most on the x-y plane, but This some holes can have the cross section of other shapes (such as rectangle or square), and this some holes Along its length can have different shapes, such as hole side can along one part or along Its whole length bottom from upper shed to hole is tapered.The bottom in hole is typically flat, but root Can be formed as that there is other shapes according to the intended use of plate, such as taper, frustum or the spherical end Portion's (that is, being the bottom transverse cross section of V or U-shaped when observing along Z axis).

The such as plate of plate 10 etc is generally of the width of 85mm to 86mm and 127mm arrives The length of 128mm, its whole height changes in the range of 10 to 20mm, and hole centrally along X and y-axis interval 9mm.ANSI/SBS 1-2004 and ANSI/SBS 3-2004 retouch respectively The area occupied for 96 hole microplates and the standard of bottom outward flange are stated.Nonetheless, plate can have There is different length, width and height dimensions, can have different pitchs of holes, and can have The hole of varying number, as long as being suitable for application-specific or the use of plate.Such as, plate can be containing 384 384 orifice plates in individual hole, this some holes is arranged as 16 row, often 24 holes of row so that the center in hole along X and y-axis interval 4.5mm.ANSI/SBS 1-2004 and ANSI/SBS 3-2004 retouch respectively The area occupied for 384 hole microplates and the standard of bottom outward flange are stated.

It is to be construction and operation of porous according to one embodiment of present invention referring now to Fig. 2 A, Fig. 2 A Plate 100, and be the axonometric chart of porous plate 100 of Fig. 2 A with reference to Fig. 2 B, Fig. 2 B, and reference Fig. 2 C and 2D, Fig. 2 C and 2D is respectively along hatching IIC-IIC and IID-IID in Fig. 2 A The three-dimensional cutaway view of porous plate 100 that obtain, Fig. 2 A and 2B.

As shown in Figure 2 A, as defined in ANSI SBS 1-2004 and ANSI/SBS 3-2004, Plate 100 is designed to be used together with existing weaponry and equipment, and therefore its size is according to currently used standard Plate size determines, wherein, the hole of plate is the most spaced apart.So, after assembling, plate 100 Looking like typical 96 orifice plates, it has upper surface 112, lower surface 114 and at upper surface 112 And the multiple sides 116 between lower surface 114.Multiple holes 117 are formed and at table in plate 100 Extend between face 112 and 114.Each hole has the aperture 118 being formed in upper surface 112, to have Help in sample fluid hand-hole.

Turning to Fig. 2 B, Fig. 2 B is the exploded view of plate 100, it can be seen that plate 100 is actually by some Part is constituted.Side 116 constitutes a part for framework 122, at the end longitudinally in each of framework, Framework 122 be internally formed a pair support member 124a and 124b, will be more detailed in conjunction with Fig. 2 C and 2D Carefully explain described support member.Support member 124a and 124b be each attached to pair of flexible arm 126, flexible arm 126 includes upper arm 126a and underarm 126b, and the most each arm arrives in its proximal attachment In support member one, and in its distal attachment to block 128.As seen in the amplifier section of Fig. 2 B Going out, each piece 128 includes upper part and low portion, and wherein arm 126a and 126b is the most attached Receive lower surface 128a and 128b of upper part and low portion.As following meeting is explained in more detail, Flexible arm 126 can be made up, this material pair of the most flexible material (typically metal or plastics) Yu Xiangkong is sensitive plus a few microgram weight.Described arm (such as can be bonded by suitable mode Agent or in some cases by melted or welding) be attached to block 128.

The cylindrical side wall in hole 117 is formed in hole receiving element 130, and hole receiving element 130 is permissible It is made up of plastics, glass or other suitable materials.Hole receiving element 130 includes upper surface 112 also And at its longitudinal end, there is flange 132.After plate 100 is assembled, each flange 132 leans against (can Selection of land is attached to) on the upper surface of upper part 128a of two blocks 128, have at the often end of flange One block, and (see Fig. 2 D) also against on support member 124a and 124b in certain embodiments. Bottom sheet 134 is piece of plastic or the glass that thickness is about 170 to 1000 microns, and it is the most attached Receive the bottom side of hole receiving element 130, in order in the way of sealing each hole at this end, form each hole The bottom of 117.

In the embodiment shown in Fig. 2 A to 2D, the topmost part of hole receiving element 130 (includes Flange 132) girth be slightly lower than the interior girth of framework 122.Therefore, when hole receiving element 130 Flange 132 when leaning against on block 128, exist little between hole receiving element 130 and framework 122 Gap 138 (see Fig. 2 D).As it is explained by following meeting, the existence in gap 138 allows hole Receiving element 130 moves along the longitudinal axis and allows arm 126 to deform therewith.In order to do not hinder this Seal clearance 138 in the case of movement, flexible material (such as suitably plastics) the thinnest (big About 7 microns) film 140 be attached to the top edge 142 of framework 122, and be attached to hole and accommodate unit The outward flange of the upper surface 112 of part 130.Realize the one of this attachment to hole receiving element 130 Mode is by having the edge 143 somewhat promoted around the girth of the top edge of element 130 so that Film 140 jointing edge along 143 and is disposed in gap when being also attached to the outward flange of upper surface 112 On 138.

As shown in Figure 2 A and 2B, Mo140 center is hollow so that the big portion of upper surface 112 Divide, particularly surface 112 includes that the region in hole 117 is exposed, and film 140 only covers hole and accommodates The top edge 142 of the edge of element 130, gap 138 and framework 122.But, will also be understood that Be, in certain embodiments, film 140 can be formed as cover framework 122 top edge 142 and The whole upper surface 112 of element 130, in this case, film 140 is formed into having multiple circle Shape opening, these circular opens can align with the aperture 118 in hole receiving element 130, to allow to make User's access hole 117.In such embodiments, hole receiving element 130 can be formed as in aperture There is around 118 the part or edge somewhat promoted, can be attached to it with film 140 to provide On other surface.

Film 140, hole receiving element 130, bottom sheet 134 and framework 122 profit are in any suitable manner (such as soft soldering, bond, melt, bond or any other suitable attachment means) is attached to that This.

As noted, after plate 100 is assembled, hole receiving element 130 leans against in pair of block 128 also And at each of which longitudinal direction end, it is attached to the pair of piece 128 alternatively.Which has limited element 130 at x With the motion on y direction, but allow it to move upward in vertical (z) side.Therefore, by fluid When inserting in the hole 117 in element 130, the weight of fluid can cause the displacement downwards of element 130 with And the deformation of arm 126.It should be understood that the fluid of the most hundreds of microlitre, and at some In application, the fluid only counting microlitre is added into given hole 117.Therefore, flexible arm 126 should have Have the most flexible to deflect in response to adding the fluid of Gamma Magnitude to hole.

Referring additionally to Fig. 2 C and 2D, Fig. 2 C and 2D illustrate in greater detail support member 124a and 124b, Arm 126 and block 128 and arm 126 arrive the attachment of support member.Fig. 2 C shows the plate 100 in Fig. 2 A, But illustrating in the way of showing the three-dimensional viewgraph of cross-section of one end of plate, this viewgraph of cross-section is Obtain along the hatching IIC-IIC in Fig. 2 A.Fig. 2 D is with along the hatching in Fig. 2 A IID-IID shows same plate from the viewgraph of cross-section of the amplification that the angle identical with Fig. 2 C obtains, should Viewgraph of cross-section shows the other end of plate.Fig. 2 C shows a pair arm 126 of the end closest to plate, And Fig. 2 D shows a pair arm 126 that the end from plate is arranged slightly inwardly.

Support member 124a inwall 122a at the longitudinal end being positioned at framework 122 and from its Adjacent longitudinal wall 122b highlights.Support member 124b highlights and with interior from relative longitudinal wall 122c The width of wall 122a septal branch support member 124a.Support member 124a and 124b is in the opposite direction from longitudinal direction Wall highlights, about three of the passage between each prominent longitudinal wall in support member 124a and 124b / mono-, the most each support member has a pair tongue and (is shown as support member 124b in Fig. 2 D 124b' and 124b "), tongue is prominent until the about interposition arrived between two longitudinal walls further Put.Distance between the upper surface of tongue is equal to the distance between arm 126a and 126b.A pair arm exists Its proximal attachment is to support tongue 124a' and 124a of support member 124a " (not shown), and another To arm at tongue 124b' and 124b of its proximal attachment to support member 124b ".Every pair of arm is attached at its far-end Receive block 128.As noted, element 130 is arranged as leaning against and being attached on block 128.If This position is considered as neutral or base position, then arm 126 is configured to have in z-axis enough Flexibility with in some in hole 117 add liquid time deform from this neutral position.

In the free space of arm, but in certain embodiments, at the point of arm with framework 122 attachment Vicinity, there is the flat thin strain gauge 144 of lower surface and the lower surface being attached to each arm 126. Each strain gauge is electrically connected to (such as by thin electric wire, not shown) and is positioned at putting down under underarm 126b Thin electronic card 146.Preferably, electronic card 146 is orientated as and is made strain gauge 144 and card 146 Between the length of connector minimize.Card 146 is electrically coupled to processor (not shown).It should be understood that , the use of strain gauge 144 and card 146 make it possible to by the deflection of arm 126 with such as utilize It also is located at that the Wheatstone bridge on card 146 (Wheatstone Bridge) records, in circuit Resistance variations is associated, enabling calculate the weight of the fluid joining hole.So, arm 126 with Strain gauge 144 forms signal provider together, for providing the fluid indicated in one or more hole The signal of change of amount.If fluid density is known, then this contributes to calculating the fluid added Volume.In certain embodiments, plate 100 also includes the power supply being such as connected to electronic card 146 Device (not shown), such as rechargeable battery, this electric supply installation powers to the electronic unit of plate 100, And it is permissible when plate 100 is connected to power supply or the equipment of calculating by suitable port (not shown) Charging.

Such as, it is successively filled with row A to the L of plate 100 if, with 8 pipettors, then can change Generation ground calculating adds the amount of the fluid often gone, such that it is able to determine when line by line to add to certain row in real time The fluid of incorrect amount.This allows to be given up from result of calculation by that particular row at the end of experiment, Rather than give up the result of whole plate.Preferably, for fluid added equipment in hand-hole can be equipped with Control software, to allow only to get rid of affected row in operation (example further during remaining experiment As added reagent and reactant) outside.Even if should also be understood that and be filled with institute is porose simultaneously, plate 100 with appropriate software be used in combination determine that the fluid of incorrect amount is added into plate and also makes in real time User can stop utilizing specified panel to test, thus avoids wasting reagent in downstream is tested with anti- Answer thing etc..

According to some embodiments of the present invention, plate 100 includes for heating and cools down alternatively individually The unit in hole.Such heating unit can be to use following form: (a) is arranged on hole extremely Few part heating coil around, or (b) peltier (Peltier) device is (otherwise referred to as Peltier heat pump or thermoelectric (al) cooler).As should be understood, peltier device can be used in cooling and Heat single hole, and sense or temperature in monitoring holes or near it.As such, it is possible to control The individually temperature in hole, the temperature in the most each hole can maintain 37 DEG C ± 0.5 DEG C.

In one embodiment, single heating coil or peltier device can be arranged on hole receiving element On 130, heat two or more holes 117 for integrally.In another embodiment, can be one On individual or more single hole 117, heating coil or peltier device are set, for adding it Heat.

