CN107894512A - Portable sample analyzer cartridge - Google Patents

Portable sample analyzer cartridge Download PDF

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Publication number
CN107894512A
CN107894512A CN201711011147.0A CN201711011147A CN107894512A CN 107894512 A CN107894512 A CN 107894512A CN 201711011147 A CN201711011147 A CN 201711011147A CN 107894512 A CN107894512 A CN 107894512A
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China
Prior art keywords
sample
fluid
box
flow
blood
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Pending
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CN201711011147.0A
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Chinese (zh)
Inventor
P.L.罗伊蒂曼
A.帕马纳班
J.A.科克斯
R.L.巴德尔
T.M.雷扎彻克
C.卡布斯
B.S.弗里茨
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Honeywell International Inc
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Honeywell International Inc
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Publication of CN107894512A publication Critical patent/CN107894512A/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/08—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Dispersion Chemistry (AREA)
  • Ecology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

The application is related to portable sample analyzer cartridge.It is a kind of to be related to sample analyser, be more particularly to system that is simple to operate and reducing the dangerous sample analyser that error result is provided to user.In some cases, sample analyser can be the portable sample analyzer for including disposable fluid box.The operator of analyzer needs not move through training.

Description

Portable sample analyzer cartridge
It is on December 22nd, 2006, Application No. 200680053092.3, entitled " portable style the applying date that the application, which is, The divisional application of the application for a patent for invention of product analysis box ".
The rights and interests for the U.S. Provisional Patent Application 60/753,293 submitted this application claims on December 22nd, 2005.
The rights and interests for the U.S. Provisional Patent Application 60/755,014 submitted this application claims on December 29th, 2005.
The application is the part continuation application for the U.S. Patent Application No. 10/908,460 submitted on May 12nd, 2005, its It is required that the rights and interests for the U.S. Provisional Application 60/571,235 that on May 14th, 2004 submits.
The application is the part continuation application for the U.S. Patent Application No. 10/908,461 submitted on May 12nd, 2005, its It is required that the rights and interests for the U.S. Provisional Application 60/571,235 that on May 14th, 2004 submits.
The application is the part continuation application for the U.S. Patent Application No. 11/306,508 submitted on December 30th, 2005, institute State the continuation-in-part application that application is the U.S. Patent Application No. 10/950,898 that September in 2004 is submitted on the 27th.
The application is the part continuation application for the U.S. Patent Application No. 10/938,265 that September in 2004 is submitted on the 9th.
The U.S. Provisional Patent Application 60/753,293 that on December 22nd, 2005 submits is incorporated herein by reference. The U.S. Provisional Patent Application 60/755,014 that on December 29th, 2005 submits is incorporated herein by reference.In May, 2005 The U.S. Patent Application No. 10/908,460 submitted for 12nd is incorporated herein by reference.On May 12nd, 2005 U.S. submitted State's number of patent application 10/908,461 is incorporated herein by reference.On December 30th, 2005 U.S. Patent Application No. submitted 11/306,508 is incorporated herein by reference.The U.S. Patent Application No. 10/950,898 that September in 2004 is submitted on the 27th is logical Reference is crossed to be incorporated herein in.The U.S. Patent Application No. 10/938,265 that September in 2004 is submitted on the 9th is incorporated by reference into this Wen Zhong.
Technical fieldthe present application relates in general to sample analyser, and more particularly to simple to operate and reduction provides mistake As a result dangerous sample analyser.
Background technology
Chemistry and/or biological analysis are for life science, clinical diagnosis and a variety of environment and process monitoring aspect It is all critically important.In some cases, carry out and/or aid in carry out the chemistry and/or biology of sample fluid with sample analyser Analysis.According to purposes, sample fluid can be liquid or gas.
Many sample analysers are the sizable equipment used by professional in laboratory environment.In order that with many Sample analyser, before it will prepare sample and be used for sample analyser, it is necessary to handle the sample of collection first, such as dilute sample Extremely required level, add suitable agent, sample centrifugation is completed required separation etc..In order to obtain accurate result, it is often necessary to by Professional carries out such sample treatment, and this may increase the expense for carrying out sample analysis needs and time.
Many sample analysers also need to operator intervention in the analysis phase, handle if desired for input additional information or in addition sample Product.This can also increase expense and the time that sample analysis needed for progress needs.Moreover, many sample analysers only provide it is original Analyze data exports, it is often necessary to calculated and/or explained again by professional just draw suitable clinic or itself it is judged that.
The U.S. Provisional Patent Application 60/753,293 that on December 22nd, 2005 submits is incorporated herein by reference. The U.S. Provisional Patent Application 60/755,014 that on December 29th, 2005 submits is incorporated herein by reference.In May, 2005 The U.S. Patent Application No. 10/908,460 submitted for 12nd is incorporated herein by reference.On May 12nd, 2005 U.S. submitted State's number of patent application 10/908,461 is incorporated herein by reference.On December 30th, 2005 U.S. Patent Application No. submitted 11/306,508 is incorporated herein by reference.The U.S. Patent Application No. 10/950,898 that September in 2004 is submitted on the 27th Part continuation application is incorporated herein by reference.The U.S. Patent Application No. 10/938,265 that September in 2004 is submitted on the 9th is logical Reference is crossed to be incorporated herein in.
The content of the invention
This patent disclosure relates generally to sample analyser, it is more particularly to simple to operate and reduce give user provide mistake As a result dangerous sample analyser.In some cases, sample analyser can be portable comprising disposable fluid box Sample analyser.
The present invention can include embodiments below：
A kind of 1. sample analyzer cartridge of scheme, the sample analyzer cartridge include：
At least one flow channel；And
Wherein：
Flow channel includes the volume in one or more walls and passage；
Two or more electrodes are located on one or more walls of flow channel；And
Described two or multiple electrodes can be connected with signal source.
The box of the scheme 1 of scheme 2., wherein：
The voltage and current feature of the signal source of spaning electrode indicates the resistivity of the volume；
Suitable fluid be present in resistivity instruction volume in particular range；
Incorrect reagent be present in resistivity instruction fluid not in particular range, bubble be present and/or can not connect The characteristic of fluid received；And
Resistivity not in particular range causes sample analyser not provide analysis result or instruction mistake.
The box of the scheme 1 of scheme 3., wherein：
The voltage and current feature of the signal source of spaning electrode indicates the resistance of the volume；
Correct fluid be present in resistance instruction volume in particular range；
Not in particular range resistance instruction fluid in exist exist in incorrect fluid reagent, volume bubble and/ Or unacceptable characteristic of fluid in volume；And
Resistance not in particular range causes sample analyser not provide analysis result or instruction mistake.
The box of the scheme 1 of scheme 4., wherein：
The voltage and current feature of the signal source of spaning electrode indicates the electric capacity of the volume；
Suitable fluid be present in electric capacity instruction volume in particular range；
Incorrect reagent be present in electric capacity instruction fluid not in particular range, bubble, incorrect fluid be present And/or unacceptable characteristic of fluid；And
Electric capacity not in particular range causes sample analyser not provide analysis result, the incorrect fluid of instruction or refer to Show mistake.
A kind of 5. sample analyzer cartridge of scheme, the sample analyzer cartridge include：
At least one flow channel；And
Wherein sensor is located in flow channel.
The box of the scheme 5 of scheme 6., wherein：
Sensor is PH sensor；
The PH that signal designation from PH sensor measures in flow channel；And
It whether there is suitable fluid in the PH instruction flow channels of measurement.
The box of the scheme 5 of scheme 7., wherein：
Sensor is thermal conductive sensor；
The thermal conductivity that signal designation from thermal conductive sensor measures in flow channel；And
It whether there is suitable fluid in the thermal conductivity instruction flow channel of measurement.
The box of the scheme 5 of scheme 8., wherein：
Sensor is specific heat sensor；
The specific heat that signal designation from specific heat sensor measures in flow channel；And
It whether there is suitable fluid in the specific heat instruction flow channel of measurement.
A kind of 9. box of scheme, the box include：
At least one flow channel；With
The time marker being connected with box；And
Wherein event causes time marker to work.
The box of the scheme 9 of scheme 10., wherein：
In box is originally located in and packed；And
The event is to take out the box from packaging, and the event starts time timing of the time marker to consumption.
The box of the scheme 10 of scheme 11., if wherein consumption time be more than the acceptable time, by box inserting instrument Afterwards, the sample analyser of card and instrument composition can without analysis, result is not provided and/or wrong instruction will be provided.
The box of the scheme 9 of scheme 12., wherein：
Time marker has band covering；And
The event is to remove band from time marker, and the event starts time timing of the time marker to consumption.
The box of the scheme 12 of scheme 13., if wherein consumption time be more than the acceptable time, by box inserting instrument Afterwards, the sample analyser of card and instrument composition can without analysis, result is not provided and/or wrong instruction will be provided.
The box of the scheme 9 of scheme 14., wherein：
Time marker is to maintain correct time and the clock chip on date；And
The event is that the event causes the age of clock chip indication box by box inserting instrument.
The box of the scheme 14 of scheme 15., wherein the age such as compartmentalized box for holding assorted fruits and candies is unacceptable, then by after box inserting instrument, sample analysis Instrument can without analysis, result is not provided and/or wrong instruction will be provided.
The box of the scheme 9 of scheme 16., wherein time marker have the change colour band of instruction time amount.
A kind of 17. box of scheme, the box include：
Flow channel；With
Spring driving lancet；And
Wherein：
Lancet is inclined to extension bit；
Lancet is locked in retraction position until release by release device；And
Blood sample is transported in box by lancet.
The box of the scheme 17 of scheme 18., wherein lancet have scale, the depth of lancet when being discharged for adjusting.
A kind of 19. box of scheme, the box include：
At least one flow channel；And
Wherein described passage includes bubble grabber.
The box of the scheme 19 of scheme 20., wherein the bubble grabber includes perforated membrane, as a part for conduit wall, when Bubble when bubble passes through in passing away.
The box of the scheme 20 of scheme 21., wherein the film is hydrophobic.
The box of the scheme 19 of scheme 22., wherein the bubble grabber includes the deformation of flow channel wall.
Brief description of the drawings
Fig. 1 is the perspective view of exemplary sample analyzer and box (cartridge)；
Fig. 2 is the schematic diagram of Fig. 1 exemplary samples analyzer and box；
Fig. 3 is the more detailed schematic diagram for the flow control for showing Fig. 2 sample analysers and box；
Fig. 4 is the schematic diagram of some features of exemplary cartridge；
Fig. 5 is the schematic diagram for the multiple exemplary storage pools that can be included in box；
Fig. 6 is the schematic flow diagram for the illustrative methods for showing analysis blood sample；
Fig. 7 is the flow chart for showing the illustrative methods for obtaining a variety of erythrocyte parameters；
Fig. 8 is the schematic flow diagram for another illustrative methods for showing analysis blood sample；
Fig. 9 a, 9b, 9c, 9d, 9e and 9f show pin-every interface (needle-septum interface), axle-film respectively (shaft-membrane) interface and membrane-membrane interface.