As should be understood, if the temperature in periodic measurement hole, and if for would measuring the dress of temperature Put the controller being couple to control the heater for each single hole, then with periodic measurement list The single hole heating unit that only temperature in hole is used in combination can provide improvement in given bore The method that situation is controlled.It is therefoie, for example, the plate 100 with such heating unit can store up Exist in couveuse, and can the temperature of periodically monitoring holes, and as necessary by heating (or Person cools down) individually hole regulate the temperature in single hole.Alternatively, heating unit itself can be used In realizing insulation, such as, can realize temperature monitoring (such as every 15,10 or 5 minutes) continually And regulation, the temperature in particular bore to be maintained at such as 37 DEG C ± 0.5 DEG C, to realize insulation.Therefore, By plate 100, hole receiving element 130 or hole 117 being equipped with the single heating for each hole Element, can regulate in the case of discovery temperature is incorrect and control temperature.

It should be understood that the hole owing to reagent and other fluids can be joined hole receiving element 130 Remove in 117 or from hole 117, wherein hole receiving element 130 can remove from plate 100 and Being disposed off alternatively, therefore plate 100 can be used for multiple times and/or for multiple experiments, as long as at plate Hole receiving element 130 is changed between 100 each uses.

Referring now to Fig. 3 A to 3G, Fig. 3 A to 3G show according to embodiments of the invention structure and The porous plate 300 of operation and parts thereof.Specifically, Fig. 3 A and Fig. 3 B is the solid of porous plate 300 Figure；Fig. 3 C is the exploded view of porous plate 300；Fig. 3 D is propping up of a part for composition porous plate 300 The amplification stereogram of support member, arm and block；Fig. 3 E, 3F and 3G are along the hatching in Fig. 3 A IIIE-IIIE, IIIF-IIIF and IIIG-IIIG obtain, the sectional view of porous plate 300.

As shown in figs.3 a and 3b, plate 300 is designed to be used together with existing weaponry and equipment, therefore its Size determines according to currently used on-gauge plate size, and the hole of plate 300 is the most spaced apart. Therefore, after assembling, plate 300 looks like typical 96 orifice plates, and it has upper surface 312, following table Multiple sides 316 between face 314, surface 312 and 314, and it is formed with multiple in plate 300 Hole 317.

As shown in Figure 3 C, Fig. 3 C is the exploded view of plate 300, if plate 300 is actually by stem portion structure Become.Side 316 is a part for framework 322, at longitudinal end of framework, in side 316 Defining a pair support member 324a and 324b in portion's part, each support member includes multiple " step " 325, these support member will be explained in greater detail in conjunction with Fig. 3 D, 3F and 3G.Framework 322 includes setting Put end wall 322a and 322d at longitudinal end of framework and longitudinal wall 322b and 322c.

Support member 324a and 324b be each attached to multiple flexible arm 326, the most each arm In its proximal attachment to support member one, and in its distal attachment to block 328.Hereinafter can With reference to Fig. 3 D, 3F and 3G more detailed description flexible arm 326 and the 26S Proteasome Structure and Function of block 328.As Hereinafter can be explained in more detail, flexible arm 326 can by suitable material (typically metal or plastics), Making, this material is suitably flexible to add for Xiang Kongzhong or removing smaller body from hole Long-pending material is sensitive.Such as, flexible wall 326 can be quick for the material of amount below adding to hole Sense: less than 300 microlitres (μ l), less than 250 μ l, less than 200 μ l, less than 150 μ l, less than 100 μ l, Less than 75 μ l, less than 50 μ l, less than 45 μ l, less than 40 μ l, less than 35 μ l, less than 30 μ l, be less than 25 μ l, less than 20 μ l, less than 15 μ l, less than 10 μ l, less than 5 μ l, less than 4 μ l, less than 3 μ l, Less than 2 μ l or less than 1 μ l.

Arm 326 can be by suitable mode (such as binding agent or in some cases by melted Or welding) it is attached to block 328.

Plate 300 also includes eight identical hole support components 330, and each hole support component includes fitting Together in by longitudinal aperture 333 contained therein for hole receiving element 348.Each hole receiving element 348 Having formed therein 12 cylinder 320, these cylinders form the sidewall of tubulus 317.Unit Each in part 330 also has pair of flanges 332, has one at the end longitudinally in each of element 330 Individual flange.Hole support component 330 can be made up of plastics or other suitable material, and permissible Other materials containing such as glass etc.After assembling, each flange 332 leans against and preferably It is attached on two blocks 328, one block of each flange；Block 328 below can be discussed in more detail relative It is maintained at the mode in appropriate location in framework 322.

Thickness be of about 170 to 1000 microns, multiple bottom sheet of being made up of plastics or sheet glass 334 bottom sides being sealingly attached to hole receiving element 348, in order to each hole of the bottom end seal in hole Mode form the bottom in each hole 317.In the illustrated embodiment, (each close for three sheets 334 Back cover hole 317) it is attached to each hole receiving element 348.Nonetheless, it is possible to use any properly Arrange or any amount of bottom sheet, such as, single 334 can be utilized to accommodate unit to seal single hole Institute in part 348 is porose, can seal each hole 317 by single bottom sheet 334, or can To use 6 bottom sheet 334 to seal the paired hole 317 in single hole receiving element 348.? In some embodiments, framework 322 includes the separator 350 adjacent with its base section, separator 350 By the framework section of being divided into 352, each section 352 is appropriately determin size to coordinate in bottom sheet 334 One and be attached to the hole 317 of bottom sheet.

It should be understood that after fitting together, the topmost part of the set of hole support component 330 Girth (including flange 332) be slightly less than framework 322 interior girth so that at hole support component When the flange 332 of 330 leans against on block 328, between hole support component 330 and framework 322 (see Fig. 3 E) and there is little gap 338 (see Fig. 3 E) between element 330 itself.As will under Face is explained, the existence in gap 338 makes hole support component 330 can move along the longitudinal axis and make Obtain arm 326 can deform therewith.For seal clearance 338 in the case of not hindering this movement, The film 340 of the thinnest (the most about 7 microns) be made up of flexible material (such as suitably plastics) It is attached to the top edge 342 of framework 322, and is attached to the upper surface of hole support component 330 extremely A few part.Film 340 includes eight alignd with the aperture 333 in the hole support component 330 assembled Individual rectangular aperture 343.

Film 340, hole support component 330, bottom sheet 334 and framework 322 utilize suitable mode (example Such as soft soldering, bond, melt, bond or any other suitable attachment means) it is attached to each other. It should be understood that in the illustrated embodiment, sensitive structure and the function of arm 326 can not damaged In the case of, hole receiving element 348 is easily removed from hole support component 330, hereinafter to it It is more fully described.

As noted, after plate 300 is assembled, hole support component 330 leans against and indulges in each of which It is attached at end in pair of block 328.Which has limited element 330 in horizontal and vertical (x and y side To) on motion, but allow element 330 to move upward in vertical (z) side.Therefore, will flow Body insert in the hole in the hole receiving element 348 being positioned in any one hole support component 330 (or from Hole removes) time, the increase (or reduction) of fluid weight can cause being attached to this hole support component 330 The deformation of arm 326.It should be understood that the most hundreds of microlitre and the most only Number microlitre or less fluid are added into given hole 317.Therefore, flexible arm 326 should have Suitably flexible with in response to fluid (or the equivalence adding (or removing from hole) this amount to hole Quality) and deflect.For example, it is possible in any given time the fluid of following amount added hand-hole 317: Less than 300 microlitres (μ l), less than 250 μ l, less than 200 μ l, less than 15 μ l, less than 100 μ l, little In 75 μ l, less than 50 μ l, less than 45 μ l, less than 40 μ l, less than 35 μ l, less than 30 μ l, be less than 25 μ l, less than 20 μ l, less than 15 μ l, less than 10 μ l, less than 5 μ l, less than 4 μ l, less than 3 μ l, Less than 2 μ l or less than 1 μ l.

An attachment in arm with " step " 325 (it can be described in more detail below) The vicinity of point, flat thin strain gauge 344 is attached to the upper and lower surface of each arm 326.Ying Li Solve, alternatively, be not by strain gauge place be that a strain gauge is put on an upper and not Put on the lower surface of arm, two strain gauges can be placed on the upper surface of arm, a strain gauge Near the position that arm and framework 322 are attached, and another strain gauge is in the position of arm with block 328 attachment Near putting；Or can two strain gauges be placed only on the lower surface of arm, a strain gauge is at arm Near the position of framework 322 attachment, and another strain gauge is attached with the position that block 328 is attached at arm Closely.

Each strain gauge 344 is conductively coupled to (such as by thin electric wire, not shown) and is positioned at underarm 326 Under flat thin electronic card 346.Preferably, electronic card 346 is orientated as and is made strain gauge 344 With the length of the connector between card minimizes.Fig. 8 to 9B describes as described below in references to, card Sheet 346 is conductively coupled to the port 358 being positioned on framework 322, port 358 by many electric wires 356 It is configured for connection to the electric port of the plate pedestal of data reader and suitable configurations.In certain embodiments, Fig. 5 A to 7 describes as described below in references to, and data reader can run graphic user interface.Excellent Selection of land, outside port 358 does not extends to the outer surface of framework 322 and preferably with described outer surface Flush, and do not affect the overall dimensions of plate 300, thus allow to use standard set-up.Real at some Executing in example, plate 300 also includes the electric supply installation (not shown) being such as connected to electronic card 346, example Such as rechargeable battery, described electric supply installation is powered to the electronic unit of plate 300, and is led at plate 300 Cross port 358 or USB port is connected to when power supply or the equipment of calculating to charge.

Electronic card 346 can have and is positioned at thereon, the element of resistance in measuring circuit, Such as Wheatstone bridge.Caused by the change of the capacity contained in one or more hole 317 or weight The deflection of arm 326 cause the change of length of resistor in corresponding strain gauge 344.Strain gauge 344 This change with utilized such as Wheatstone bridge records, circuit by the element on electronic card 346 In resistance variations be correlated with.Resistance variations in circuit allows calculating to add hand-hole 317 (or from hole 317 In remove) the quality of fluid.Specifically, the fluid of the bigger quality of hand-hole (removing from hole) is added Causing the large change of the deflection of arm 326, this causes the large change of the resistance in circuit then.Cause This, the measurement result of the resistance variations in circuit indicates and allows the quality calculating the fluid in hole to become Change.If fluid density is known, then this contributes to the fluid of calculating addition (or removing) Volume.So, arm 326 forms signal provider together with strain gauge 344, is used for providing instruction one The signal of the change of the amount of the fluid in individual or more hole.

Such as, in succession row A to the L of plate 300 is filled with if, with 8 allotters, then may be used To calculate the amount of the fluid in each hole added in each column iteratively, such that it is able to hole-specifically determine in real time The fluid of incorrect amount (or too much or very few) is when added to particular bore.Preferably, use In equipment fluid added in hand-hole can equipped with control software, described control software can allow used by set Standby correction error.Under having been added to very few fluid situations, other fluid can be assigned to involved And hole so that the fluid in this hole reaches correct amount, and/or this software can be by later Operation in proportionally less reagent or reactant liquid are added involved by hole regulate by mistake Difference.Similarly, if adding too much fluid to particular bore, then add in operation later Reagent or reactant can the most proportional increase.

Alternatively, can the other operation during remaining experiment include involved hole or Hole receiving element, and by calculate be adjusted with consider carry out between experiment periods use the most just True amount, at the end of experiment, the result of particular bore may be used for calculating.

As another alternative, the identification to the particular bore of the fluid having been added to incorrect amount makes Can give up from result of calculation when off-test particular bore rather than give up residing for this hole whole The result of individual row or column or the result of whole plate.

Even if it will also be appreciated that and be filled with institute is porose simultaneously, plate 300 and the knot of appropriate software Conjunction use is added into specific hole support component 330 with the fluid of the incorrect amount of Real time identification and makes User can stop the experiment utilizing the hole in that particular element 330 or plate 300 to carry out, from And avoid wasting reagent and reactant etc. in downstream is tested.

Additionally, electronic card 346 can have with its electric coupling, for by being couple to this card The data collected of various sensor elements carry out the parts that process, such as by Wheatstone bridge Analogue signal is converted to the Analog-digital Converter parts of digital signal, and for collected signal The normalization parts being normalized.

In certain embodiments, plate 300 also includes one or more temperature sensor (not shown), This temperature sensor is conductively coupled to electronic card 346 and is configured to provide for one or more hole Temperature near 317 or the instruction of variations in temperature.It should be understood that the variations in temperature in system can Can affect strain gauge 344, therefore understanding and calculating consideration to variations in temperature can allow for more accurately Weight in identifying hole, and allow to guarantee in hole may be sensitive to variations in temperature the stablizing of sample Temperature.

According to some embodiments of the present invention, plate 300 includes for heating and cools down alternatively individually The unit in hole.Such heating unit can be to use following form: (a) is arranged on hole extremely Few part heating coil around, or (b) peltier device (otherwise referred to as peltier heat pump Or thermoelectric (al) cooler).As should be understood, peltier device can be used in cooling and heating is single Hole, and sense or in monitoring holes or temperature near it.As such, it is possible to control in single hole Temperature, the temperature in the most each hole can maintain 37 DEG C ± 0.5 DEG C.

In certain embodiments, heating coil or peltier device can be arranged on hole support component 330 Some or all on, support by this hole support component 330 for entirety heating two or more Hole 117.In other embodiments, heating coil or peltier device can be arranged on single hole 317 Some or all on, be such as arranged on its cylinder 320 so that each heating coil or peltier Particular bore 317 on or in which set by it is heated by device.

As should be understood, if the temperature in periodic measurement hole, and if for would measuring the dress of temperature Put the controller being couple to control the heater for each single hole, then with periodic measurement list The single hole heating unit that only temperature in hole is used in combination can provide improvement in given bore The method that situation is controlled.It is therefoie, for example, the plate 300 with such heating unit can store up Exist in couveuse, and can the temperature of periodically monitoring holes, and as necessary by heating (or Person cools down) individually hole regulate the temperature in single hole.Alternatively, heating unit itself can be used In realizing insulation, such as, can realize temperature monitoring (such as every 15,10 or 5 minutes) continually And regulation, the temperature in particular bore to be maintained at such as 37 DEG C ± 0.5 DEG C, to realize insulation.Therefore, By plate 300, hole support component 330 or hole 317 being equipped with the single heating for each hole Element, can regulate in the case of discovery temperature is incorrect and control temperature.

It is support member 324a and 324b including arm 326 and block 328 referring now to Fig. 3 D, Fig. 3 D Amplification stereogram, and with reference to Fig. 3 F and 3G, Fig. 3 F and 3G respectively along in Fig. 3 A The sectional view that hatching IIIF-IIIF and IIIG-IIIG obtains.Fig. 3 D, 3F and 3G show in more detail Go out the attachment to support member of support member 324a and 324b, arm 326, block 328 and arm 326.

As found out, eight blocks 328 are positioned near the end longitudinally in each of framework 322 so that Mei Gekong Support component 330 leans against and is attached on two blocks 328, at the end longitudinally in each of element 330 There is a block 328.As described below, in order to accommodate eight blocks at the often end of framework 322, Support member 324a and 324b and block 328 design in the way of ladder-step.First support member 324a From the inwall 322d of a longitudinal end of framework 322 and highlight from the longitudinal wall 322b being adjacent. At another longitudinal end of framework 322, the second support member 324a highlights and with interior from longitudinal wall 322b Wall 322a is spaced slightly apart.In both cases, to arm 326 and block is contributed to accommodate four The suitable location of 328, support member 324a is with step-step-wise manner structure, and it has the two of parallel formation Group " step ", upper group 360a and bottom group 360b.All " steps " of support member 324a from The inwall 322b of framework 322 highlights, but all " step " has phase along the longitudinal axis of framework 322 Same width, the top often organized " step " 325a and 325a' is minimumly prominent from inwall 322b, " step " 325b and 325b' prominent somewhat multiple spot, " step " 325c and 325c' is morely prominent, And " step " 325d and 325d' is projected between wall 322b and wall 322c the position in the middle of about.

Between the upper surface of every pair corresponding " step " (i.e. between 325a and 325a', 325b and 325b' Between, between 325c and 325c' and between 325d and 325d') the lower surface of distance and every pair of arm Between distance identical.Therefore, first couple of arm 326a and 326a' is attached to " step " in its proximal end 325a and 325a', second couple of arm 326b and 326b' be attached in its proximal end " step " 325b and 325b', the 3rd couple of arm 326c and 326c' are attached to " step " 325c and 325c' in its proximal end, And the 4th couple of arm 326d and 326d' is attached to " step " 325d and 325d' in its proximal end." step " It is spaced apart from each other so that the arm in every pair of arm is parallel to each other, and makes during normal use, The every pair of arm can not contact another to arm in the case of move.

As found out in Fig. 3 D and 3F, arm 326 in its distal attachment to block 328 so that every pair Arm is attached to single piece 328 abreast.In order to contribute to the compact Layout of arm, each piece 328 includes For being attached to the upper inner surface of the first arm, for being attached to the lower inner surface of the second arm and allowing additionally The recess that passes therethrough of arm.Therefore, the arm 326a being attached to step 325a is attached to closest The upper inner surface 328a' of the block 328a of frame center, and block 328a is configured to have recess 328a ", to allow arm 326b, 326c and 326d contacting with each other and not contact block 328a In the case of pass wherein.Similarly, the arm 326a' being attached to step 325a' arrives in its distal attachment The bottommost surface 328a of block 328a " ', wherein arm 326b', 326c' and 326d' is on bottommost surface 328a " passes under ' in parallel with each other.Block 328b constructs in a similar manner, to allow arm 326b and 326b' Be respectively attached to surface 328b' and 328b' " place, and allow arm 326c and 326d pass therethrough with And arm 326c' and 326d' under it through.Block 328c is configured to allow for arm 326c and 326c' attachment At surface 328c' and 328c' " place, and allow arm 326d to pass therethrough and arm 326d' is under it Pass.Closest to the block 328d of wall 322c by structure in four blocks 328a, 328b, 328c and 328d Make as allowing arm 326d and 326d' to be respectively attached to surface 328d' and 328d " ' place.

It should be understood that due to this structure, the upper part of block 328a, 328b, 328c and 328d Size different from each other.It will also be appreciated that in block 328a, 328b, 328c and 328d is each Individual be respectively provided with different whole heights, although the position of the upper space of the most each piece relative to The top of framework 322 is identical, but can there be difference slightly the position of the upper space of each piece Different, this be due to for calculate displacement and thus calculate the software of quality of the fluid adding hand-hole can It is programmed in view of such difference.Due to identical, all pieces 328 not necessarily have phase Same quality.

As apparent in Fig. 3 G, support member 324b is with the arrangement phase with support member 324a As mode arrange in the opposite direction.At a longitudinal end of framework 322, the first support member 324b is from the inwall 322a of a longitudinal end of framework 322 and from the longitudinal wall 322c being adjacent Prominent.At another longitudinal end of framework 322, the second support member 324b highlights from longitudinal wall 322c And it is spaced slightly apart with inwall 322d.Near wall 322d, support member 324b spaced away with Accommodate arm 326a, 326a', 326b, 326b', 326c, 326c', 326d and 326d'.In order to accommodate Four pairs of arms 326 and contribute to the suitable location of block 328, support member 324b is with step-step-wise manner Structure, it has two groups " steps " of parallel formation, upper group 362a and bottom group 362b.Support All " step " inwall 322a (or 322d) from framework 322 and 322c of part 324b highlight, But all " step " has identical width, therefore, from wall 322a along the longitudinal axis of framework 322 (or 322d) prominent identical distance, the top often organized " step " 325e and 325e' is from interior Wall 322c is minimumly prominent, " step " 325f and 325f' prominent somewhat multiple spot, " step " 325g Morely prominent with 325g', and " step " 325h and 325h' be projected into wall 322c and wall 322b it Between about in the middle of position.

Between the upper surface of every pair corresponding " step " (i.e. between 325e and 325e', 325f and 325f' Between, between 325g and 325g' and between 325h and 325h') the following table of distance and every pair of wall Distance between face is identical.Therefore, first couple of arm 326e and 326e' is attached to " platform in its proximal end Rank " 325e and 325e', second couple of arm 326f and 326f' be attached to " step " 325f in its proximal end With 325f', the 3rd couple of arm 326g and 326g' are attached to " step " 325g and 325g' in its proximal end, And the 4th couple of arm 326h and 326h' is attached to " step " 325h and 325h' in its proximal end." step " It is spaced apart from each other so that the arm in every pair of arm is parallel to each other, and makes during normal use, The every pair of arm can not contact another to arm in the case of move.

As shown in Fig. 3 D and 3G, arm 326 is attached to block 328 at its far-end so that every pair of arm is put down It is attached to single piece 328 capablely.In order to contribute to the compact Layout of arm, each piece 328 include for It is attached to the upper inner surface of the first arm, for being attached to the lower inner surface of the second arm and allowing other arm The recess passed therethrough.Therefore, the arm 326e being attached to step 325e is attached to closest to framework The upper inner surface 328e' of the block 328e at center, and block 328e is configured to have recess 328e ", With allow arm 326f, 326g and 326h do not contact with each other and not in the case of contact block 328e Wherein pass.Similarly, the arm 326e' of step 325e' it is attached in its distal attachment to block 328 Bottommost surface 328e " ', wherein arm 326f', 326g' and 326h' is at bottommost surface 328e " under ' each other Pass through abreast.Block 328f constructs in a similar manner, to allow arm 326f and 326f' to be respectively attached to Surface 328f' and 328f' " place, and allow arm 326g and 326h to pass therethrough and arm 326g' With 326h' under it through.Block 328g is configured to allow for arm 326g and 326g' and is attached at surface 328g' With 328g' " place, and allow arm 326h to pass therethrough and arm 326h' under it through.Four In block 328e, 328f, 328g and 328h, the block 328h closest to wall 322b is configured to allow for arm 326h and 326h' is respectively attached to surface 328h' and 328h " ' place.

It should be understood that due to this structure, the upper part of block 328e, 328f, 328g and 328h Size different from each other.It will also be appreciated that in block 328e, 328f, 328g and 328h is each Individual be respectively provided with different whole heights, although the position of the upper space of the most each piece relative to The top of framework 322 is identical, but the position of the upper space of each piece can have slightly Difference, this is due to for calculating displacement and thus calculating the software energy of quality of the fluid adding hand-hole Enough it is programmed in view of such difference.Due to identical, all pieces 328 not necessarily have phase Same quality.