Fig. 9 g displays promote stream (pusher fluid), solvent soln (lysing solution), sphering solution The table of (sphering solution) and sheath stream (sheath fluid) cavity diameter；
Figure 10 is the schematic flow diagram for showing the illustrative methods for establishing and operating sample analyser；
Figure 11 a are the flow charts for the illustrative methods for showing operation sample analyser；
Figure 11 b are the flow charts for another illustrative methods for showing operation sample analyser；
Figure 12 is the flow chart for another illustrative methods for showing operation sample analyser；
Figure 13 is exemplary optics instrumentation plan, identifies in fluid circuit flow channel when exist not available for help Correct or unwanted fluid；
Figure 14 is the schematic diagram of another exemplary optics measurement, available for what is helped to identify in fluid circuit flow channel When incorrect or unwanted fluid be present；
Figure 15 is electrical measurement schematic diagram, available for help to identify in fluid circuit flow channel when exist it is incorrect or not The fluid needed；
Figure 16 is another instrumentation plan, available for help identify in fluid circuit flow channel when exist it is incorrect Or unwanted fluid；
Figure 17 is the schematic diagram of illustrative examples, when occurs one or more available for sample fluid in identification flow channel Individual bubble or other unwanted particles；
Figure 18 is another illustrative examples schematic diagram, when occurs one available for sample fluid in identification flow channel Or multiple bubbles or other unwanted particles；
Figure 19 is illustrative examples schematic diagram, when one or more occurs available for sample fluid in identification flow channel Bubble or other unwanted features；
Figure 20 shows that exemplary pressure pulse 900 can be supplied to the sample fluid in Figure 19 flow channels by pressure source；
Figure 21 is illustrative examples schematic diagram, can help to sample fluid end in determination or estimating of fluid loop flow channel End or the position of distal end；
Figure 22-23 is illustrative examples schematic diagram, available for determining two or more fluids when in fluid circuit downstream Collect；
Figure 24 is the schematic diagram of exemplary instrument and box, and wherein box and instrument are matchings (keyed), only allows box with just In true direction inserting instrument；
Figure 25 is exemplary cartridge schematic diagram；
Figure 26 is the exemplary cartridge schematic diagram for including spring driving lancet (spring activated lancet)；
Figure 27 is with the exemplary cartridge schematic diagram for removing the film of bubble in flow channel；With
Figure 28 is the illustrative examples schematic diagram of flow channel bubble grabber.
Embodiment
The present invention relates to sample analyser, more particularly to simple to operate and reduction provides the dangerous of error result Sample analyser, in some cases, as needed, sample analyser can be such as blood analyser such as flow cytometer, Hematology analyzer, clinical chemistry analyzer (such as glucose analyser, ion analyser, blomelicalbloodgasandelectrolrteanalyzers, dissolved gas point Analyzer etc.), Urine Analyzer or any other suitable analyzer.
If the present invention meets some requirements, its own or the test carried out with it can be supervised from regulation.It can implement The present invention can be laboratory inspection and the test of code to provide and/or carry out, and the test is simple and accurate, so that providing The possibility of error result be can be neglected, or the wind for the patient harm that can be deduced will not be produced in incorrect tested Danger.A kind of clinical labororatory's improvement amendment (CLIA) exempted type and may be from 1988.
Fig. 1 is flow cytometer perspective view.Description stream type cell analyzer is served only for the purpose illustrated, it is contemplated that necessary When be applicable to other type of sample analyzers.Exemplary sample analyzer is generally such as 10 displays, including shell 12 and movable Or disposable cassette 14.Example housings 12 include substrate 16, lid 18 and the hinge 20 for being connected substrate 16 with lid 18, but this differs It is fixed to need.In illustrative examples, substrate 16 includes the first light source 22a, secondary light source 22b and the 3rd light source 22c and association Optics and operation sample analyser need electronic equipment.Each light source can be single light source or multiple light courcess, depend on Purposes.In some cases, the overall dimensions of shell be less than 1 cubic feet, less than 1/2 cubic feet, less than 1/4 cubic feet It is or smaller if necessary.Equally, the overall weight of shell be smaller than 10 pounds, less than 5 pounds, it is less than 1 pound or smaller if necessary.
Exemplary cap 12 includes pressure source (as having the balancing gate pit of control micro-valve), the first photodetector 24a, the inspection of the second light Device 22b and the 3rd photodetector 22c is surveyed, each there is association optics and electronic equipment.Each photodetector can also be Monochromatic light detector or more photodetectors, depending on purposes.If desired, polarizer and/or filter disc can be provided according to purposes.
Example activity formula box 14 fits through sample collection mouth and receives sample fluid, the collection port bag in illustrative examples Include lancet 32.In some cases, lancet 32 is being retractable into and/or equipped with spring.When movable box 14 without using When, cap 38 can be used for protection sample collection mouth and/or lancet 32.
In illustrative examples, movable box 14 carries out blood analysis to whole blood sample.Lancet 32 makes available for puncture User's finger obtains blood sample, the capillary for having anti-coagulants coating that it is sucked by capillarity in movable box 14 It is interior.Movable box 14 can be made up of fluid circuit, and some of fluid circuits are formed with the layer structure with etched channels.So And, if it is desired, it is expected that injection or any other suitable preparation process or method composition can be included by any suitable method Movable box 14.
In use, after blood sample to be sucked to movable box 14, movable box 14 can be inserted in shell.In certain situation Under, movable box 14 can be inserted in shell when lid 18 is in release position.However, in other cases, can be by any Suitable mode inserts movable box 14 in shell.For example, shell there can be the line of rabbet joint, movable box 14 can be inserted shell In the line of rabbet joint.
Fig. 1 illustrative examples are looked back, movable box 14 may include the hole for receiving fastening screw 28a and 28b in substrate 16 Eye 26a and 26b, can help to be directed at and couple the different piece of instrument.Movable box 14 may also include the first transparent flow window 30a, the second transparent flow window 30b and the 3rd transparency window 30c, are respectively aligned to first, second, and third light source 22a, 22b and 22c And first, second, and third photodetector 24a, 24b and 24c.
When lid, which is moved into closed position and system, to pressurize, lid 18 can respectively by pressure feed mouth 36a, 36b, 36c and 36d provides control pressure to pressure receiving port 34a, 34b, 34c and 34d in example activity formula box 14.According to purposes, in advance More or less pressure feeds and pressure receiving port can be used in phase.Besides or furthermore, it is contemplated that can be for example quiet by one or more Micropumps Electric actuation micro pump (meso pump) offer provides operation fluid circuit on movable box 14 or wherein, for movable box 14 Required pressure.Some exemplary electrostatics actuating micro pump be described in for example U.S. Patent number 5,836,750,6,106,245, 6179,586,6,729,856 and 6,767,190, these patents all transfer assignee of the present invention, are all incorporated by reference To herein.
Once pressurization, exemplary instrument can carry out blood analysis to the blood sample of collection.In some cases, blood analysis It may include that whole blood count (CBC) is analyzed, but other type analysis can be carried out according to purposes.
In order to red blood cell count(RBC) and classification, parts whole blood sample be separated and be provided to the red blood cell of movable box 14 Measurement channel.Then if desired, blood sample can be diluted, (on the fly) formation is spherical in real time for red blood cell, and gained sample can be in Hydrodynamics is concentrated, and is formed core, is ultimately provided to the first cytolytic dose passage.First cytolytic dose passage can be along movable The first transparent flow window 30a positioning of box 14, so that fluid cell can be by the first light source 22a and the first photodetector 24a optics Ask and visit.In some cases, first flow sensor can be provided on movable box 14, measurement is led to by the first cytolytic dose The flow velocity in road.
In some cases, measurement parameter may include such as sample flow rate (FR), time of measuring (T) duration, sample The coefficient of dilution (DF), red blood cell count(RBC) (NRB), platelet count (NPlt), each cell dia (drbc) and each cellular hemoglobin Concentration (CHC).From these parameters, many red blood cell analytical parameters can be calculated, including such as red blood cell count(RBC) (RBC=NRB/(DF× FR × T)), platelet count (Plt=Nplt/ (DF × FR × T)), mean cell hemoglobin concentration (MCHC=<CHC>), it is flat Equal cell volume (MCV=(π/6) ×<drbc3>), mean cellular hemoglobin (MCH=(π/6) ×<drbc3×CHC >), Relative distribution width (RDW=[(π/6) × drbc3]/MCV standard deviation), packed cell volume parameter (Hct=RBC × ) and/or hemoglobin concentration (Hb=MCHC × Hct) MCV.
In some instances, some blood samples are also oriented to absorptiometry passage.Absorptiometry passage can be along movable box 14 The 3rd transparency window 30c positioning, visited so that blood sample can be ask by the 3rd light source 22c and the 3rd photodetector 24c optics.Can be by flow Sensor is provided on movable box 14, measures the flow velocity into or by absorptiometry passage.Absorptiometry passage is measurable By the absorption of the 3rd light source 22c incident lights provided.The absorption level of measurement can be provided as totality or average cell in blood sample Hemoglobin concentration reading.
In order to white blood count and differential, parts whole blood sample be separated and be provided to the leucocyte of movable box 14 Measurement channel.Then if desired, blood sample can be diluted, red blood cell can dissolve in real time, and gained sample can be in that hydrodynamics is concentrated, Core is formed, is ultimately provided to the second cytolytic dose passage.Second cytolytic dose passage can be along the second transparent of movable box 14 Window 30b positioning is flowed, is visited so that fluid cell can be ask by secondary light source 22b and the second photodetector 24b optics.Flow can be passed Sensor is provided on movable box 14 to measure the flow velocity by the second cytolytic dose passage.In some cases, measurement is white Cell parameters may include that such as three (3) or (5) part leukocyte differentiation, total leukocyte count and/or positive axis (on-axis) are white thin Cell space accumulates.According to purposes it is also measurable or calculate other parameters.
Fig. 1 shows a kind of exemplary sample analyzer and box assembly.It is contemplated, however, that other sample analysers can be used to match somebody with somebody Put.For example, sample analyser 10 and movable box can be similar to authorize Schwichtenberg etc. U.S. Patent application 2004/ 0211077 description, its is incorporated herein by reference.
In some cases, sample analyser 10 be adapted to patient care point as doctor clinic, household or scene it is other Side uses.Sample analyser 10 needs seldom or does not need professional training reliably to be used outside laboratory environment, has This sample analyser 10 can help sample analysis process streaming, reduce expense and medical worker's burden, and increase analysis is permitted The convenience of more Patient Sample As, including need related frequency to monitor/analyze the patient of blood.
During operation, sample analyser 10 can receive the sample of collection, the whole blood such as collected, once start analyzer, sample Analyzer 10 can automatically process sample, and the information for making clinical judgment is provided for user.In some instances, sample analyser 10 can show or print quantitative result (such as within preset range and/or outside), need not calculate again so as to user or Explain.
Fig. 2 is the schematic diagram of Fig. 1 exemplary samples analyzer and box.As detailed above, in illustrative examples, substrate 16 It may include multiple light sources 22, the optics of association and the required control of Operations Analyst instrument and processing electronic equipment 40.Substrate 16 may also include battery 42, transformer or other power supplys.Shown lid 12 is with pressure source/flow control block 44 and with associated light Learn multiple photodetectors 24 of device.
Movable box 14 can receive sample fluid by sample collection mouth or lancet 32.When pressure source/flow control block During 44 pressurization, movable box 14 can carry out blood analysis to receiving blood sample.In some instances, as described above, movable box 14 may include plurality of reagents 49, and the fluid circuit for making reagent be mixed with analysis blood sample with blood sample.Moreover, in certain situation Under, movable box 14 may include the multiple flow sensors for helping control and/or examining fluid circuit whether correctly to run.
In some cases, (such as dissolving, nodularization, dyeing, dilution and/or other processing) blood sample is prepared, then at one Or hydrodynamics is concentrated in multiple accompanying (on-board) cytolytic dose passages such as cytolytic dose passage 50, forms core. In illustrative examples, cytolytic dose passage 50 passes through transparent flow window such as the first transparent flow window 30a of movable box 14.Base A series of light sources 22 can pass light through core fluid with optics is associated via flowing window 30a in plate 16.A series of light detections Device 24 can also receive scattering and the non-scattered of core with optics is associated via flowing window 30a.Controller or processor 40 The output signal for carrying out the array of self-detector 24 can be received, selected cell present in core fluid can be made a distinction and/or be counted Number.
Expected activity formula box 14 may include fluid control block 48, help to control the speed of at least some fluids in movable box 14 Degree.In illustrative examples, fluid control block 48 include that the speed of various fluids can be predicted and by speed report to controller or The flow sensor of processor 40.Then controller or processor 40 can adjust one or more control signals, provide it to Pressure source/flow control block 44, reaches required pressure, so as to obtain the required fluid velocity of correct Operations Analyst instrument.
Because blood and other biology waste liquids can spread disease, movable box 14 may include waste liquid pool 52, be located at The downstream of exemplary cells measurement channel 50.Waste liquid pool 52 can receive and store the fluid in movable box 14.When testing is complete, The movable box 14 of analyzer is can be taken off, such as is discarded in the container compatible with biology waste liquid.
Fig. 3 is more detailed schematic diagram, shows the flow control of Fig. 2 sample analysers and box.In illustrative examples, lid 18 pressure source/flow controller 44 provides 5 kinds of control pressures, including sample promote (P) pressure 36a, dissolving (L) pressure 36b, Nodularization (SP) pressure 36c, sheath stream (SH) pressure 36d and dilution (D) pressure 36e.These are served only for for example, according to purposes, Expecting pressure source/flow controller 44 can provide more, less or different pressure (the dyeing pressure such as to color pond).And And, it is contemplated that lid 18 can not include pressure source/flow controller 44.It the substitute is, as needed, movable box 14 can Including accompanying the pressure source such as example above-mentioned electrostatically actuated micro pump in compressed air pond, one or more Micropumps or any other conjunction Suitable pressure source.Light source and detector array are not shown in Fig. 3.
In illustrative examples, pressure source 36a carries by promoting stream 65 to provide pressure to blood sample pond 62, pressure source 36b Voltage supply power is to dissolving tank 64, and pressure source 36c provides pressure to nodularization pond 66, and pressure source 36d provides pressure to sheath flow pool 68, pressure Source 36e provides pressure to diluting tank 70.
In an illustrative examples, each pressure source may include the first pressure room for receiving input pressure, and provide control Pressing pressure is to the second pressure room of movable box.First valve can be between first pressure room and second pressure room, for inciting somebody to action Discharge to second pressure room the pressure controllable of first pressure room.The second valve being in fluid communication with second pressure room can be by the Discharge into air the pressure controllable of two pressure chamber.This can allow pressure source/flow controller 44 by control pressure provide to Each pressure receiving port on movable box 14.Each valve can be can individual operations and control electrostatically actuated micro-valve array, such as It is described in such as U.S. Patent number 6,240,944, its is incorporated herein by reference.Or each valve can be electrostatically actuated Micro-valve array, the micro-valve are adjusted by the duty cycle pulse controlled, realize the flow velocity or leakage speed (leak of control " effective " rate).If desired, it is possible to use other valves.
Example activity formula box 14 includes 5 pressure receiving port 34a, 34b, 34c, 34d and 34e, each receives from pressure The corresponding control pressure of power source/flow controller 44.In illustrative examples, pressure receiving port 34a, 34b, 34c, 34d and Control pressure is transferred to storage blood pool 62, dissolving tank 64, nodularization pond 66, sheath flow pool 68 and diluting tank 70 by 34e respectively.Movable Box 14 is assembled for that before use, can fill dissolving tank 64, nodularization pond 66, sheath flow pool 68 and diluting tank 70, and is received by sample Ji Kou or the scene of lancet 32 filling storage blood pool 62.
As illustrated, flow sensor may be provided in every kind of or selected fluid line.Each flow sensor 80a-80e can Measure the speed of corresponding fluids.Flow sensor 80a-80e can be hot gas flow velocity type (thermal anemometer type) Flow sensor and microbridge type flow sensor.Microbridge flow sensor is described in as U.S. Patent number 4,478,076, the U.S. are special Profit number 4,478,077, U.S. Patent number 4,501,144, U.S. Patent number 4,651,564, U.S. Patent number 4,683,159 and U.S. State's patent No. 5,050429, it is fully incorporated herein by quoting.
Besides or furthermore, sensor 80a-80e can be used for detection fluid one or more features, as thermal conductivity, specific heat, Fluid density, resistivity and/or other characteristic of fluid, it is being expected through the fluid of flow channel as helped to identify or verify Fluid or expected fluid type.Strictly expected fluid when this can help to verify concrete analysis or operation for flow channel. It can be expected whether fluid is used for flow channel really by Programmable detection with controller, in some cases, give a warning and/or cut Disconnected sample analyser.
Each flow sensor 80a-80e output signal can be provided to controller or processor 40.As illustrated, control Device or processor 40 can be provided control signal to pressure source/controller 44.For example, in order to control the pressure applied to blood sample, When blood sample speed is decreased below first predetermined value, controller or processor 40 can be opened first in pressure source/controller 44 The first valve between balancing gate pit and second pressure room, the pressure controllable of first pressure room is discharged to second pressure room.Together Sample, when blood sample speed increases above second predetermined value, controller or processor 40 can open the second valve, release the second pressure The pressure of power room.Controller or processor 40 can control the speed of lytic agent, nodulizer, sheath stream and diluent by similar fashion Degree.
In some cases, controller or the detectable one or more through flow channel flow velocity of processor 40 change. Flow velocity change be attributable to for example, one or more bubbles in flow channel, the flow channel occlusion as caused by blood sample coagulation or In Partial occlusion, flow channel need not or other negative characteristics of external object and/or flow channel.In certain situation Under, some further features of rise time, fall time or flow velocity can be used.Controller or processor 40 can be made by Programmable detection This category feature of flow velocity, in some cases, give a warning and/or cut off sample analyser.
Hot gas flow velocity type flow sensor generally includes heating element heater (can produce one or more in a fluid when energized Thermal pulse), in addition to (it is one or more hot to detect to be located at heating element heater upstream and/or downstream for one or more heat sensors Pulse).The speed of fluid through flow channel may reach what an interval heat sensor needed with thermal pulse from heating element heater Time correlation.
In some cases, hot gas flow velocity type flow sensor can be used for detection fluid thermal conductivity and/or specific heat.Fluid is led It is hot and/or specific heat to change the change that may correspond to characteristic of fluid, change (blood sample coagulation), fluid gas such as fluid state Bubble, in fluid need not or foreign body etc..Besides or furthermore, hot gas flow velocity type flow sensor can be used for detection a kind of or more Kind characteristic of fluid such as thermal conductivity, specific heat etc., for example to help to identify or to verify that the fluid through flow channel is expected fluid Or expected fluid type.Strictly expected fluid when this can help to verify concrete analysis or operation for flow channel.One In a little examples, it is contemplated that controller or processor 40 can pass through the thermal conductivity of fluid of the monitoring through overfire air stream speed type flow sensor And/or specific heat detection characteristic of fluid.Negative characteristics (such as gas of controller or processor 40 by Programmable detection such as fluid can be made Bubble), and/or it is expected whether fluid is used for flow channel really, in some cases, give a warning and/or cut off sample analysis Instrument.
In some cases, it is possible to provide impedance transducer is in fluid communication with flow channel.Controller or processor 40 can be made Couple with impedance transducer.The change of fluid impedance can prompt the change of characteristic of fluid, as fluid state change (blood sample coagulation), In fluid bubbles, fluid need not or external object, correct fluid type etc..Therefore, in some instances, it is contemplated that control Device or processor 40 can detect characteristic of fluid by the fluid impedance monitored by impedance transducer.
It may also provide substantially in the downstream valve of 110 displays.Controller or processor 40 can open/closed downstreams as needed Valve 110.For example, downstream valve 110 may remain off until system is fully pressurized.This can help prevent blood, lytic agent, nodularization Agent, sheath stream and diluent are in incoming fluid loop 86 before system is fully pressurized.Moreover, controllable downstream valve 110 help into The some tests of row, such as zero delivery are tested.In another example, such as when the lid is closed, can be opened down by mechanism Swim valve 110.
Fig. 4 is the schematic diagram of some features of example activity formula box.Overall such as 100 displays of example activity formula box, can class It is similar to the movable box 14 that Fig. 1-3 is shown and described.It should be understood that movable box 100 is served only for for example, this example is applicable In many microfluidic cartridges, regardless of its form, function or configuration.For example, this example is applicable to be adapted to flow cytometry, blood Liquid, clinical chemistry, blood chemical analysis, urinalysis, blood gas analysis, virus analysis, bacterial analysis, electrolyte measurement etc. Movable box.It is also contemplated that any suitable material or material system (such as glass, silicon, one or more polymer or any can be used Other suitable materials or material system) or material or for example movable box of movable box of material system combination preparation the system 100。
Example activity formula box 100 includes the first Measurement channel 102 and the second Measurement channel 104, but can make as needed With more or less Measurement channels.In illustrative examples, the first Measurement channel 102 is red blood cell measurement channel, and second measures Passage 104 is leucocyte Measurement channel.Movable box 100 receives whole blood sample by blood receiving port 106, is made by capillary With sucking known quantity blood has in the blood sample storage capillary 108 of anti-coagulants coating.Sample is promoted into (P) pressure, such as Fig. 3 Sample promote (P) pressure 36a, there is provided fluid pool is promoted to sample, such as Fig. 3 sample promotes fluid pool 65.When application pressure When, force sample to promote stream to promote fluid pool to enter blood sample from sample and promote in passage 110
In some illustrative examples, valve 112 and flow sensor 114 can be provided and promote the line of passage 110 in blood sample In road.When needing to promote blood sample to pass through fluid circuit, controllable valve 112 opens.114 measurable blood sample of flow sensor pushes away The flow velocity of dynamic stream, so as to measure the blood sample flow velocity through the capillary 108 for having anti-coagulants coating.What flow sensor 114 provided Flow velocity can be used for helping to control to provide to the sample of movable box 100 promoting (P) pressure.
In illustrative examples, whole blood sample is distributed, provided by branch 116 to red blood cell measurement channel 102 and white Cell measurement passage 104.In illustrative examples, valve 118 is provided in branched line, flowing into Erythrocyte measure with control leads to The blood sample in road 102, there is provided valve 120 flows into the blood sample of leucocyte Measurement channel 104 to control.
Specific to red blood cell measurement channel 102, by red blood cell sphering agent pressure (SP), such as Fig. 3 nodularization pressure (SP) 36c, there is provided to nodularization pond, such as Fig. 3 nodularization pond 66.When the pressure is exerted, the nodulizer in nodularization pond 66 is forced to enter nodulizer In passage 124.
In some illustrative examples, valve 126 and flow sensor 128 can be also provided in the line of nodulizer passage 124 In road.When needing nodulizer being pushed into fluid circuit, controllable valve 126 opens.128 measurable nodulizer of flow sensor Flow velocity, measure the nodulizer flow velocity through nodulizer passage 124.The flow velocity that flow sensor 128 provides is controlled available for help System is provided to the nodularization pressure (SP) of movable box 100 by pressure source/controller 44.
In normal functionality operation example sexuality formula box 100, nodulizer is pushed into intersection 130 with nodulizer flow velocity It is interior, by blood sample with blood sample flow velocity push-in intersection 130.Blood sample flow velocity and ball can be controlled by Fig. 3 pressure source/controller 44 Agent flow velocity.
Configurable intersection 130 surround flowing by nodulizer during intersection 130 so as to two kinds of flow of fluid around blood sample. In some cases, nodulizer flow velocity can be higher than blood sample flow velocity, and this can help improve the real-time nodularization (sphering-on- in downstream The-fly) the flow performance of passage 132, in some cases, help form blood faciola (thin ribbon), by nodulizer In fully and uniformly surrounding.Such band stream can help nodulizer uniformly geochemical red blood cell (when red blood cell passes through real-time ball When changing passage 132).Moreover, the length of nodulizer and the real-time nodularization passage 132 of blood sample flow rate set can be combined, to make blood sample Exposed to the one suitable time of nodulizer.