It should be understood that owing to reagent and other fluids are joined the pore volume that can remove from plate 300 Receiving in the hole 317 of element 348 or remove from hole 317, therefore principle upper plate 300 can be repeatedly Use and/or for multiple experiments, as long as change hole receiving element 348 between plate 300 uses i.e. every time Can.

The religion according to embodiment herein is shown referring now to Fig. 4 A to 4C, Fig. 4 A to 4C Lead and be construction and operation of porous plate and parts thereof.Specifically, Fig. 4 A is the axonometric chart of porous plate 400, Fig. 4 B is the exploded view of porous plate 400, and Fig. 4 C is to take along the hatching IVC-IVC in Fig. 4 A Obtain, the sectional view of porous plate 400.

As shown in Figure 4 A, after assembling, plate 400 seems basic with the plate 300 of Fig. 3 A to 3G Similar.But, although according to Fig. 4 B and description herein book it is to be appreciated that plate 300 He The purpose of 400 is similar with purposes, but the structure of plate 400 is somewhat different with the structure of plate 300.

Plate 400 is designed to be used together with existing weaponry and equipment, and therefore, its size is according to currently used On-gauge plate size determine, wherein the hole of plate is the most spaced apart；The most after assembling, Plate 400 looks like typical 96 orifice plates, and it has upper surface 412, lower surface 414 and upper table Multiple sides 416 between face 412 and lower surface 414, and in plate 400, it is formed with multiple hole 417。

As shown in Figure 4 B, Fig. 4 B is the exploded view of plate 400, if plate 400 is actually by stem portion structure Become.Side 416 is a part for framework 422, and framework 422 also includes limiting 96 in framework 422 The hole of individual eyelet 452 limits skeleton 450, and each eyelet has almost circular transversal along horizontal plane Face, and along vertical plane, there is generally rectangular cross section.

Plate 400 also includes 96 single identical cylindrical hole support components 430, and each of which is all wrapped Including aperture 433, the size in each aperture is confirmed as coordinating an eyelet 452 and being suitable to accommodate Single hole limits element 419, and hole limits element 419 can be from its hole support component contained therein 430 easily remove.Each single hole 417 is limited element 419 by hole and limits, and hole limits element 419 are formed by cylindrical part 466 and seal with almost circular bottom sheet 434 bottom it.

Each hole support component 430 is adhered to or is otherwise attached to lay respectively at plate 474 With two arms 426 and 426' in 476.Arm 426 and 426' can (but not essential) be integrally It is formed in plate 474 and 476.For ease of quoting, unless expressly stated otherwise, the most later Middle arm 426 and 426' can be referred to as 426.As following meeting is explained in more detail, flexible arm 426 is permissible Being made up of suitable material (typically metal or plastics), this material is the most flexible, in order to for Xiang Kongzhong addition or the material removing small size from hole are sensitive.

Arm 426 is substantially flat, and as shown in the illustration in Fig. 4 B, each arm 426 and 426' There is generally rectangular part 426a, in two adjacent corners of part 426a of rectangle from this The part of rectangle extends outthrust, this outthrust forming part annulus 426b, part-toroidal thing But 426b extends beyond half length halfway around cylindrical hole support component 430, and its chi The very little interior girth being confirmed as there is the outer perimeter less times greater than cylindrical hole support component 430.In portion It is formed with being sized to have and cylindrical hole of ring 426c, ring 426c in dividing annulus 426b The interior girth that support component 430 is identical.Therefore, cylindrical hole support component 430 is such as by bonding Agent pastes ring 426c, and (upper surface of cylindrical hole support component 430 is attached to the ring 426c of arm 426 Lower surface, and the lower surface of cylindrical hole support component 430 is attached to the ring 426c of arm 426' Upper surface).This structure make a pair arm 426 and 426' hole support component 430 can be maintained at x and Position in y-axis, but allow element and the hole wherein comprised to move along z-axis, cause arm therewith The bending of 426.

Strain in order to make arm sense at rectangle part 426a and part-toroidal thing 426b maximizes And localization, part-toroidal thing 426b and rectangle part 426a is by suitable thin and flexible material (example Such as metal or plastics) make.In certain embodiments, in order to promote bending, arm 426 and 426' divides It is not made into thinner than the remainder of plate 474 and 476.In certain embodiments, plate 474 He 476 outside arm 426 and 426' part bond or be otherwise attach to framework 422 and/or Electronic card 446 (being hereinafter more fully described), with to plate 474 and 476 need not bending Part is strengthened, so that the strain localization sensed by arm 426.

Should be understood that the most hundreds of microlitre and the most only count microlitre or less Fluid is added into given hole.For example, it is possible to the fluid of following amount is added given hole: be less than 300 microlitres (μ l), less than 250 μ l, less than 200 μ l, less than 150 μ l, less than 100 μ l, be less than 75 μ l, less than 50 μ l, less than 45 μ l, less than 40 μ l, less than 35 μ l, less than 30 μ l, less than 25 μ l, Less than 20 μ l, less than 15 μ l, less than 10 μ l, less than 5 μ l, less than 4 μ l, less than 3 μ l, less than 2 μ l Or less than 1 μ l.Therefore, flexible arm 426 should have suitably flexible with in response to adding to hole (or Person removes from hole) fluid (or equivalent mass) of this amount and deflect.

After fitting together, the outer perimeter of cylindrical hole support component 430 is slightly less than eyelet 452 Interior girth, thus limit in hole formed between skeleton 450 and cylindrical hole support component 430 little Gap 438 (see Fig. 4 C).The existence in these gaps allows each hole support component 430 along the longitudinal axis (z-axis) is independent mobile and arm 426 can be deformed therewith, below can explain it.

For seal clearance 438 in the case of not hindering this vertically moving, flexible material is (such as Suitably plastics) film 440 of the thinnest (the most about 7 microns) made is attached to framework 422 Top edge 442, and it is (the most more detailed to be also attached to top card 446 in certain embodiments Describe).Film 440 includes 96 circular opens 443, these openings and (described below) card Aperture 447 in 446, the ring 426d discussed more fully below and at the hole support component assembled Align in aperture 433 in 430.

Film 440 profit (such as soft soldering, bonds, melts, bonds or any in any suitable manner Other suitable attachment means) it is attached to framework 422.It should be understood that in the embodiment shown, Each hole limits element 419 can be from it in the case of the sensitive structure not damaging arm 426 and function Residing hole support component 430 easily removes.

Each arm 426 has at rectangle part 426a and is attached at the most side by side on the upper surface of this arm A pair flat strain gauge 444.Alternatively, strain gauge can be attached to the upper surface of rectangle part 426a And lower surface.Each strain gauge is such as conductively coupled to electronic card 446 by electric wire (not shown). In some embodiments, arm 426 can be formed as having hole 445, with the most such electric wire from it In pass.Electronic card 446 is orientated as and is made the length of the connector between strain gauge 444 and card Littleization.

In certain embodiments, such as in the embodiment as shown in the amplifier section in Fig. 4 B, in order to Some details are shown, described amplifier section around the longitudinal axis of hole support component relative to remaining of Fig. 4 B Partial turn 90 degree, hole support component 430 can include that at its top and edge, bottom highlight dashes forward Go out thing 431a, prominent outthrust 431a to be designed to protect strain gauge 444.Additionally, it is real at some Executing in example, hole support component 431 can include offseting the top of 180 degree with outthrust 431a rotationally Plate 474 and 476 and limit the inclined of arm 426 is engaged with lower protrusion 431b, outthrust 431b Turn scope.

In certain embodiments, card 446 (each card can be actually multiple card) leads to Too much root electric wire (not shown) is conductively coupled to the port 458 being positioned on framework 422, as hereinafter joined Can describe according to Fig. 8 to 9A, port 458 is configured for connection to data reader and suitable configurations The electric port of plate pedestal.In certain embodiments, (each card can be actually card 446 Multiple cards) it is conductively coupled to USB port (not shown) or electricity by many electric wire (not shown) The similar input/output end port that is couple to be positioned on framework 422 is (the most currently known or in the future can The input/output end port that can develop), this port is configured to that plate 400 is connected to power supply and/or calculating sets Standby.Data reader and/or the calculating equipment that can be connected with plate 400 can run below with reference to Fig. 5 A To 7 graphic user interfaces described.Preferably, port 458 and/or USB port (not shown) Flush outside not extending to the outer surface of framework 422 and preferably with described outer surface, and not shadow The overall dimensions of castanets 400, thus allow to use standard set-up.

In certain embodiments, plate 400 also includes the electric supply installation being such as connected to electronic card 446 (not shown), such as rechargeable battery, described electric supply installation power to the electronic unit of plate 400 and Can fill when plate 400 is connected to power supply or the equipment of calculating by port 458 or USB port Electricity.

Each electronic card 446 includes 96 apertures 447 with circular cross section so that at plate 400 After assembled, align with ring 426d, section 452 and hole support component 430 in aperture 447.It is arranged in hole Near mouthfuls 447 is less apertures 448, other 96.Aperture 448 allows strain gauge 444 The electric wire (not shown) being connected with card 446 passes.

Electronic card 446 can have the element being positioned at the resistance in measuring circuit thereon, example Such as Wheatstone bridge.The deflection of arm 426 causes the length of the resistor in corresponding strain gauge 444 to change, This change with utilized by the element on electronic card 446 that such as Wheatstone bridge records, in circuit Resistance variations is correlated with.Resistance variations in circuit allows to calculate and adds each hole (or from each hole Hole removes) the quality of fluid.Specifically, the bigger quality of hand-hole (removing from hole) is added Fluid causes the large change of the deformation of arm 426, and this causes the large change of the resistance in circuit then. Therefore, the mass change of fluid in the measurement result indicator hole of the resistance variations in circuit, and make This change can be calculated.If fluid density is known, then this contribute to calculate add (or move Remove) the volume of fluid.So, arm 426 forms signal provider together with strain gauge 444, uses Signal in the change providing the amount indicating the fluid in hole associated there.In certain embodiments, Electronic card 446 includes memory unit, and it is for being such as not attached to data reader (example at plate 400 Data reader such as Fig. 8) time the signal that produced by signal provider of storage.It is connected at plate 400 During data reader, then can again obtain such storage letter by data reader from card 446 Number.

Such as, one after the other row A to the L of plate 400 is filled with if, with 8 allotters, or If single hole is one after the other filled with by person, if or be filled with institute is porose, the most simultaneously Then can calculate the amount of the fluid added in each hole, such that it is able to hole-specifically determine when to spy in real time Determine hole and add the fluid of incorrect amount (too much or very few).

Preferably, the equipment being used for adding in hand-hole by fluid can be equipped with controlling software, this control software Device therefor can be allowed to correct error.Under having been added to very few fluid situations, can be by other stream Body is assigned to involved hole, so that the fluid in hole reaches correct amount, and/or by later Operation in the reagent of proportional minimizing or reactant liquid added involved by hole, this software can Regulation error.Similarly, if adding too much fluid to particular bore, then in operation later The reagent of middle addition or reactant can the most proportional increases.

Alternatively, the other operation during remaining experiment can include involved hole or Hole receiving element, and by calculate be adjusted with in view of carry out between experiment periods use not Correct amount, at the end of experiment, the result of particular bore may be used for calculating.As another alternative Formula, the identification to the particular bore of the fluid adding incorrect amount makes it possible to when off-test from meter Calculate in result and give up particular bore rather than give up the result of whole row or column residing for hole or whole plate Result.