Can be by sheath stream (SH) pressure, such as Fig. 3 sheath stream (SH) pressure 36d, there is provided to sheath flow pool such as Fig. 3 sheath flow pool 68. When the pressure is exerted, sheath stream is forced to enter from sheath flow pool 68 in sheath circulation road 134., can be by valve in some illustrative examples 136 and flow sensor 138 provide in the circuit of sheath circulation road 134.When needing sheath stream being pushed into fluid circuit, can control Valve 136 opens.The flow velocity of 138 measurable sheath stream of flow sensor, the measurable sheath stream flow velocity through sheath circulation road 134.Stream The flow velocity that quantity sensor 138 provides can be used for helping to control the sheath flowing pressure (SH) provided to movable box 100.
In illustrative examples, sheath stream is provided to intersection 140 with sheath stream flow velocity, by nodularization blood sample (sphered Blood sample) provided with nodularization blood sample flow velocity to intersection 140.Available pressure source/controller, such as Fig. 3 pressure source/control Device 44 processed, control nodularization blood sample flow velocity and sheath stream flow velocity.
Configurable intersection 140, so that when two kinds of flow of fluid are by intersection 140, sheath stream surrounds nodularization blood sample ring Around flowing.In some cases, for sheath stream flow velocity apparently higher than nodularization blood sample flow velocity, this can help improve downstream fluidic cell metering Core in passage 142 is formed.For example, in the application of some flow cytometries, intersection 140 is can configure, makes nodularization haemocyte Neutralize and be arranged in single file core in hydrodynamics collection, to pass through the optical window area of movable box 100 when each red blood cell When 144, analyzer optics inquiry spy one by one can be all used.In some cases, flowed to through the fluid of cytolytic dose passage 142 with band Waste liquid pool.
Specific to leucocyte Measurement channel 104, by leukocytolysis agent pressure (L), such as Fig. 3 solution presasure (L) 36b, There is provided to lytic agent pond, such as Fig. 3 dissolving tank 64.When the pressure is exerted, the lytic agent of dissolving tank 64 is forced to lead into lytic agent In road 154
In some illustrative examples, valve 156 and flow sensor 158 can be provided in the circuit of lytic agent passage 154 It is interior.When needing lytic agent being pushed into fluid circuit, controllable valve 156 opens.158 measurable lytic agent of flow sensor Flow velocity, measure the lytic agent flow velocity through lytic agent passage 154.The flow velocity that flow sensor 158 provides controls available for help There is provided by pressure source/controller 44 to the solution presasure (L) of movable box 100.
In normal functionality operation example sexuality formula box 100, lytic agent is provided to intersection with lytic agent flow velocity 160, blood sample is provided to intersection 160 with blood sample flow velocity.Available pressure source/controller, such as Fig. 3 pressure source/controller 44, Control blood sample flow velocity and lytic agent flow velocity.
Configurable intersection 160, so that when two kinds of flow of fluid are by intersection 160, lytic agent is surround around blood sample Flowing.In some cases, lytic agent flow velocity can be higher than blood sample flow velocity, and this can help improve dissolving (lysing-on- in real time The-fly) the flow performance of passage 162, in some cases, help form blood faciola, by lytic agent fully and uniformly In surrounding.Such faciola stream can help lytic agent, and equably lysed erythrocyte (dissolves passage 162 in real time when red blood cell passes through When).Moreover, the length of passage 162 can be dissolved in real time with reference to lytic agent and blood sample flow rate set, to make blood sample exposed to dissolving The one suitable time of agent.
Can be by sheath stream (SH) pressure, such as Fig. 3 sheath stream (SH) pressure 36d, there is provided to sheath flow pool, such as Fig. 3 sheath flow pool 68. When the pressure is exerted, sheath stream is forced to enter from sheath flow pool 68 in sheath circulation road 164., can be by valve in some illustrative examples 166 and flow sensor 168 provide in the circuit of sheath circulation road 164.When needing sheath stream being pushed into fluid circuit, valve can control Door 166 opens.The flow velocity of 168 measurable sheath stream of flow sensor, the measurable sheath stream flow velocity through sheath circulation road 164.Flow The flow velocity that sensor 168 provides can be used for helping to control providing to the sheath flowing pressure (SH) of movable box 100.In certain situation Under, the sheath stream flow velocity through sheath circulation road 164 is identical with the flow velocity through sheath circulation road 134.However, in other cases, wear The sheath stream flow velocity for crossing sheath circulation road 164 is different from the flow velocity through sheath circulation road 134.
In illustrative examples, sheath stream is provided to intersection 170 with sheath stream flow velocity, by dissolving blood sample to dissolve blood sample stream Speed is provided to intersection 170.Available pressure source/controller, such as Fig. 3 pressure source/controller 44, control dissolving blood sample flow velocity and Sheath stream flow velocity.
Configurable intersection 170, so that when two kinds of flow of fluid pass through intersection 170, sheath stream is around dissolving blood sample ring Around flowing.In some cases, for sheath stream flow velocity apparently higher than dissolving blood sample flow velocity, this can help improve downstream fluidic cell metering The center of passage 172 is formed centrally.For example, in the application of some flow cytometries, configurable intersection 170 makes white in dissolving blood sample Cell is neutralized in hydrodynamics collection and is arranged in single file core, so as to the light passed through when each leucocyte in movable box 100 During Xue Chuan areas 174, analyzer can carry out optics one by one and ask spy.In some cases, through the fluid stream of cytolytic dose passage 172 To accompanying waste liquid pool.
In some cases, it may also provide absorptiometry passage.In illustrative examples, will be partly dissolved blood sample provide to In absorbing path 180.Valve 182 can be provided and pass through absorbing path or area 184 so that selectivity allows to be partly dissolved blood sample.Analysis Instrument may include that the light source for illuminating absorbing path or area 184, and detection are not absorbed by the dissolving blood sample in absorbing path or area 184 Light detector.Then analyzer can determine absorption level, therefrom obtain with overall absorption (bulk absorption) as base The hemoglobinometry value of plinth, in some cases if desired, as Fig. 8 shows that absorbing path 184 can lead to positioned at cytolytic dose The downstream of road 172.In other cases, whole blood sample can be directly provided to absorbing path (such as from branch 116).In this feelings Under condition, absorbing path may include the mechanical device of the lysed erythrocyte before absorptiometry is carried out.Although example activity formula box 100 It is adapted to carry out whole blood sample whole blood count (CBC) analysis, it is anticipated that can configure using other movable boxes as needed And analysis type.
Fig. 5 is the multiple exemplary storage pool schematic diagrames that can be included in movable box.It is movable in illustrative examples Box such as Fig. 4 movable box 100 may include such as lytic agent pond 64, promote stream pond 65, nodulizer pond 66, sheath flow pool 68, dilution Flow pond 70, color pond 190 and waste liquid pool 52.These are served only for illustrating, it is contemplated that can carry more, less or different storage pools For on movable box or wherein.
Each storage pool can have different size, accommodate the appropriate amount fluid and/or reagent of operation needed for support activities formula box. Diluting tank 70 can accommodate the dilution fluid for diluting new sample such as whole blood sample.In Fig. 4 illustrative examples, nodulizer And/or lytic agent can play diluent functions, it is thus possible to necessarily or even without single diluting tank 70.Equally, exist In some examples, it may be desired to added dyestuff in leucocyte passage to support leukocyte differential count with color pond such as color pond 190.Root According to purposes, it is contemplated that reagent and/or fluid in storage pool can initially use liquid or lyophilized form.
Fig. 6 is to show the illustrative methods schematic flow diagram with movable box analysis blood sample.In illustrative methods, first Blood sample is gathered in step 200.Then, blood sample is provided to the anti-coagulants coatings capillary pipe of movable box.Then blood sample is distributed, There is provided into red blood cell and blood platelet (RBC/P) Measurement channel 204 and leucocyte (WBC) Measurement channel 206.
In RBC/P Measurement channels 204, such as 212 displays make red blood cell nodularization first, are then concentrated in hydrodynamics, And provided along the RBC/P cytolytic doses passage 214 of movable box with single file.When cell passes through RBC/P cytolytic doses passage 214 During analysis area, light source 216, such as vertical cavity surface emitting laser (VCSEL), light is impinged upon in individual cells.In certain situation Under, there is provided VCSEL equipment arrays, only it is aligned through the VCSEL of the individual cells of the analysis area of RBC/P cytolytic doses passage 214 It is activated.Some incident lights that VCSEL is provided are scattered, the detection scattering light of detector 218.In some cases, detector 218 Detectable anterior angle scattering light (FALS), small-angle scattering light (SALS) and large-angle scatter light (LALS).
In some cases, laser (or other) source focuses on RBC/P cytolytic doses passage 214, the line source as extension Or it is used as two single point sources.RBC and blood platelet in RBC/P cytolytic doses passage 214 is by focusing on light.The receipts of high quality Collection optics can be used for forming the picture rich in detail of cell, and illumination is concentrated on containing one, two or more parallel fractures On opaque screen (screen), the longitudinal axis in the crack and flow direction in RBC/P cytolytic doses passage 214 are at right angles orthogonal. Fracture interval is from can be expected average cell interval for example in RBC/P cytolytic doses passage 214.Can be by containing the impermeable of crack Bright screen is placed in one or more fronts of detector 218.When cell image passes through crack, the light being incident on crack is fuzzy not Clearly, the signal up to detector 218 is attenuated to, produces the width impulse waveform proportional to cell dia.It is spaced when providing two During crack, two kinds of waveforms can allow to calculate cell flowing velocity, so as to calculate cell size.High noise can be obtained with the technology Than so as to easy counting event and identification various kinds of cell event.Pulse width and amplitude can also distinguish some cell types.
In some cases, make cell and light source image be all imaged on detector 218 before double slit hole on.Double slit hole provides The geometry hole of sharp outline and high s/n ratio are to count cell.As discussed above, carrying out the signal of endokinetic fissure can allow accurate measurement thin Born of the same parents' flow velocity, it can then allow to calculate cell dia.
In some cases, such as 220 displays, many kinds of parameters can be measured in the analysis, including such as sample flow rate (FR), survey Measure (T) duration time and the sample coefficient of dilution (DF)., can by monitoring detector output and/or corresponding scattered signal Measure red blood cell number (NRB), platelet count (Nplt), each cell dia (drbc) and each Cell Hb Concentration.
From these parameters, such as 282 displays, a variety of red blood cell analytical parameters can be calculated, including such as red blood cell count(RBC) (RBC =NRB/ (DF × FR × T)), platelet count (Plt=NPlt/ (DF × FR × T)), mean cell hemoglobin concentration (MCHC =<CHC>), mean corpuscular volume (MCV=(π/6) ×<drbc3>), mean cellular hemoglobin (MCH=(π/6) ×< drbc3×CHC>), Relative distribution width (RDW=[(π/6) × drbc3]/MCV standard deviation), packed cell volume parameter (Hct =RBC × MCV) and/or hemoglobin concentration (Hb=MCHC × Hct).
In exemplary WBC Measurement channels 206, first if 232 displays are by erythrocytolysis, then in hydrodynamics collection In, and WBC cytolytic doses passage 234 is provided with single file along movable box.Light source 236, such as vertical cavity surface emitting laser (VCSEL), by illumination in the individual cells through the analysis area of WBC cytolytic doses passage 234.In some cases, there is provided VCSEL equipment arrays, the VCSEL for being only aligned through the individual cells of the analysis area of WBC cytolytic doses passage 234 are just activated. Scattered by VCSEL some incident lights provided, the detection scattering light of detector 238.In some cases, detector 238 detects Anterior angle scattering light (FALS), small-angle scattering light (SALS) and large-angle scatter light (LALS).In some cases, can such as 240 displays Many kinds of parameters is measured in analysis, including such as positive axis cell volume, total WBC count and WBC five (5) parts are classified.