Even if it will also be appreciated that and be filled with institute is porose simultaneously, plate 400 is combined with appropriate software Use to determine that the fluid of incorrect amount is added into specific hole support component 430 and makes user in real time The experiment utilizing the hole in that particular element or plate 400 to carry out can be stopped, thus avoid Reagent and reactant etc. are wasted in downstream experiment.

It will also be appreciated that plate 400 can also operate in the case of not continued to monitor.? Under such circumstances, the reference measurement of hole or plate is obtained from signal provider.It is then possible to by this plate Disconnect with power supply and/or the processor or the data reader that are provided data, and can will flow Body adds plate or removes from plate.It is then possible to again this plate is connected to power supply and/or digital independent Device or processor, and secondary signal can be obtained from signal provider.Initial signal and secondary signal Comparison make it possible to identify the particular bore of the fluid that there is incorrect amount, thus allow by those holes from Further experiment and calculating are given up.

In certain embodiments, plate 400 also includes one or more temperature sensor (not shown), Described temperature sensor is conductively coupled to electronic card 446 and is configured to provide for one or more hole Temperature near 417 or the instruction of variations in temperature.It should be understood that the variations in temperature in system can Can affect strain gauge 444, therefore understanding and calculating consideration to variations in temperature can allow for more accurately Weight in identifying hole, and allow to guarantee in hole may be sensitive to variations in temperature the stablizing of sample Temperature.

Additionally, electronic card 446 can have with its electric coupling, be couple to this card for locating reason The parts of the data that the various sensor elements of sheet are collected, such as the simulation of resistance bridge being believed Number be converted to the Analog-digital Converter parts of digital signal and for collected signal is returned The normalization parts that one change processes.

Owing to the deflection of each arm can be calculated, therefore, it is possible to calculate the material adding each separate openings in real time The amount of material or the volume of liquid, the use of plate 400 contributes to the amount that correction to add the material in each hole Or ignore single hole rather than ignore a line hole or whole plate in subsequent experimental operates.This Outward, as hereafter this configuration utilized can to observe material over time with reference to Fig. 5 A to described in 7 The passage loss from given hole.

According to some embodiments of the present invention, plate 400 includes for heating and cools down alternatively individually The unit in hole.Such heating unit can be to use following form: (a) is arranged on hole extremely Few part heating coil around, or (b) peltier device (otherwise referred to as peltier heat pump Or thermoelectric (al) cooler).As should be understood, peltier device can be used in cooling and heating is single Hole, and sense or in monitoring holes or temperature near it.As such, it is possible to control in single hole Temperature, the temperature in the most each hole can maintain 37 DEG C ± 0.5 DEG C.

In one embodiment, the peltier device for each hole can be built upon described in Fig. 4 B One or two electronic card 446 in, such as adjacent with each aperture 447, with to specific hole Support component 430 or be arranged on aperture hole limit element 419 heat.Alternatively, permissible Hole support component 430 or hole limit element 419 some or each on heating coil or amber ear are set Note device, to be internally heated hole associated there or hole.As another replacement scheme, Heating coil or peltier device could be arranged to limit element with groups of hole support component 430 or hole 419 is adjacent, such as, be arranged on electronic card 446, carries out with the inside to the hole in group or hole Heating.Although have references to Fig. 4 B, it should be understood that the setting of such hole heating unit does not limits In the plate that hole can shift along z-axis wherein, and such heating unit can be arranged on hole In the plate that can not shift wherein.

As should be understood, if the temperature in periodic measurement hole, and if for would measuring the dress of temperature Put the controller being couple to control the heater for each single hole, then with periodic measurement list The single hole heating unit that only temperature in hole is used in combination can provide improvement in given bore The method that situation is controlled.It is therefoie, for example, the plate 400 with such heating unit can store up Exist in couveuse, and can the temperature of periodically monitoring holes, and as necessary by heating (or Person cools down) individually hole regulate the temperature in single hole.Alternatively, heating unit itself can be used In realizing insulation, such as, can realize temperature monitoring (such as every 15,10 or 5 minutes) continually And regulation, the temperature in particular bore to be maintained at such as 37 DEG C ± 0.5 DEG C, to realize insulation.Therefore, It is equipped with the list for each hole by plate 400, hole support component 430 or hole are limited element 419 Only heating element heater, can regulate in the case of discovery temperature is incorrect and control temperature.

It should be understood that due to reagent and other fluids can be joined hole limit in element 419 or Person removes from it, and its mesopore limits element 419 and can remove from plate 400 and be disposed off alternatively, Therefore plate 400 can be used for multiple times and/or for multiple experiments, as long as between plate 400 uses more every time Change hole and limit element 419.

The sectional drawing of graphic user interface is a diagram that referring now to Fig. 5 A to 5D, Fig. 5 A to 5D, should Graphic user interface joins the religion according to embodiment herein for online (in real time) monitoring fluid The porous plate led.

As described above, according to an embodiment of the invention porous plate (such as Fig. 3 A to 3G's The porous plate 400 of porous plate 300 and Fig. 4 A to 4C) can be such as by as with reference to Fig. 8 to 9B The plate data reader being suitably equipped with that describes or pass through USB or be connected to calculating equipment (such as Computer) other cables be conductively coupled to processor.The graphic user interface of Fig. 5 A to 5D is coupling Run on this processor of plate, utilize the electronic card (such as electronic card 546 and 646) from plate It is supplied to the data of processor.This processor is configurable to only provide graphical user information, or its It is also configured as controlling the amount of the fluid being assigned in hole.

It should be understood that for providing the data of on-line monitoring to depend on by the strain gauge on plate (such as Strain gauge 344 and 444) measurement result of reference resistance that records, this reference measurement result is in monitoring Emptying aperture is corresponded essentially to during to the filling in hole.During once fluid is assigned to hole, electronic card is just by right The instruction of the volume adding the fluid in each hole is supplied to processor, thus promotes graphic user interface Function as described below.In certain embodiments, by the conjunction being positioned on the electronic card of plate Suitable element, would indicate that the analog data normalization of reference resistance and is converted to numerical data so that Processor receives the data being suitable for using in graphical user interfaces.

As found out, graphic user interface 500 is associated with planning experiment software (not shown), makes The detail of the experiment just carried out must be shown, the most in fact in the message box 502 of graphic user interface Test title, used material, the volume of liquid to be allocated, the upper and lower bound of volume, required precision (i.e. testing sensitivity) and any other suitable experiment parameter.As described below, message box 502 In the details that comprises provided a user with for remind user's material added improperly any one or The instruction of the standard in more holes.It should be understood that in certain embodiments, at distribution fluid The software run on equipment can correct amount to be allocated and spirit to be used based on these experiment parameters Sensitivity.

Based on the information provided from the electronic card of plate, graphic user interface 500 is the most just additionally included in Carry out the diagram 504 of the porous plate tested.The diagram 504 of plate includes multiple circle 506, each circle correspondence Hole (being shown in which to be 96 orifice plates) in plate and being represented by reference 508 and 510 respectively The instruction of row and column of plate.

The purpose that on-line monitoring fluid is added in plate is the volume of the promotion fluid to adding in plate Control in real time.Graphic user interface 500 allows user to monitor situation in real time, and initial in parameter After input to the incomplete automatization of control of process in the case of, it is allowed to come order system school as required Positive fluid volume or take other steps to compensate the incorrect volume in given bore.Generally, should Graphic user interface also provides for having reached target fluid volume or whether should be by other stream Body adds the figure instruction in plate.In certain embodiments, such as shown in Fig. 5 A to 5D, figure refers to Show and include filling pattern or color instruction so that the first filling pattern or color represent emptying aperture, and second fills out Fill pattern or color represent that wherein fluid volume is less than the hole of target fluid volume, the 3rd fill pattern or Color represent wherein fluid volume correct and in predetermined allowance equal to the hole of target fluid volume.? In some embodiments, use the 4th filling pattern or color to represent and wherein already more than target fluid body Long-pending hole.

Fig. 5 A illustrates the graphic user interface 500 before experiment starts.So, all of circle 506 have without filling pattern (or being in the first color), and this indicates emptying aperture.

Fig. 5 B illustrates the graphic user interface when fluid has begun to the row 1 being assigned to plate 500.As found out, diagram 504 in, corresponding to row 1 hole (hole Al, Bl, C1, Dl, El, Fl, Gl and H1) there is the second filling pattern (or being in the second color), at this with from dextrad Left-oblique diagonal illustrates, its instruction fluid volume in hole is less than target volume, and corresponds to Remaining circle 506 holding of row 2 to 12 is in pattern or the color of instruction emptying aperture.

(not shown) in certain embodiments, it is illustrated that 504 indicate that the fluid target body reached in hole Amass and must be added to the fluid volume in this hole.Such as, this can refer to by rolling on a circle 506 Pin realizes, such as, controlled by computer mouse, thus produces instruction and should join respective aperture In the pop-up box of volume.

Find out in figure 5 c, along with fluid is assigned to the carrying out in the hole of row 1, fill with the 3rd Pattern (or being in the 3rd color) represents corresponding to the great majority having reached target fluid volume Circle 512, is shown in which to reach the fine and close diagonal tilted from left to right of target volume for instruction.Logical Cross and would correspond to the circle 514 of hole C1 and be maintained at cornerwise second tilted from right to left and fill pattern In (or with identical color), it is illustrated that 504 also indicate and are also not reaching to target fluid in the C1 of hole Volume.

Alternatively, the fluid only determined after completing to distribute a fluid in hole in hole amount (and It not to carry out lasting or repeatedly determination when hole is filled, if but the most liquid continuous slow Ground distribution or with drop-wise dispensing) embodiment in, it is illustrated that 504 do not provide shown in such as Fig. 5 B Information.On the contrary, once liquid has been allocated, it is illustrated that 504 with the side similar to shown in Fig. 5 C Formula, indicates the hole that the volume of fluid wherein is volume required less than (or exceeding).

Fig. 5 D and Fig. 5 C is identical, but be a diagram that the deficiency when in order to correct initial and by other body Long-pending fluid is assigned in the C1 of hole so that the volume of fluid in the C1 of hole is equal to the target for experiment Graphic user interface after volume.As row 1 porose be correctly filled with target volume now Fluid, fills pattern (or the 3rd color) with the densification the cornerwise 3rd from left to right tilted and comes Representing corresponding circle 512, instruction has reached target volume.

Along with fluid is assigned in the hole in the additionally row of plate, it is illustrated that 504 change so that Mei Geyuan The volume of the fluid in the color instruction corresponding aperture of 506, thus the body to the fluid in each hole is provided Long-pending real-time instruction, and contribute to preventing the error of the volume of the fluid being added in hole.

In certain embodiments, by fluid incrementally, continue lentamente or same time-division continuously and healthily It is fitted in the institute porose 506 of plate.In such embodiments, it is illustrated that 504 once carry for institute is porose For to the similar instruction of instruction shown in Fig. 5 B, 5C and 5D rather than the most line by line Instruction.

The sectional drawing of graphic user interface is a diagram that referring now to Fig. 6 A and 6B, Fig. 6 A and 6B, should Graphic user interface is used for off-line monitoring according to the fluid in the porous plate of the teaching of embodiment herein Amount.