Fig. 7 is to show the exemplary method flowchart for obtaining a variety of erythrocyte parameters.In illustrative methods, in step 260 obtain blood sample.Then, by diluting blood sample to the required coefficient of dilution (DF), such as 264 display nodularizations.Then dilution and nodularization are made Haemocyte in hydrodynamics concentrate, provided along the RBC/P cytolytic dose passages of movable box with single file.Light source 216 is as hung down Straight cavity surface-emitting laser (VCSEL) is by illumination in the individual cells through RBC/P cytolytic dose multichannel analysis area.By Some incident lights that VCSEL is provided are scattered, and scattering light can be detected with detector.In some cases, detector detection is each The anterior angle scattering light (FALS) and small-angle scattering light (SALS) of cell.Then processor etc. can be by two kinds of each cell independent scatterings Parameter is that SALS and FALS map to cell dia parameter and Cell Hb Concentration parameter, as follows：
{SSALSi, SFALSi}->(drbci, CHCi)
Such as 270 displays, if scattering SSALSi+SFALSiIntensity is not more than predetermined detection threshold value, then control reaches step 268. If however, scattering SSALSi+SFALSiIntensity is more than predetermined detection threshold value, then control reaches step 272.Step 272 determines SSALSi +SFALSiWhether sum is more than predetermined blood platelet threshold value.If SSALSi+SFALSiSum is not more than predetermined blood platelet threshold value, then Particle " i " is blood platelet, and control reaches step 274.Step 274 makes platelet count (NPlt) increase by 1, control return to step 268。
If SSALSi+SFALSiSum is more than predetermined blood platelet threshold value, then cell is red blood cell, and control reaches step 276.Step 276 makes red blood cell count(RBC) (NRBC) increase by 1, control arrival step 278.Step 278 determines whether to have reached predetermined Time of measuring.If it is not, control return to step 268.
Once reaching time of measuring in step 278, then control reaches step 280.Step 280 shows a variety of measurement parameters, Including such as sample flow rate (FR), time of measuring (T) duration, the sample coefficient of dilution (DF), red blood cell count(RBC) (NRBC), blood it is small Plate counts (NPlt), each cell dia (drbci) and each Cell Hb Concentration (CHCi).From these parameters, such as step 282 It has been shown that, a variety of blood cell analysis parameters can be calculated, including such as red blood cell count(RBC) (RBC=NRBC/ (DF × FR × T)), blood platelet meter Number (Plt=NPlt/ (DF × FR × T)), mean cell hemoglobin concentration (MCHC=<CHCi>, mean corpuscular volume (MCV= (π/6)×<drbci 3>), mean cellular hemoglobin (MCH=(π/6) ×<drbci 3×CHCi>), Relative distribution width (RDW=[(π/6) × drbci 3]/MCV standard deviation), packed cell volume parameter (Hct=RBC × MCV) and/or hemoglobin Concentration (Hb=MCHC × Hct), wherein symbol<Xi>Refer to whole cell XiAverage cell parameter.
Fig. 8 is another illustrative methods schematic flow diagram for showing analysis blood sample.In this illustrative methods, obtain Blood sample, there is provided into blood sample pond, as step 300 is shown.Then, blood sample is provided to the anti-coagulants coatings capillary pipe of movable box It is interior, dilution.Then blood sample is distributed, there is provided surveyed to red blood cell and blood platelet (RBC/P) Measurement channel 304 and leucocyte (WBC) Measure in passage 340.
In RBC/P Measurement channels 304, by red blood cell nodularization first as shown in 306, it is in hydrodynamics collection then to make it In, provided along the RBC/P cytolytic doses passage 308 of movable box with single file.First light source 310 such as vertical cavity surface emitting laser (VCSEL) with associate optics focus on light beam be provided in the individual cells through the analysis area of RBC/P cytolytic doses passage 308 On.In some cases, there is provided VCSEL equipment arrays, be only aligned through of the analysis area of RBC/P cytolytic doses passage 308 The VCSEL of body cell is activated.
When individual cells/particle is through over-focusing incident beam, some light are blocked, scatter or stopped, this available inspection Survey the detection of device (not shown).When two or more light-resource fousings are in the point of different interval on RBC/P cytolytic doses passage 308, It can detect the leading edge and/or opisthogenesis of each cell.By measuring cell by the spacing from a focus point to next focus point From the time used, flow velocity can be determined so as to determine cell speed.Determine cell speed after, can by cells blocks, scattering or Stop that the time span of light beam associates with cell size and/or cell volume.
In some instances, analyzer can provide another light source 314 and associate optics.The association optics of light source 314 Device can collimated light, measure off-axis scattering such as SALS and FALS and scatter.As noted above, SALS and FALS scatterometries can be used for example Red blood cell count(RBC) (NRBC) 316, platelet count (NPlt) 322, each cell dia (drbci), cell volume 318 and each cell blood (the CHC of hemoglobin concentration 320i).It is as discussed above from these parameters, a variety of blood cell analysis parameters can be calculated, including it is for example red Cell count (RBC=NRBC/ DF × FR × T)), platelet count (Plt=NPlt/ (DF × FR × T)), Mean Cell Hb egg White concentration (MCHC=<CHCi>, mean corpuscular volume (MCV=(π/6) ×<drbci 3>), mean cellular hemoglobin (MCH=(π/6) ×<drbci 3×CHCi>), Relative distribution width (RDW=[(π/6) × drbci 3]/MCV standard deviation), it is red Cell pack parameter (Hct=RBC × MCV) and/or hemoglobin concentration (Hb=MCHC × Hct), wherein symbol<Xi>Refer to complete Portion cell XiAverage cell parameter.
In exemplary WBC Measurement channels 340, lysed erythrocyte, dyestuff is suitably injected, such as 342 displays.Then cell is made Concentrate in hydrodynamics, provided along the WBC cytolytic doses passage 344 of movable box with single file.Such as vertical cavity surface of light source 346 is sent out Laser (VCSEL) is penetrated by illumination in the individual cells through the analysis area of WBC cytolytic doses passage 344.In some cases, VCSEL equipment arrays are provided, the VCSEL for being only aligned through the individual cells of the analysis area of WBC cytolytic doses passage 344 is swashed It is living.
When individual cells/particle is through over-focusing incident beam, some light are blocked, scatter or stopped, this available inspection Survey the detection of device (not shown)., can when two or more light-resource fousings are in the point of different interval on WBC cytolytic doses passage 344 Detect the leading edge and/or opisthogenesis of each cell.Passed through by measuring cell from a focus point to distance between next focus point Time used, flow velocity can be determined so as to determine cell speed., can be by cells blocks, scattering or stop after determining cell speed The time span of light beam associates with cell size and/or cell volume.
In some instances, it is possible to provide light source 350 with associate optics and/or polarizer.The association optics of light source 350 Device can collimated light, measure off-axis scattering such as SALS, FALS and LALS and scatter, such as 354 displays.As noted above, can use SALS, FALS and LALS scatterometries such as white blood cell count(WBC) (NWBC) 352, and leucocyte is helped distinguish between, such as 356 displays.In some feelings Under condition, there is provided one or more polarizers make the light polarization that light source provides, and polarization extinction/optically-active of detector detection is horizontal to be can use In helping distinguish between leucocyte, but and not all example be required for so.
In illustrative examples, the cell for leaving WBC cytolytic doses passage 344 can be provided to total absorbing path 360.Light On the cell that source 362 can occur illumination in absorbing path 360, detector 364 is detectable not by intrinsic cell (resident Cell) the light absorbed.Therefore absorbing path 360 can be used for the total absorption for measuring intrinsic cell horizontal.Absorption level can be such as Measure the totality or mean cell hemoglobin concentration of blood sample.Hemoglobin passage can have the optics for adjusting zero point again, It is automatic to focus on and/or calibrate.Light source 362 can be the LED with the output signal close to absorption peak center, therefore can be not required to Want filter disc.It can be received with curvette and accommodate sample, to assess hemoglobin.Humidity and temperature sensor can be located at card (card) on, to show to determine card article part of these parameters at that time with history.The time that card is heated or cooled can be shown that operation just Temperature before beginningization.Monitoring such condition can be relevant with the material on card and solution.Grasping these conditions can be used as safety to arrange Apply the chance for eliminating or significantly reducing card or box structure delamination.
The interface shown by Fig. 9 a-9f can realize contamination-freely transfer and mobile fluid.Once reagent is stored in instrument In the kit of device, the compression sex chromosome mosaicism of fluid in each supply line from reagent to fluid boundary there is.It is high in order to reach Fidelity fluid flow controls, and should be minimized the problem.Compressibility may be attributed to bubble, when bubble is from temperature change Dissolved gas caused by solution or the air spread from the gas-permeable wall by supply line.Solves one kind side of the problem Method can be that foamed solution such as reagent are evacuated to and can entered in the valve of kit waste liquid tank from instrument flow interface, such as Zhou Xin Fresh fluid, instead.Once bubble has been gradually resorbed or rushed to waste liquid, then valve can be turned again, make fluid/air build-up of fluid extremely Fluid boundary.In build-up of fluid close to after fluid boundary, another urgent problem to be solved is probably that instrument is polluted by blood sample It is potentially possible.The flow that several solns are used to control blood sample and reagent can be provided, while the contact of control need not be contacted.
The pin shown in Fig. 9 a and 9b-and every in interface, pin 1201 can pierce barrier film 1202, the liquid that will be stored on instrument It is delivered to the card of passage 1,203 1204.Flow sensor and controller can be located on instrument.When measure terminates to take out pin 1201, every The seal itself of film 1202, card are leak-frees, are easily processed.Although the reagent that instrument is stored can be led to card by this method well 1204, but sample blood is present on card, once needle-penetration barrier film 1202, will contact blood.The pin 1201 of bent at its tip It can be designated specifically to be not required to (coring) i.e. pierceable barrier film of coring.
It during operation, can minimize the pollution of pin 1201, there is several methods that overcoming.During measure, promote in stream flushing needle Portion.At the end of measure, available membrane 1202 is wiped outside pin 1201 when taking out pin.The small size of pin 1201 can limit reservation Blood volume in its tip surface area.Instrument can be very quick heating/cooling cycle to the heat sterilization process of needle point, Because small size and the geometric similarity of pin and heat transfer latch.Sterilization process can use experiment to prove.Moreover, during power-off just The valve that normal off is opened can prevent any fluid from backflowing in instrument.
Fig. 9 c and 9d axle-membrane interface can be mentioned.In the method, the cylindrical shape that one end with elastic film 1206 can be used to seal Storage of samples room replaces long and thin sample loop.Film 1206 can be located in plastic housing (molded case) 1207, in storage of samples pond 1208 tops.In order to allocate sample, the film described in the leading screw backup rotated as micro-stepping motor.This substantially can be syringe pump, Make the piston in the backup film 1206 of axle 1205 rather than propulsion syringe cylinder.The advantages of this method is that physical barriers film 1206 can disappear Depollution problem.
Method may include the zero shift (i.e. a contact membranes 1206) that axle 1205 is found after card is arranged in instrument.Sample is store The stereomutation reaction for depositing room may be in non-linear relation with axial displacement, it is necessary to calibrate.The tip of axle 1205 can be directed to displacement efficiency Design.Actual conditions can be that axle operates (at full stroke) completely can deliver 80% sample in storeroom.Film 1206 needs To be recessed enough so as to finger will not surprisingly be pressed onto/drive membrane and allotment sample.
Membrane-membrane interface can be shown such as Fig. 9 e and 9f.In the method, sample can be still stored in the sealing of one end with elastic film Cylindrical shape storage pool in.The displacement of film 1206 can be caused with its sophisticated driver 1211 is closed with film 1212.If two films 1206 and 1212 have contacted, and film 1212 and 1206 can be made all to deform the driving pump of liquid 1213 to the tip of driver 1211, mobile Isometric fluid in sample cell 1208.