The graphic user interface 600 of Fig. 6 A and 6B and the graphic user interface 500 of Fig. 5 A to 5D Similarity be that graphic user interface runs on the processor coupled with plate, utilize by plate number According to other connectors may developed in reader or USB or currently known or future from the electronics of plate Card (such as electronic card 346 and 446) is supplied to the data of processor.Similarly, based on from The information that the electronic card of plate provides, graphic user interface 600 includes carrying out the most wherein testing many The diagram 604 of orifice plate.The diagram 604 of plate includes multiple circle 606, each circle corresponding in plate hole ( This is shown as 96 orifice plates) and the instruction of row and column of plate by reference 608 and 610 instruction.

But, during off-line monitoring, purpose is not to indicate to the user that the most distribution is suitable in hole When the fluid of volume, but the volume of the fluid in hole due to certain reason less than target volume or Less than providing alarm during predetermined threshold.So, graphic user interface 600 is not and planning experiment software Association, but to its input value, when this value, the volume that user should receive in hole does not conforms to Suitable instruction, such as, take the alarm of corrective action or voice or text notification.In certain embodiments, Described value is predetermined absolute value so that when the volume of the fluid in hole descends below predetermined, Graphic user interface 600 provides the instruction of the particular bore that volume is low.In certain embodiments, such as scheme Showing in embodiment, described value is the changing value of volume so that the graphic user interface 600 stream in hole The stereomutation of body is more than providing instruction during predetermined value.In its modification (not shown), can be at body Long-pending to provide instruction during more than certain percentage drop less than pre-determined reference value.For providing a user with instruction Value can be default value, or can by user based on experiment sensitivity or based on other consider Suitably set.

Find out in Fig. 6 A and 6B, difference fill pattern or color indicates different size of body Long-pending change, and provide legend 612 so that user can filling pattern based on circle 606 or face Color identifies to lose how many fluids in corresponding aperture.In the illustrated embodiment, cornerwise blank map The volume of the fluid in case instruction corresponding aperture is constant and equal to initial volume, chain-dotted line blank map Case indicates the change less than 1 microlitre of the volume of the fluid in corresponding aperture, and grid is filled pattern and referred to Show at least 1 microlitre of the volume of the fluid in corresponding aperture but be less than the change of 3 microlitres.

Graphic user interface 600 also includes one or more chart 614, wherein can draw out with The time and change, the volume of fluid in one or more particular bore.In certain embodiments, Information is displayed on the particular bore in chart 614 can be by user such as by making cursor of mouse point to spy Determine hole or select by keying in the mark (not shown) in hole in suitable text box.At some In embodiment, the information corresponding to each hole can show in chart 614 successively and/or repeatedly.

Generally, data reader or USB or other connectors of associating with the electronic card of plate are with fixing Speed (the most once a day, the most once, per minute once, per half a minute once or Even once per second) volume recorded in each hole is reported to processor.Definite speed can be by work Factory encodes in electronic card, or can be set according to the requirement of the experiment just carried out by user.

Turn to Fig. 6 A, it can be seen that the fluid volume in first time point T1, arbitrary hole does not has Change, the most all circles 606 are filled by the filling pattern (diagonal) corresponding to nominal volume.By The volume of the fluid in arbitrary hole is not changed in, and does not therefore have line chart to be present in chart 614.

Illustrating in Fig. 6 B being later than the graphic user interface of the second time point T2 of T1, can To find out, the fluid volume being instructed in hole corresponding to the circle 616 of hole CI, Dl and El less than 1 The filling pattern (point) of the change of microlitre is filled, corresponding to the circle 618 of hole A4, Bl, F 1 and Gl At least 1 microlitre of the fluid volume being instructed in hole but be less than the filling pattern (side of the change of 3 microlitres Lattice) fill.In the example presented in the figure, repeatedly reading based on the volume to the fluid in the A4 of hole, figure Table 614 depicts the time dependent line chart of the volume in the A4 of hole 620.

The sectional drawing of graphic user interface is a diagram that, this graphic user interface referring now to Fig. 7, Fig. 7 For off-line monitoring according to the temperature of the fluid in the porous plate of the teaching of embodiment herein.

The graphic user interface 700 of Fig. 7 is similar to the graphic user interface 600 of Fig. 6 A and 6B, but It is that graphic user interface 700 difference is that the filling pattern of circle 706 or (or color) represent The temperature of corresponding aperture that recorded by one or more temperature sensor of the part constituting plate, in plate Degree, and be one or more chart 714 can include one or more particular bore along with time Between change temperature profile.

In certain embodiments (such as shown in Fig. 7), there is the temperature sensor associated with each hole, And in other embodiments, the temperature sensor fewer than hole can be there is, but still there is multiple temperature Degree sensor.

Finding out as in Fig. 7, different temperatures is filled pattern (or color) by difference and is indicated, and Provide legend 712 so that user can identify based on the filling pattern (or color) of circle 706 In hole or neighbouring temperature is how many.

Find out in the figure 7, at time point T1, each hole have by correspondence circle 706 filling pattern refer to The specified temp shown.Such as, corresponding to the temperature of filling pattern indicator hole E1 of circle 706 of hole E1 It it is 39 DEG C.

In the example presented in the figure, chart 714 includes line chart 720, it is shown that the temperature at the A5 of hole is in time Change.

Generally, data reader or USB or other connectors of associating with the temperature sensor of plate are with solid Fixed speed (the most once a day, the most once, per minute once, per half a minute once or Person's even once per second) report in each hole to processor or the temperature of each sensor proximity.Really The speed cut can be encoded in electronic card by factory, or can be by user according to the reality just carried out The requirement tested sets.So, record by temperature sensor in data reader instruction, corresponding aperture The change of temperature time, the filling pattern (or color) of the circle 706 in graphic user interface 700 changes Become.

It should be understood that owing to hole receiving element 348 and hole restriction element 419 can be respective from it Plate 300 and 400 removes, and element 348 or element 419 can be utilized the most as mentioned above to obtain and measure As a result, then can remove element 348 or element 419 being inserted into and not have described in detail above Detector unit other, simpler plate (not shown) is used for storing, be such as stored in refrigeration In device or couveuse.In later moment, if it is desired to measurement additionally, then element 348 or element 419 can be respectively again insertable into plate 300 or 400.

Show that the teaching according to embodiment herein is construction and operation of referring now to Fig. 8, Fig. 8 Plate pedestal and the axonometric chart of data reader 800, it is for receiving from according to teaching herein The signal of porous plate.

As shown in Figure 8, plate pedestal and data reader 800 include pedestal 802, on pedestal 802 Be formed suitably shape and determine size for by porous plate (plate 200 that is such as outlined above, 300 or 400) framework 810 contained therein.In certain embodiments, substrate and digital independent Device 800 can form a part for optical instrument or imaging device, such as can be from Israel Lei Huowo The Hermes system that special Idea Bio-Medical company obtains (http://www.idea-bio.com/page-87-Hermes.aspx).In some such embodiments, Pedestal 802 can be transparent at least some illumination wavelengths, to allow to be arranged on number at plate According to passing through optical instrument or imaging device time in reader 800 to the imaging of samples in porous plate.

In certain embodiments, framework 810 includes for making plate keep stablizing and at data reader Immovable maintaining body in 800.In certain embodiments, maintaining body includes the framework with plate The outthrust 812 engaged, outthrust 812 can be retracted into frame the most under spring force In frame 810.So, when plate is inserted in data reader 800 by user, plate is promoted and leans on by user Outthrust 812, cause outthrust 812 to be retracted in framework 810.Once user stops promoting plate, Such as when plate is in suitable position, spring pushes out outthrust 812 so that outthrust 812 Engage plate and keep the plate in data reader 800.In certain embodiments, maintaining body Can include for being combined in by board in the position of data reader 800, that plate can be made to lean against is thereon The mechanism at edge etc..

In certain embodiments, framework 810 includes recess 814, in order to when user wishes to remove plate Help user to grasp and be arranged on the plate in framework 810.Can also use and be adapted to assist in plate from framework 810 Other mechanisms removed, such as ejector button.

Framework 810 also includes that electricity port 820, electricity port 820 are positioned and configured to electric interlock and are arranged on The corresponding ports on plate in data reader, the port of the port 358 or Fig. 4 B of such as Fig. 3 B 458.Electricity port 820 is also connected electrically to processor (not shown), for the information from plate being provided To processor, such as in order to for the special-purpose software (experiment such as described referring below to Fig. 5 A to 7 Planning software or Graphic User Interface software) use.

It is for hole receiving element or hole are limited element referring now to Fig. 9 A and 9B, Fig. 9 A and 9B Remove from porous plate and/or for by such component placement device porous plate, this device according to The teaching of embodiment herein and construct and operate.

Find out in Fig. 9 A and 9B, for handle hole receiving element (such as element 330) or Handle hole limit element (such as element 419) device 900 functionally with plate bearing base 902 phase Association, plate bearing base 902 is arranged as having the porous plate 904 being disposed therein.Plate bearing base 902 can be data reader and pedestal (data reader being such as described below and pedestal 800), Or can be the simple pedestal supporting porous plate as illustrated in figures 9a and 9b.

Arranging porose bonding part 906 on plate supporting base 902, bonding part, hole 906 can be moved It is installed on vertical dislodgment feature 908 dynamicly.Vertical dislodgment feature 908 is configured to allow junction surface, hole 906 are divided vertically to shift toward and away from the plate 904 being arranged on plate bearing base 902.At some In embodiment, vertical dislodgment feature 908 includes electrical installation 910 and can be along installed part 910 Vertical movement can displacing part 912 so that bonding part, hole 906 is arranged on can displacing part 912 Go up and can therewith shift.

Be arranged on the lower surface 914 of bonding part, hole 906 is multiple holes connecting protrusion 916, Each hole connecting protrusion is configured to be contained in be placed to the hole restriction element in plate 904 or hole receiving Remove in the hole of element one or from the plate 904 for being attached with it.In certain embodiments, Hole connecting protrusion 916 engages corresponding aperture by snap fastener, but it is also contemplated that other joint sides Method, such as, pass through vacuum.

It is placed in plate 904 to hole be limited element or hole receiving element, hole connecting protrusion 916 Engage hole and limit element or hole receiving element, and then bonding part, hole 906 is vertical towards plate 904 Ground displacement until hole limit element or hole receiving element coordinate its in plate 904 (such as at plate 300 Section 352 in or in the hole support component 430 of plate 400) correct position.Then, hole connects Close outthrust 916 and limit element or hole receiving element debonding, and bonding part, hole 906 with hole Vertically shift away from plate 904 so that in described element is suitably disposed plate 904 and can For reagent is plugged into.

Remove from plate 904 to hole be limited element or hole receiving element, bonding part, hole 906 towards Plate 904 vertically shifts until the hole being positioned at plate 904 limits element or hole receiving element is joined to hole Connecting protrusion 916.Bonding part, hole 906 is together with hole connecting protrusion 916 and engages Hole away from plate 904 vertical movement, cause hole limiting element or hole receiving element from it at plate 904 Interior position removes.When bonding part, hole fully shifts from plate 904, hole connecting protrusion 916 Then element or hole receiving element debonding are limited with hole.

It should be understood that and similar device can be used to engage suction nozzle etc. and for by fluid (example Such as reagent) it is assigned in the hole in plate 904.

Be described below is can be with porous plate (as described herein in reference to Fig. 2 A to 4C Plate) modification of structure that is used together and is used together with other porous plate in some cases with And use the modification of the method for these plates.