Some advantages of this method can be apparent.Flow sensor technology can be used for the flow velocity of control driving liquid 1213, Final control sample flow rate.Because driving is fluid-operated, film 1206 and 1212 is easily deformed to provide a high position naturally Move efficiency.This method can also eliminate pollution problem by isolating blood sample after physics film.
Method may include to find zero shift after installation card in instrument, to make film 1212 and 1206 contact just without moving Move any blood sample.The stereomutation reaction of storage of samples room 1208 may be with the stereomutation of driver film 1212 slightly offset from line Sexual intercourse is, it is necessary to calibrate.Film 1206 on card must be recessed enough so as to finger will not surprisingly be pressed onto/drive membrane 1206 and allotment Sample.
Fig. 9 e and 9f sample loop are not galleries, but shallow cylindrical cavity.Film 1212 and 1206 initially contacts Very well (i.e. therebetween without air entrapment), the volume that driving liquid 1213 deploys can make the repeatable amount (adjustable) of film deflection.
There may be dynamics change in membrane interface.The compliance that elastic membrane introduces should be small, because typical elastomeric such as silicone Rubber and Neoprene Poisson's ratio are almost incompressible generally in 0.45-0.50 scopes.Substantially, elastomer is all deformable, It is but incompressible；Their shape easily changes but its volume does not allow malleable.Therefore, the wherein hard material of plastic housing and driver The kinetic results significantly from elastomer Low compliance should not occur in the membrane-membrane interface that limitation elastomer shape changes.
The deflection of film 1206 can not allocate all samples or reagent accommodated in storeroom.Allotment ratio can use displacement efficiency Characterize.The efficiency of ε=80% should be regarded as reasonably.If it is also assumed that the ratio of film deflection and chamber diameter (for example, δ=1/3), Then displacement volume may be about
Vdisp=ε δ (π/4) d3
The diameter of storeroom can be estimated as follows
D=((4Vdisp/(εδπ))1/3。
Fig. 9 g table lists the storeroom diameter that enough store samples promote stream and every kind of reagent, it is assumed that measure will carry out 4 Minute, half the time measurement RBC, half the time measurement WBC.For on the card of sphering solution and sheath solution reagent storeroom it is big Card of the I based on enough sizes considers.
With the pin of the reagent storage box in instrument-supply reagent has remarkable advantage every interface.If on instrument Small-sized sterilizing mechanical device is provided, then can be by film-type interface or pin-every Interface Control blood sample.
Figure 10 is the illustrative methods schematic flow diagram for showing assembling and operation sample analyser.In illustrative examples, Blood analysis box can be used and analyzed such as 351 displays, can be used as shown in 370 and analysis control box is to help to verify analyzer Performance, and/or can as shown in 380 using and analytic set box to help to calibrate analyzer.Blood analysis can be installed every time Box carries out blood analysis.Control box can be arranged on analyzer as shown in 372, as shown in 374 cycling service as 1 time a day, It is accurate result with verify that analyzer obtains.As shown in 376, instrument can show measurement whether the mark in the range of.The mark Note may depend on measurement whether in normal, low or high scope.As shown in 380, can as shown in 382 calibration box on installation calibrating Device is simultaneously run as shown in 384.Instrument can adjust the calibration factor for meeting calibration as shown in 386.Calibration card can be arranged on analysis In instrument, with the frequency less than control card, such as every 3 months 1 time, with recalibration analyzer.Calibration may include before operating or after operation Make accurate pearl stream (precision bead flow) by flow channel, so as to such as calibration pulse width, there is provided through passage Granular size information.
Each box can accommodate all required fluids and/or composition to play corresponding function.This way it is not necessary to how much train just Operable and/or maintenance analysis instrument, and still obtain accurate result.What is provided has movable and/or disposable cassette sample Product analyzer can reliably be used by the personnel without professional training outside laboratory environment, can help to make sample analysis Process streaming, expense and medical worker's burden are reduced, increase the convenience of many Patient Sample A's analyses, including need quite frequency The patient of numerous blood monitoring/analysis.System may indicate that whether reagent and/or sample fluid addle, be stale, be contaminated, no It is correct or inappropriate or can not receive.The final activity of system may include without analysis, not provide result, offer mistake mark Note etc..
When shown in such as 351 using blood analysis box, by blood sample collection and it can be placed in blood analysis box, such as 353 and 355 Display.Blood sample can be sucked in blood analysis box as desired by capillarity or manual pumps.Then can be by blood analysis It is box-packed in analyzer instrument.In illustrative examples, then analyzer can voluntarily be directed at the phase of blood analysis box and analyzer Should part (such as light source/photodetector), such as 357 displays.Then, pressable one or more button starts blood analysis Journey.In some cases, button etc. is not pressed, but only by box-packed analyzer can be caused to start alignment and blood into analyzer Liquid analyzes process.
Card can be such as 358 operations.Once driving analyzer, analyzer can carry out a variety of tests.For example, analyzer can close All valves on blood analysis card, pressure is applied to various fluid intakes on card.Then analyzer is measurable flows through upper one of card Or the flow velocity of multiple flow sensors.Flow should be zero, because all valves are all closed.However, if flow sensor carries Show non-zero points flow velocity, then analyzer can be by flow sensor recalibration clear point flow.This can help to increase that flow sensor is surveyed The accuracy of amount.Analyzer can check and start to remove bubble as needed.Besides or furthermore, analyzer can Survey Operations formula box The solidification of middle blood, such as by measuring the blood sample flow velocity (as used flow sensor) under pressure applied, if flow velocity phase It is too low for the pressure of application, it can determine that blood sample has solidified.If it find that blood clotting, analyzer, which can be shown, to be shown to survey Measure failure.
Then analyzer can implement blood analysis box timing.Blood analysis box timing can be similar to 2004 9 The scheme that the U.S. Patent Application Serial Number 10/932,662 that the moon is submitted on the 2nd is shown and described, it transfers assignee of the present invention, It is incorporated herein by reference.Specific blood analysis box timing may depend on the specific design of blood analysis box.Point Whether analyzer can also verify stable core fluid in any cytolytic dose passage on blood analysis box, if there is then identifying The position of core fluid.
Then blood analysis box can be for example dissolved the red blood cell of the blood sample part for measuring leucocyte, make by for The red blood cell nodularization of the blood sample part of red blood cell is measured, core flow is formed in any cytolytic dose passage on blood analysis box Body, and/or play any other required function.Analyzer can be provided light to for example any cell of selected areas of blood analysis box Measurement channel, detect the light through selected areas.
So, analyzer can be counted and classified to the particle in sample such as leucocyte, red blood cell, blood platelet etc., so After show, print, send sound or for user mark blood analysis result.In some instances, analyzer shows or beaten Quantitative result (such as within preset range and/or outside) is printed off, so that user need not calculate or explain again.It can be considered Into measurement, as shown in 361, result is shown.Finally, the blood analysis box of analyzer is can be taken off, is thrown aside as shown in 363.
When operation will be controlled such as 370 displays, control box can be used.In some cases, can periodically be controlled Operation, as 1 time a day or 1 times a week.Control box may include the control sample with known features.Therefore, when with analyzer pair When control sample is analyzed, known results should be obtained.In illustrative methods, by control box in analyzer, such as 372 is aobvious Show.Then, analyzer is started, result is analyzed and shown to such as 374 displays, analyzer, such as 376 displays.In some instances, Analyzer shows or printed quantitative result (such as within preset range and/or outside), so that user need not calculate again Or explain.Finally, it can be taken off the control box of analyzer and throw aside., can be excellent if controlling the result of operation outside preset range Choosing carries out correcting travel, such as correcting travel 380.
When by the correcting travel for carrying out 380 displays, calibration box can be used.In some cases, can periodically be calibrated Operation, such as monthly 1 time, or as needed.Calibration box may include the calibration sample with known features.Therefore, when with analysis When instrument is analyzed calibration sample, known results should be obtained.In illustrative methods, will calibrate it is box-packed in analyzer, such as 382 displays.Then, start analyzer, such as 384 displays, obtain multiple results.By comparing expected results with being obtained during correcting travel The result arrived, analyzer can automatically adjust one or more of memory calibration factor with recalibration analyzer, so as under When once running, analyzer will produce expected or required result, such as 386 displays.
Figure 11 a are the flow charts for showing operation sample analyser illustrative methods.Overall such as 400 displays of illustrative methods, Enter in step 402.Control reaches step 404, wherein blood sample is provided to disposable fluid box.Then control reaches step 406, wherein disposable fluid box is inserted in blood sample analysis instrument.Then control reaches step 408.Step 408 starts blood sample point Analyzer, step 410 obtain blood analysis result from blood sample analysis instrument, and no longer need blood sample analysis instrument user it is any mutually Effect.Then control reaches step 412, exit step.
Figure 11 b are the exemplary method flowcharts for showing another operation sample analyser.Illustrative methods are overall such as 500 It has been shown that, starts in step 502.Control reaches step 504, wherein blood sample is provided to disposable fluid box.Then control reaches Step 506, wherein disposable fluid box is inserted in blood sample analysis instrument.Then control reaches step 508.Step 508 starts blood Sample analyzer, step 510 obtain blood analysis result from blood sample analysis instrument, and no longer need that blood sample analysis instrument user's is any Interaction.Then control reaches step 512.Whether within a predetermined range step 512 determines blood analysis result.As above institute State, in some instances, analyzer can show or print quantitative result (such as within preset range and/or outside), so as to User need not calculate or explain again.Then control reaches step 514, exit step.
Figure 12 is another exemplary method flowchart for showing operation sample analyser.Overall such as 600 displays of method, Step 602 enters.In illustrative methods, blood analysis box can be used and analyze as indicated at 604, can be as shown at 620 using simultaneously Analysis and Control box to help to verify the performance of analyzer, and/or can as shown in 640 using and analytic set box to help to calibrate point Analyzer.Blood analysis box can be installed when carrying out blood analysis every time.Can be by control box periodically as being mounted in analyzer 1 time a day In, to verify that analyzer can produce accurate result.Can more low frequency such as will calibrate for every 3 months 1 time it is box-packed in analyzer, with Recalibration analyzer, or calibration as needed.
Every kind of box type can all include all required fluids and/or play the composition of corresponding function.So, can be not required to Just operable and/or maintenance analysis instrument is much trained, obtains accurate result.What is provided has movable and/or disposable cassette Sample analyser can pass through seldom or can reliably be used outside laboratory environment without professional training, can help Make sample analysis process streaming, reduce expense and medical worker's burden, increase the convenience of many Patient Sample A's analyses, including Need the quite frequently patient of blood monitoring/analysis.
In Figure 12 illustrative methods, when using blood analysis box, control reaches step 604.In step 606, Blood sample is provided to disposable fluid box.Then control reaches step 608, wherein disposable fluid box is inserted into blood sample analysis instrument It is interior.Then control reaches step 610.Step 610 starts blood sample analysis instrument, and step 612 obtains analysis result from blood sample analysis instrument.
When using control box, control reaches step 620.Step 620 causes the control to step 622, wherein by control box Insert in blood sample analysis instrument.Then control reaches step 624.Step 624 starts blood sample analysis instrument, step 626 control fluid Box obtains controlling analysis result.Then control reaches step 628.Step 628 determines whether control analysis result controls expected In the range of.If controlling analysis result not in desired extent, not it is believed that the result that blood analysis box obtains.In certain situation Under, calibration box recalibration sample analyser can be used, then with operation/calibration of another control box verification sample analyzer.
When using box is calibrated, control reaches step 640.Step 640 causes the control to step 642.Step 642 will calibrate In box insertion blood sample analysis instrument.Then control reaches step 644.Step 644 starts blood sample analysis instrument, and step 646 is flowed with calibration Body box obtains calibrating analysis result.Then control reaches step 648.According to calibration analysis result, step 648 is adjusted as needed Analyzer.