Above-mentioned plate uses hole to be assigned in one or more hole along the physical displacement of Z axis to determine The volume of fluid.In the above-described embodiments, such physical displacement is coupled in strain gauge, to produce The signal relevant to shift amount and the volume of fluid that is thus assigned in the hole under observing (assuming that The fluid of known density and quality occupies the volume that can determine that).However, it should be understood that replace strain The use or in addition of meter, can use additive method to determine volume.

It is therefoie, for example, if there is the porous plate in the hole that can shift in z-axis with have the most right The reading device of focusing mechanism is used in combination, then this is determined for the displacement in hole.Entitled The U.S. of " Auto-focusing method and device for use with optical microscopy " Patent the 7th, 109,459 describes the example of this autofocus mechanism, by way of reference by it Content is expressly incorporated herein.

In order to illustrate, the porous plate of shift holes can be incorporated into having there is autofocus mechanism Reading device (such as can obtain from the Idea Bio-Medical company of Rehovot, Israel Wiscan^TMScanner) in.By autofocus mechanism is combined with suitable feed back control system, The bottom of target hole can be arranged to identical height before distribution fluid.Then fluid can be divided It is fitted in hole；It should be understood that in some cases, this can be in the situation that plate does not moves to another location Complete online down, and in other cases, plate may need to be moved to distribution station.At distribution fluid Afterwards, autofocus mechanism (if desired after plate returns automatic focusing position) can be again with, Determine hole motion in z-axis specifically；As it has been described above, this information can be subsequently used in determine allocated The amount of the fluid in one or more hole.Determine furthermore, it is possible to obtain periodic measurement result One or more hole the most such as loses fluid due to evaporation.As it has been described above, the method is permissible For with single hole or there is groups of hole.As noted, the method can be combined with strain gauge and make With or replace strain gauge use, to determine the displacement in one or more hole.

Owing to utilizing method described above, the stream of the incorrect amount in hole or in groups of hole The detection of body contributes to the amount of the fluid in correction hole, contributes to hole from further operation and/or meter Calculation is got rid of, and contributes to correction calculating in certain embodiments.

For determining that the other method of the amount of the fluid lost in hole relates to periodically monitoring the temperature of separate openings Degree.Generally, the temperature of the porous plate comprising living cells is maintained at 37 DEG C.But, the heat in couveuse Distribution is probably uneven, or other factors may cause the uneven Temperature Distribution in plate, This may cause the different fluid loss in different hole and may negatively affect cell therein.Logical Cross the temperature in periodically (such as one hour once) single hole of tracking measurement and by considering The character of the fluid in hole, it may be determined that the amount of the fluid lost as time goes by hole, and And can such as utilize the heating or cooling units being outlined above to carry out the temperature in correction hole.By inciting somebody to action Individually temperature sensor is placed at each hole and can promote this (such as bottom it or on sidepiece) Plant monitoring.Such sensor can be conductively coupled to card (the most above-mentioned 346 or 446), to promote Reading in data reader.Alternately, one or more thermal imaging system can be used to carry out the cycle Property detection separate openings temperature.

Owing to utilizing method described above, the stream of the incorrect amount in hole or in groups of hole The detection of body contributes to the amount of the fluid in correction hole, contributes to hole from further operation and/or meter Calculation is got rid of, and contributes to correction calculating in certain embodiments.Can be along z-axis in the hole of plate In the case of displacement, the method can be used in combination with strain gauge or replace strain gauge to use, with And be used in combination with the method utilizing autofocus mechanism as above or replace it to use.But, The method that should be understood that and utilize strain gauge or automatic focusing mechanism is different, and the method may be used for wherein The plate that hole can not shift.

Should be understood that the embodiment shown in accompanying drawing is for illustration purposes only, within the scope of the invention may be used Imagine these modification.Such as, the quantity in the hole of each plate, the shape in hole and material therefor may From shown herein or that specifically describe those are different, be used for detecting fluid be added into plate or from The unit removed in plate may also be such.Additionally, each hole can include other layer or inserts, Such as hole inserts, cell grows wherein and makes it possible to add reagent be used for the most directly engaging inserts Make agent penetration to the environment in the hole in hole in the case of the cell of middle growth.

Should be understood that for some of the clear and present invention described in the context of separate embodiment Feature can also provide in combination in single embodiment.On the contrary, in order to briefly and in single embodiment Context described in the different characteristic of the present invention can also be individually or with any suitable subgroup Incompatible offer or suitably time provide in any other embodiment described of the present invention.Different enforcements Some features described in the context of example are not considered as the essential feature of those embodiments, unless In the case of those elements each, embodiment can not be implemented.

Although the specific embodiment already in connection with the present invention describes the present invention, but it is clear that for ability For field technique personnel, many changes, modifications and variations can be apparent from.Correspondingly, its purport Comprising all these changes, modifications and variations fallen within the scope of the appended claims.

In the quoting or mark of any reference content in the application is not necessarily to be construed as recognizing this reference Holding is prior art for the present invention.

Chapter title is used for making it easy to understand description in this article, and is not necessarily to be construed as necessity Limit.

Claims

1. a plate, including:

First substantially flat surface, it has and is limited at least one first aperture therein；

Second substantially flat surface, it is substantially parallel with described first substantially flat surface, and described second Substantially flat surface is spaced with described first substantially flat；

In described plate limit at least one hole, at least one hole described have with described at least one An aperture correspondence in first aperture and the second aperture of alignment, at least one hole described has sidewall And bottom, and at least one hole described from described first substantially flat surface towards described second basic Flat surfaces extends, and at least one hole described can shift outwardly away from described first substantially flat；With

At least one signal provider, it is functionally associated with at least one hole described, it is possible to response Signal is produced away from the displacement of described first surface at least one hole described.

2. plate as claimed in claim 1, wherein:

Described first surface has and is limited to multiple first aperture therein；With

Defining multiple hole in described plate, each hole has and restriction in described first surface The first aperture in the plurality of first aperture is corresponding and the second aperture of alignment, each in described hole Hole all has sidewall and a bottom, and each hole from described first substantially flat surface towards described second Substantially flat surface extends.

3. plate as claimed in claim 2, wherein, each Kong Douke in the plurality of hole is away from institute State the first substantially flat to shift outwardly.

4. a porous plate, including:

First substantially flat surface, it has and is limited to multiple first aperture therein；

The multiple holes limited in described plate, each hole has and the institute limited in described first surface Stating the second aperture that an aperture in the first aperture is corresponding and aligns, each hole in described hole has Have sidewall and a bottom, and each hole from described first substantially flat surface towards described second the most flat Smooth surface extends, and each Kong Douke in described hole moves outwardly away from described first substantially flat Position；With

At least one signal provider, it is functionally associated with the plurality of hole, and described signal provides Device can produce signal in response to hole at least one described away from the displacement of described first surface.

Plate the most according to any one of claims 1 to 4, wherein, described first surface and described Two surfaces are spaced by multiple sidewalls of extension between described first surface and described second surface Open.

6. the plate as according to any one of claim 2 to 5, wherein, movement all couplings in all described holes Close so that described signal provider can be in response to any one in described hole or the shifting in more hole Position and individual signals is provided.

7. the plate as according to any one of claim 2 to 5, wherein, the shifting of the some holes in described hole Move and be coupled in two or more groups, and at least one signal provider described includes multiple signal Provider, each signal provider can provide signal in response to the displacement of a group in described group.

8. the plate as according to any one of claim 2 to 5, wherein:

At least one signal provider described includes multiple signal provider, each signal provider and institute State in multiple hole hole to be associated；

Each hole in the plurality of hole can shift away from described first surface independently；With

Each signal provider in the plurality of signal provider can be in response to the plurality of Kong Zhongyu The displacement in its hole being associated and signal is provided.

9. the plate as according to any one of claim 1 to 8, wherein, at least one signal described provides Device can provide signal in response to being inserted by the material of following amount in described hole: the material of 300 milligrams, The material of 250 milligrams, the material of 200 milligrams, the material of 150 milligrams, the material of 100 milligrams, 75 millis Gram material, the material of 50 milligrams, the material of 45 milligrams, the material of 40 milligrams, the material of 35 milligrams, The material of 30 milligrams, the material of 25 milligrams, the material of 20 milligrams, the material of 15 milligrams, 10 milligrams Material, the material of 5 milligrams, the material of 4 milligrams, the material of 3 milligrams, the material of 2 milligrams, or 1 Material, the material of 500 micrograms (μ g), the material of 300 μ g, the material of 200 μ g or the 100 μ g of milligram Material.

10. the plate as according to any one of claim 1 to 9, wherein, at least one signal described carries In response to being inserted by the fluid of following amount, described hole can provide signal for device: 300 microlitres (μ l) Fluid, the fluid of 250 μ l, the fluid of 200 μ l, the fluid of 150 μ l, the fluid of 100 μ l, 75 μ l Fluid, the fluid of 50 μ l, the fluid of 45 μ l, the fluid of 40 μ l, the fluid of 35 μ l, the fluid of 30 μ l, The fluid of 25 μ l, the fluid of 20 μ l, the fluid of 15 μ l, the fluid of 10 μ l, the fluid of 5 μ l, the stream of 4 μ l Body, the fluid of 3 μ l, the fluid of 2 μ l, the fluid of 1 μ l, the fluid of 0.5 μ l, the fluid of 0.3 μ l, 0.5 μ l Fluid or the fluid of 0.1 μ l.

11. plates as according to any one of claim 1 to 10, wherein, described signal provider can Signal is provided towards the displacement of described first surface in response to hole at least one described.

12. plates as according to any one of claim 1 to 11, wherein, at least one signal described carries Signal can be provided in response to being removed from described hole by the material of following amount: the material of 300 milligrams for device Material, the material of 250 milligrams, the material of 200 milligrams, the material of 150 milligrams, the material of 100 milligrams, The material of 75 milligrams, the material of 50 milligrams, the material of 45 milligrams, the material of 40 milligrams, 35 milligrams Material, the material of 30 milligrams, the material of 25 milligrams, the material of 20 milligrams, the material of 15 milligrams, 10 The material of milligram, the material of 5 milligrams, the material of 4 milligrams, the material of 3 milligrams, the material of 2 milligrams, Or the material of 1 milligram, the material of 500 micrograms (μ g), the material of 300 μ g, the material of 200 μ g, Or the material of 100 μ g.

13. plates as according to any one of claim 1 to 12, wherein, described signal provider can Signal is provided in response to being removed from described hole by the fluid of following amount: the fluid of 300 microlitres (μ l), The fluid of 250 μ l, the fluid of 200 μ l, the fluid of 150 μ l, the fluid of 100 μ l, the fluid of 75 μ l, 50 μ l Fluid, the fluid of 45 μ l, the fluid of 40 μ l, the fluid of 35 μ l, the fluid of 30 μ l, the fluid of 25 μ l, The fluid of 20 μ l, the fluid of 15 μ l, the fluid of 10 μ l, the fluid of 5 μ l, the fluid of 4 μ l, the fluid of 3 μ l, The fluid of 2 μ l, the fluid of 1 μ l, the fluid of 0.5 μ l, the fluid of 0.3 μ l, the fluid of 0.2 μ l or 0.1 μ l Fluid.

14. plates as according to any one of claim 1 to 13, wherein, at least one in described plate Described in Kong Kecong, plate removes.

15. plates as according to any one of claim 1 to 14, wherein, described plate includes and described hole In at least one temperature sensor that is associated of at least one hole.

16. plates as claimed in claim 15, wherein, described temperature sensor is positioned in described hole Among or on one hole.