In some cases, sample analyser can be instrument, integral type and/or the self-holding tester of full automation Device.Sample analyser can receive and analyze direct untreated sample such as capillary blood (needle-holding hand refers to), venous whole, nose swab Or urine etc..Besides or furthermore, sample analyser can only need basic non-technical dependence sample operations, including any decontamination Dye operation.Equally, sample analyser can only need basic non-technical dependence reagent operation, such as " mix reagent A and reagent B ", operator can not needed to intervene in analytical procedure.In some cases, sample analyser may include or provide specification (in some cases, when exact p-value is clinically where appropriate, sample analyser may include or provide acquisition and transports for true Recognize the material used in the sample of test).
Sample analyser can be equipped with Quick Reference specification guide.Quick Reference Guide can provide operation sample analyser Quick Reference.In use, user is referring to Quick Reference Guide to how to operate when sample analyser has any problem.
In some cases, Quick Reference Guide may include to self solve image or chart, and diagram illustrates various operation steps Suddenly, sometimes by sample collection until analysis illustrates.In an illustrative examples, Quick Reference Guide only includes figure Picture or chart, not including word or including minimum word.This user that can help not being proficient in concrete syntax (such as English) has Effect ground operation sample analyser.In an illustrative examples, Quick Reference Guide can show and/or describe step：From packaging Interior taking-up disposable cassette；The congested cap for removing box lancet and/or the lid (such as band) for removing label, the label exposed to Air changes colour after one section of scheduled time；Extract blood samples of patients；The blood of extraction is provided to box；By box-packed in instrument；Operation Instrument and reception result；Box is taken out from instrument, throws aside box.This is an example.
It is expected that tool housing may include to place pocket of Quick Reference Guide etc..In use, user can open pocket Quick Reference Guide is referred to.Or Quick Reference Guide can be fixed on sample analyser shell with helical form clip etc., This can allow user to stir each page of Quick Reference Guide when in use., can be by Quick Reference in another illustrative examples Guide is fixed on movable box, or can be printed in the packaging for filling movable box.In also having another illustrative examples, Quick Reference Guide can be printed upon on leaflet, leaflet can be attached on wall of sample analyser etc..
In some cases, in order to further reduce produce error result danger, it is possible to provide one or more failure reports Alert and/or failure safe mechanical device.For example, in an illustrative examples, sample analyser can help to detect user be The no sample type that mistake is provided.For example, if setting sample analyser carries out the white blood cell count(WBC) of whole blood sample, sample point Whether the sample that analyzer can help to detect user's offer is not blood.
In an illustrative examples, sample analyser can be analyzed, if one or more output parameters are predetermined Outside scope, then sample analyser may not provide result and/or send error message or error code.If for example, sample analyser It is the flow cytometer for carrying out white blood cell count(WBC) to whole blood sample, sample analyser is not (or a small amount of white to any leucocyte Cell) count, then sample analyser may not provide result, in some cases, there is provided error message or error code.
In some instances, one or more optical measurement are identified in flow channel with the presence or absence of incorrect available for help Fluid, such as when user provides incorrect sample, or when the correct flowing that not provide reagent to fluid box is led to During road.Figure 13 shows a kind of such optical measurement.In fig. 13, sample fluid 700 is present in by the conduit wall of such as fluid box In 704 passages 702 limited.In illustrative examples, conduit wall 704 has refractive index " nw", sample fluid has refractive index “ns”.The incident beam (sometimes collimated light beam) of one of the offer of light source 706 and conduit wall 704 angulation.The detector 708 of placement For detecting the light 710 from conduit wall/example interface reflection.The amount that the light of detector 708 is reflexed to from passage/example interface will Depending on conduit wall " nw" and sample fluid " ns" relative index of refraction.When required sample fluid 700 is present in passage 702, It can determine that required volume reflection or reflected signal.When by incorrect sample type or incorrect reagent or other incorrect samples When product fluid is provided to flow channel 700, " the n of incorrect sample fluidic" refractive index can cause detector 708 to measure light 710 different reflected signals.Such change can be shown that incorrect sample fluid in flow channel 702 be present.Besides or furthermore, Such change can be shown that bubble, clot or the further feature of other unwanted particles or sample fluid be present.When such detection When, sample analyser may not provide result, in some cases, it can be possible to send error message or error code to user.
Figure 14 displays are another to be can be used for helping to identify incorrect or unwanted fluid in flow channel when be present Optical measurement.In fig. 14, sample fluid 720 is present in the flow channel 722 of the restriction of conduit wall 724 of such as fluid box. In illustrative examples, conduit wall 724 has refractive index " nw", sample fluid has refractive index " ns”.Light source 726 is provided and led to The incident beam (sometimes collimated light beam) of one of road wall 724 angulation.The detector 728 of placement is used to detect through passage 722 With the light 730 of sample fluid 720.
In the illustrative examples, make passage 722 sufficiently fine, so as to as sample fluid refractive index " ns" within the required range When allow optics tunnelling (optical tunneling) pass through passage 722 and sample fluid 720.If sample fluid refractive index “ns" less than required scope, then light will not pass through passage 722, but be reflected.If sample fluid refractive index " ns" higher than required Scope, then light will tend to through passage 722 and sample fluid 720, therefore the example may be best suitable for being used to detect refractive index “ns" the incorrect sample fluid of the refractive index of sample (such as blood) less than needed for.Besides or furthermore, the illustrative examples can root According to the presence needed for detecting bubble, clot or other unwanted particles or sample fluid further feature.When such inspection During survey, sample analyser may not provide result, in some cases, it can be possible to provide error message or error code.
Figure 15 is another incorrect or unwanted available for when existing in the flow channel for identifying such as fluid box The illustrative examples of fluid.In the illustrative examples, sample fluid 750 is provided and led in the flowing limited by conduit wall 754 In road 752.In illustrative examples, two or more electrodes 760 are provided on one or more conduit walls 754, at some In example, two or more electrodes 760 can be formed on one or more plastic sheets, it is formed together in layered laminate or fixation The fluid circuit of fluid box.In the flow channel 752 that can extend into two or more electrode assemblings on fluid box or along stream Flow channel 752 on body box extends, and is connected with required drive circuit.
Power supply 758 can provide signal between electrode 760, the resistance between the measurable electrode by sample fluid 750. The resistivity of sample fluid 750 in this measurable passage 752.When incorrect sample fluid appears in flow channel 752, no The resistivity of correct sample fluid can be outside desired extent.Resistivity can also prompt bubble, clot be present beyond desired extent Or the further feature of other unwanted particles or sample fluid.When such detection, sample analyser can not provide result, In some cases, it can be possible to provide error message or error code.
In some cases, power supply 758 can provide low potential AC signals (such as less than 10V peak-peaks, less than 5V peak-peaks, small In 3V peak-peaks, less than 1V peak-peaks, less than 0.5V peak-peaks or less than 0.1V peak-peaks), cause sample fluid to limit electrode 760 750 electrochemical reaction.Electrochemical reaction can be introduced into sample fluid 750 such as by bubble, and this can in some cases It can be not intended to occur.
In addition to using above-described resistivity measurement or it the substitute is, it is contemplated that capacitance measurement can be used. In the illustrative examples, the electric capacity between two or more electrodes can be measured by sample 750.When by incorrect sample fluid When providing to flow channel 752, the electric capacity result of incorrect sample fluid may exceed desired extent.Electric capacity exceeds desired extent It can also prompt bubble, clot or the further feature of other unwanted particles or sample fluid be present.When such detection, sample Product analyzer may not provide result, in some cases, it can be possible to provide error message or error code.
Figure 16 is another incorrect or unwanted available for when existing in the flow channel for identifying such as fluid box The illustrative examples of fluid.In the illustrative examples, sample fluid 770 is provided and led in the flowing limited by conduit wall 774 In road 772.In illustrative examples, there is provided PH sensor 776 is in fluid communication with sample fluid 770.PH sensor 776 is detectable The PH of sample fluid 770, by signal reports to controller 780.There is provided when by incorrect sample fluid to flow channel 772 When, the PH of incorrect sample fluid can exceed desired extent.PH it is horizontal beyond desired extent can also prompt to exist bubble, clot or The further feature of other unwanted particles or sample 770.When such detection, sample analyser can not provide result, Under certain situation, it may be possible to provide error message or error code.
Figure 17 is to can be used for when sample fluid in identification flow channel one or more bubbles occurs or other be not required to The illustrative examples for the particle wanted.In the illustrative examples, sample fluid 800 is present in by the conduit wall of such as fluid box In 804 flow channels 802 limited.The incident beam of one of the offer of light source 806 and conduit wall 804 angulation (is sometimes collimated light Beam).The detector 808 of placement be used for detect by existing bubble in sample fluid 800 in flow channel 802 or it is other need not Particle scattering light 730.If such as sample fluid 800 does not have any bubble, then light will pass through sample flow unscattered Body, detector 808 will can't detect signal (or low signal).When detector 808 finds the light scattering signal higher than a certain threshold value When, show that the sample fluid 800 in flow channel 802 has one or more bubbles or other unwanted particles, sample point Analyzer may not provide result, in some cases, it can be possible to provide error message or error code.
Figure 18 be can be used for identification flow channel in sample fluid when occur one or more bubbles or it is other not The illustrative examples of the particle needed.In the illustrative examples, sample fluid 820 is present in by the conduit wall of such as fluid box In 824 flow channels 822 limited.Ultrasonic transducer 826 and the adjacent flow channel 822 of ultrasonic receiver 828 are provided.At some In the case of, there is provided ultrasonic transducer 826 be located at the side of flow channel 822, there is provided ultrasonic receiver 828 be located at offside. In the case of other, there is provided ultrasonic transducer 826 and ultrasonic receiver 828 be located at the homonymy of flow channel 822.In any feelings Under condition, ultrasonic receiver 828 can be used in detection and cause ultrasound by the bubble in fluid sample 820 or other unwanted particles The scattering for the ultrasonic signal that transducer 826 is sent.When such detection, sample analyser may not provide result, in some feelings Under condition, it may be possible to provide error message or error code.
Figure 19 be another sample fluid that can be used in identification flow channel when occur one or more bubbles or The illustrative examples of other unwanted features.In the illustrative examples, sample fluid 850 is located at by the logical of such as fluid box In the flow channel 852 that road wall 854 limits.The flow sensor 856 of offer is in fluid communication with flow channel 852, for detecting The flow velocity of sample fluid 850.Flow sensor can be such as hot gas flow velocity type flow sensor and/or microbridge type flow sensing Device.Microbridge flow sensor is described in for example, U.S. Patent number 4,478,076, U.S. Patent number 4,478,077, United States Patent (USP) Numbers 4,501,144, U.S. Patent number 4,651,564, U.S. Patent number 4,683,159 and U.S. Patent number 5,050,429, all It is incorporated herein by reference.
Variable pressure can be supplied to the sample fluid 850 in flow channel 852 by pressure source 860.Controller 862 can receive Flow velocity signal from flow sensor 856, in some cases, it can control pressure source 860.In an illustrative examples, In order to detect the bubble of sample fluid, controller 862 can cause the suddenly change of pressure source 860 to be applied to the pressure of sample fluid 850 Power.Then utilizable flow sensor 856 monitors flow velocity caused by sample fluid 850 and changed.