17. plates as described in claim 15 or 16, wherein, at least one temperature sensor described is joined It is set to provide the signal representing the temperature at least one hole described or near at least one hole described.

18. plates as claimed in claim 17, wherein, at least one temperature sensor described is configured to Temperature in detection at least one hole described constantly, and the institute representing described temperature is periodically provided State signal.

19. plates as according to any one of claim 1 to 18, also include electronic storage element, described Electronic storage element is passed by least one signal provider described and at least one temperature described for storage At least one signal that at least one in sensor provides.

20. plates as according to any one of claim 15 to 19, wherein, at least one temperature described Sensor configuration is to detect the temperature in one group of hole in the plurality of described hole.

21. plates as according to any one of claim 15 to 19, wherein, at least one temperature described Sensor include being configured to detection porose in the single temperature sensor of temperature.

22. plates as according to any one of claim 15 to 19, wherein, at least one temperature described Sensor includes multiple temperature sensor, each temperature sensor and a hole phase in the plurality of hole Association, for the temperature detected in the plurality of hole in one hole associated there.

23. plates as according to any one of claim 1 to 22, also include and at least one hole phase described Association at least one heater block, at least one heater block described be located close enough to described at least One hole is to be internally heated at least one hole described or at least one hole described.

24. plates as claimed in claim 23, wherein, at least one heater block described includes multiple Heater block, each heater block is associated with a hole in the plurality of hole and is positioned at enough Close to one hole associated there, with other holes in not heating the plurality of hole In the case of one hole or one hole are internally heated.

25. plates as described in claim 23 or 24, wherein, at least one heater block described includes Heating coil.

26. plates as described in claim 23 or 24, wherein, at least one heater block described can also Enough coolings at least one hole described.

27. plates as claimed in claim 26, wherein, described heater block includes peltier device.

28. plates as according to any one of claim 23 to 27, wherein, at least in described plate The described heater block being associated with at least one removable hole described is not being moved by individual hole from described plate Can remove from described plate in the case of removing.

29. plates as according to any one of claim 23 to 27, wherein, at least in described plate Plate described in individual Kong Kecong removes, and the described heating being associated with at least one removable hole described Parts are attached at least one hole described or integral formed and can therewith remove.

30. plates as according to any one of claim 1 to 29, also include electricity port, its functionally with At least one at least one signal provider described and at least one temperature sensor described is correlated with Connection.

31. plates as according to any one of Claim 1-3 0, also include chargeable electric supply installation, Its functionally with at least one signal provider described and at least one temperature sensor described at least One is associated, and is configured to pass and is connected to power supply and charges.

32. plates as claimed in claim 31, wherein, described chargeable electric supply installation is configured to Described electricity port is electrically connected to charging during described power supply.

33. 1 kinds of data readers, it is configured to according to according to any one of claim 30 to 32 Plate contained therein, described data reader includes:

Pedestal, for being placed on it described plate；

Corresponding with the described electricity port of described plate, for the electric port of its electric interlock；With

The processor being functionally associated with described electricity port, for processing by described electricity port from institute State the signal that at least one in signal provider and described temperature sensor obtains.

34. data readers as claimed in claim 33, wherein, described processor is configured to pass Described electricity port directly at least one from described signal provider and described temperature sensor obtains institute State signal.

35. data readers as claimed in claim 33, wherein, described processor is configured to from electricity Sub-memory unit obtains described signal, and described electronic memory component stores by described signal provider and institute State at least one signal that at least one in temperature sensor provides.

36. data readers as according to any one of claim 33 to 35, also include functionally with The display that described processor is associated, described display is configured to provide a user with the letter from treated Number obtain information.

37. data readers as claimed in claim 36, wherein, described information includes following The instruction of at least one in Xiang:

The amount of the fluid in plate described in special time；

The amount of the fluid at least one described hole of special time；

The change over a period of the amount of the fluid in described plate；

The change over a period of the amount of the fluid at least one described hole；

Temperature at least one described hole of special time；With

The change over a period of the temperature at least one described hole.

38. data readers as claimed in claim 37, wherein, described processor is configured in real time Process described signal, and described display is configured to provide in real time to user described information.

39. data readers as according to any one of claim 22 to 38, are provided with root wherein According to the plate according to any one of claim 1 to 21 and 40 to 48.

40. 1 kinds of plates, including:

At least one hole limited in described plate, at least one hole described has and at described first table An aperture correspondence at least one first aperture described limited in face and the second aperture of alignment, At least one hole described has sidewall and a bottom, and at least one hole described is from described first the most flat Smooth surface extends towards described second substantially flat surface；With

At least one heater block being associated with at least one hole described, its be positioned at sufficiently close to described At least one hole is with heating at least one hole described or the inside at least one hole described.

41. plates as claimed in claim 40, wherein:

Described first surface has and is limited to multiple first aperture therein；

At least one hole described is included in described plate the multiple holes limited, each hole have with described A first aperture correspondence and the second of alignment in the plurality of first aperture limited in first surface Aperture, each hole in described hole has sidewall and a bottom, and each hole is from described first the most flat Smooth surface extends towards described second substantially flat surface；With

At least one heater block described includes multiple heater block so that each hole tool in described hole There is a heater block associated there in the plurality of heater block, every in described heater block Individual heater block is located close enough to the described hole being associated with described heater block, to be substantially not added with Described hole or described hole are internally heated in the case of other holes by heat.

42. plates as described in claim 40 or 41, wherein, described heater block includes heating coil.

43. plates as described in claim 40 or 41, wherein, described heater block can also cool down institute State hole.

44. plates as claimed in claim 43, wherein, described heater block includes peltier device.

45. plates as according to any one of claim 40 to 44, wherein, at least in described plate The described heater block being associated with at least one removable hole described is not being moved by individual hole from described plate Can remove from described plate in the case of removing.

46. plates as according to any one of claim 40 to 44, wherein, at least in described plate Plate described in individual Kong Kecong removes, and the described heating being associated with at least one removable hole described Parts are attached at least one hole described or integral formed and can therewith remove.

47. plates as according to any one of claim 40 to 46, described plate is also according to claim 1 To the plate according to any one of 32.

48. plates as according to any one of claim 40 to 46, described plate is not according to claim 1 To the plate according to any one of 32.

49. 1 kinds join according to the plate according to any one of Claim 1-3 2 and 47 for measurement In the method for amount of fluid, including:

The initial signal that record is provided by signal provider；With

After fluid being added at least one hole in described plate, it is thus achieved that provided by described signal The secondary signal that device produces in response to the addition of described fluid,

Wherein, the amount joining the described fluid at least one hole described can be based on described initial letter Number and described secondary signal between difference calculate.

50. methods as claimed in claim 49, after being additionally included in the initial signal of described record and Before described acquisition secondary signal, add a fluid in described plate.

51. methods as described in claim 49 or 50, also include based on described initial signal and described Difference between secondary signal, calculates the amount of the described fluid joined at least one hole described.

52. methods as claimed in claim 51, wherein, calculate described amount and include calculating the following In at least one: (a) joins the volume of the described fluid at least one hole described, and (b) adds Quality to the described fluid at least one hole described；C () joins the described of at least one hole described The volume of fluid and quality.

53. 1 kinds for measure from according to according to any one of claim 1 to 22 and 47 containing orifice plate The amount of the fluid lost, described plate has the stream of the primary quantity at least one hole being placed on described plate Body, described method includes:

The initial signal that record is provided in the very first time by signal provider；

Described signal is obtained from described signal provider in the second time being later than the described very first time；With Based on the difference between described initial signal and described secondary signal, calculate from described in described plate The amount of the described fluid that at least one hole loses.

54. methods as claimed in claim 53, wherein, calculate described amount and include calculating the following In at least one: the volume of the described fluid that (a) loses from least one hole described, (b) is from institute State the quality of the described fluid that at least one hole loses；C () loses from least one hole described described in The volume of fluid and quality.

55. methods as according to any one of claim 53 to 54, also include:

It is repeated cyclically the step of described acquisition signal；With

Based on the difference between the signal that the time different at two obtains, calculate in said two different The amount of the fluid lost from least one hole described in the persistent period between the time.

56. a method, including:

The reference measurement result of the displacement at least one hole in acquisition porous plate, is arranged in described plate Have displacement measurement assembly, institute's displacement measurement assembly for measure at least one hole in described plate, The displacement produced in response to the change of amount of the fluid at least one hole described, described reference measurement Result is obtained by institute's displacement measurement assembly；

A time after the described reference measurement result of acquisition, it is thus achieved that the position at least one hole described The second measurement result moved；With

Based on described second displacement measurement, the change of the amount of the fluid in calculating at least one hole described Change.

57. 1 kinds of methods, comprising:

In the very first time, it is thus achieved that the displacement datum measurement result at least one hole in porous plate, in institute Stating and be provided with displacement measurement assembly in plate, institute's displacement measurement assembly is used for measuring in described plate at least One hole, the displacement that produces in response to the change of amount of the fluid at least one hole described, institute State reference measurement result to be obtained by institute's displacement measurement assembly；

In the second time being later than the very first time, measure the described displacement at least one hole described；With

Based on the change in the displacement between the described very first time and the second time, described in calculating at least one The change of the amount of the fluid in individual hole,

Wherein, at least one time in the described very first time and the second time, deposit in the hole Fluid in detectable amount.

58. methods as claimed in claim 57, also include:

It is repeated cyclically the described step of described displacement at least one hole described in the second measure of time； With

Based on the change in the displacement between two described displacement measurement, calculate described at least one Change during the amount of the fluid in the hole time period between said two displacement measurement.

59. methods as according to any one of claim 56 to 58, wherein, the amount of described fluid Described change produces owing to adding fluid at least one hole described.

60. methods as according to any one of claim 56 to 58, wherein, the amount of described fluid Described change produces owing to losing fluid from least one hole described.

61. methods as according to any one of claim 56 to 60, wherein, described plate is according to power Profit requires the plate according to any one of 1 to 32 and 47.

62. methods as according to any one of claim 51 to 61, wherein, described signal provider The change of the following amount of the volume of the sensitiveest fluid to detect at least one hole described: 300 Microlitre (μ l), 250 μ l, 200 μ l, 150 μ l, 100 μ l, 75 μ l, 50 μ l, 45 μ l, 40 μ l, 35 μ l, 30 μ l, 25 μ l, 20 μ l, 15 μ l, 10 μ l, 5 μ l, 4 μ l, 3 μ l, 2 μ l, 1 μ l, the fluid of 0.5 μ l, The fluid of 0.3 μ l, the fluid of 0.2 μ l or the fluid of 0.1 μ l.

63. methods as according to any one of claim 51 to 62, wherein, described signal provider The change of the following amount of the quality of the sensitiveest fluid to detect at least one hole described: 300 milligrams (mg)、250mg、200mg、150mg、100mg、75mg、50mg、45mg、40mg、 35mg、30mg、25mg、20mg、15mg、10mg、5mg、4mg、3mg、2mg、1mg、 500 micrograms (μ g), 300 μ g, 200 μ g or 100 μ g.

64. methods as according to any one of claim 51 to 63, also include detecting at least one hole In temperature.

65. methods as described in claim 64, are additionally included at least two different time points and detect institute State the described temperature at least one hole.

66. methods as described in claim 64 or 65, also include adjusting in response to the described temperature of detection Save the temperature in single hole.

67. the method as according to any one of claim 51 to 66, wherein, in described porous plate Porous plate described at least one Kong Kecong removes.