Figure 20 is to show to be provided by pressure source 860 to the exemplary pressure of sample fluid 850 in Figure 19 flow channels 852 The figure of pulse 900.In sample fluid 850 during little or no bubble, the flow velocity of 902 displays can obtain.When pressure pulse 900 is prominent So during increase, flow velocity 902 more quickly increases to high flow velocities value 906 from relatively low flow speed value 904, when pressure pulse 900 is unexpected During reduction, then relatively low flow speed value 904 is reduced to from high flow velocities value 906 rapidly.However, when bubble occurs in sample fluid 850, When pressure pulse 900 increases suddenly, gained flow velocity 908 (dotted line is shown) may be increased to more lenitively from relatively low flow speed value 904 High flow velocities value 906, when pressure pulse 900 reduces suddenly, gained flow velocity 908 more lenitively may drop from high flow velocities value 906 As little as relatively low flow speed value 904.Air in bubble can for example increase the compressibility of sample fluid 850, so causing flow velocity more Lenitively increase and reduce.The change of flow velocity when applying pressure change by monitoring, it is possible to find gas be present in sample fluid 850 Bubble.It is substantially reduced if it find that flow velocity changes, sample analyser may not provide result, in some cases, it can be possible to provide mistake Message or error code by mistake.
Expecting pressure source 860 can be suitable pressure source, including conventional pumps, compressed air source or needs it is any other Convenient pressure source.In some cases, pressure source 860 can be high-frequency pressure source such as piezoelectric vibrator, ultrasonic transducer or appoint What its type high-frequency pressure source.In some cases, high-frequency pressure source can be used in combination with conventional pumps or other pressure sources, can With parallel work-flow.That is, when analyzing sample fluid, conventional pumps or other pressure sources 860 can be used for making sample fluid real Border is moved through the flow channel 852 of fluid box.High-frequency pressure source may not be usable for making sample fluid substantially move along flow channel It is dynamic, but available for frequency pressure pulses are produced to sample fluid to detect some parameters of sample fluid, including such as bubble Compressibility in the presence of, sample fluid etc..The compressibility of sample fluid can be used for assisting in the sample fluid in flow channel 852 Whether 850 be expected sample fluid type, if it is not, then sample analyser may not provide result, in some cases, can Error message or error code can be provided.
In any event, in some cases, when high-frequency pressure source and conventional pumps or other pressure sources are simultaneously or parallel During operation, can fluid circuit handle sample when in-situ monitoring sample fluid.
In some cases, pressure pulse is available for sample fluid end in the flow channel in determination or estimating of fluid loop Or the position of distal end.Figure 21 shows a kind of such illustrative examples.In figure 21, two flow channels 1000 and 1002 are shown. Sample fluid 1004 is present in flow channel 1000, and sample fluid 1006 is present in flow channel 1002.Display pressure is changed Energy device (such as pressure source) 1008 and pressure receiver (such as pressure sensor) 1010 are in the known bits relative to flow channel 1000 Put to flow with sample fluid 1004 and connect.Pressure transducer 1008 can produce pressure pulse in sample fluid 1004.Pressure arteries and veins Punching propagates to end 1012 along sample fluid 1004.Some energy of pressure pulse will be anti-by the end 1012 of sample fluid 1004 It is emitted back towards pressure receiver 1010.The current position in end 1012 and pressure transducer 1008 and/or pressure receiver 1010 away from From the time correlation for propagating to end 1012 along sample fluid 1004 with pressure pulse and returning pressure receiver 1010 needs.Cause This, by measuring the time that pressure pulse propagates to end 1012 and returning pressure receiver 1010 needs, can determine end 1012 along the position of flow channel 1000.
Flow channel 1002 is similar to flow channel 1000, but end is located at along the farther distance of flow channel.Therefore, it is false It is identical with sample fluid 1004 to determine sample fluid 1006, pressure pulse propagates to end 1014 and returning pressure receiver 1018 needs The time wanted will be greater than the time of the needs of flow channel 1000.Moreover, the reflected pressure pulse that pressure receiver 1018 receives The amplitude for the pressure pulse that amplitude may receive than pressure receiver 1010 is weak.Therefore, monitoring amplitude can provide another difference Estimation determines position of the end 1012 and 1014 along flow channel 1000 and 1002.
Figure 22-23 displays determine two kinds of fluids when the illustrative methods collected in fluid circuit.In many sample analysis It is initially to provide different fluid in different flow channels in instrument.However, in fluid circuit, various fluids generally mix. For example, although blood sample and nodulizer can be initially provided in single flow channel, then in fluid circuit downstream Place is mixed.When and how various fluids are concentrated may be critically important to the allomeric function of sample analyser, such as United States Patent (USP) Patent application serial numbers 10/932, disclosed in 662, it transfers assignee of the present invention, incorporated herein by reference.
In order to assist in when two or more fluids collect in fluid circuit downstream, available pressure transducer is at least Pressure pulse is produced in a kind of fluid sample.For example, with reference to figure 22, pressure transducer 1030 (such as pump, piezoelectric vibrator, ultrasound Transducer or any other type pressure transducer) pressure can be produced in the sample fluid 1032 in the first flow channel 1034 Pulse.Pressure receiver 1036 (such as pressure sensor, ultrasonic receiver) can be with the sample fluid of second flow path 1042 1040 are in fluid communication.First flow channel 1034 and second flow path 1042 can concentrate on flow channel 1044, preferably as schemed 23 displays.
Referring again to Figure 22, by pressure transducer 1030, caused pressure pulse can be along in the first sample fluid 1032 A kind of sample fluid 1032 is propagated, but possible unobvious extend to the end or distal end 1046 of the first sample fluid 1032. In illustrative examples, initially with air or the flow channel 1044 of other gas blank maps 22 display, then work as sample fluid 1032 and 1040 are replaced when being promoted along its respective flow channel 1034 and 1042 by sample fluid 1032 and 1040.In sample Before fluid 1032 and 1040 is concentrated, pressure receiver 1036 can not possibly receive the significant pressure from pressure transducer 1030 Pulse or the pressure pulse substantially decayed.
One or more pressure source (not shown) such as pumps etc. can be started, make sample fluid 1032 and 1040 along its respective stream Dynamic passage 1034 and 1042 moves, until sample fluid 1032 and 1040 collects, as Figure 23 is preferably shown.When this feelings of appearance During condition, pressure pulse caused by pressure transducer 1030 can more freely propagate to pressure receiver 1036 now.Therefore, lead to Cross when monitoring pressure receiver 1036 starts to receive or receive the pressure of the less decay from pressure transducer 1030 Pulse, it may be determined that when sample fluid 1032 and 1040 collects.
In some cases, it is (sometimes at a relatively high can to produce pressure pulse sequence in sample fluid for pressure transducer 1030 Frequency), can be with the pump that actually moves flow channel 1034,1042 and 1044 of the sample fluid 1032 and 1040 along fluid circuit Or other pressure sources while or parallel work-flow.Therefore, pressure transducer 1030 can be used for the sample flow of in-situ monitoring fluid circuit Body, more specifically monitor when sample fluid 1032 and 1040 collects in downstream.
In some cases, sample analyser is not in horizontal plane when analyzed, can influence the operation of sample analyser.For Detection such case, it is contemplated that sample analyser may include horizon sensor.In an illustrative examples, horizon sensor can To be available from Omron Corporation Micro Tilt sensors (D6B).Other horizon sensors may include have electricity defeated The ball sensor gone out.Use level sensor, sample analyser can determine that the whether enough levels of sample analyser to be analyzed. If sample analyser does not measure up, sample analyser may be without analyzing and/or not providing result, in certain situation Under, it may be possible to provide error message or error code.
Another kind checks whether method horizontal enough includes making the one or more of receiving fluid to flow sample analyser Passage is depressured, flow velocity of the measurement fluid in one or more flow channel.If sample analyser does not measure up, gravity can be led The flow velocity of one or more flow channel is caused to exceed desired extent.If flow velocity exceeds desired extent, sample analyser can be regarded Not measure up, sample analyser may be without analyzing and/or not providing result, in some cases, it can be possible to provide mistake Message or error code.
In some cases, collision or mobile example analyzer may influence sample analyser operation during analysis.In order to send out Existing such case, it is contemplated that sample analyser may include vibrations and/or oscillation gauge.In an illustrative examples, vibrations and/ Or oscillation gauge can be available from Omron Corporation Shock/Vibration sensors (D7E-2).Use shake Dynamic and/or oscillation gauge, sample analyser can determine that whether sample analyser is collided or moved.If sample analyser is Fully collided, then sample analyser may the person of needing to use run control card or calibration card before proceeding, with verification sample Analyzer is correctly run.In some cases, whether sample analyser is collided or is moved when sample analyser can determine that analysis. If sample analyser has fully been collided in analysis, sample analyser may not provide result, in some cases, can Error message or error code can be provided.
In some cases, sample analyser may include instrument and movable and/or disposable cassette.Because the row of user To be sometimes not expectable, it is possible that needing to confirm box being correctly inserted into instrument before analysis is started.A kind of implementation Be by box with Instrument Design is into only in the right direction just can be by box inserting instrument.For example, Figure 24 is shown by the groove of instrument 1102 Sew up the box 1100 of receipts (arrow 1104).Exemplary cartridge 1100 includes the groove 1106 positioned at the upper surface of box 1100.Instrument includes Corresponding male member 1108, when with relative to instrument 1102 it is in the right direction insert box 1100 when, the male member is adapted to extend into groove In 1106.If turning upside down insertion box 1100, groove 1106 and male member 1108 will not counterpart, will prevent box 1100 from inserting completely In the line of rabbet joint for entering instrument 1102.Equally, as the inserting instrument 1102 of one end 1112 of compartmentalized box for holding assorted fruits and candies 1100 the line of rabbet joint in, then the He of groove 1106 Male member 1108 will not counterpart, by the line of rabbet joint for preventing the fully-inserted instrument 1102 of box 1100.Box 1100 is simply locked instrument by this 1102 can only be to be correctly oriented a kind of example in inserting instrument 1102 with Bedpan 1100.
Direction of the box relative to instrument can be confirmed by any method, particularly if when box does not lock pertinent instruments. For example, in some instances, when box is correctly inserted into instrument, one or more pressure ports can extend between instrument and box. Instrument can apply pressure to one or more pressure ports, check whether fluid needed for discovery.If instrument pressure port and box pressure Mouth does not dock, then can not find required fluid.If do not find needed for flow velocity, sample analyser may without analysis and/ Or result is not provided, in some cases, it can be possible to provide error message or error code.
In another example, box may include one or more optical windows or other optical textures.It is if box is correct Ground is fitted into instrument, and instrument can be ask with optics and visit the position for including one or more optical windows or other optical textures.If Can't detect intended optical reaction, then may without in the right direction ground mounting box, sample analyser may without analyzing and/or Result is not provided, in some cases, it can be possible to provide error message or error code.
In some cases, sample analyser may need sample analysis needed for one or more reagents progress.It may need Whether functional determine whether there is correct reagent and reagent., can be by reagent in a reservoir in an illustrative examples Delivering, the container may include the bar code of identification reagent various parameters or other codes.Various parameters can be with for example, indentifying substance class Type, date of manufacture, the reagent term of validity and other parameters.Sample analyser may include barcode reader or other code readers, readable Take various parameters.Then sample analyser can determine that such as reagent whether be the correct reagent of required sample analysis, reagent whether More than specified term of validity etc..If reagent be not required analysis correct reagent or performance it is bad, sample analyser may Without analyzing and/or not providing result, in some cases, it can be possible to provide error message or error code.
In some cases, reagent can be stored on movable and/or disposable cassette.The disposable cassette that Figure 25 is shown 1120 include three rooms 1122a, 1122b and 1122c, and each room is used for specific needed for the analysis that storage will be carried out with box 1120 Reagent.Display makes bar code 1124 be attached to box 1120.Once box is correctly inserted into corresponding instrument, bar can be read in instrument Shape code, determine whether reagent is the correct reagent of required sample analysis, whether reagent exceedes it and specify term of validity etc..
Bar code 1124 can also identify many kinds of parameters relevant with box 1120.For example, bar code 1124 can identify box, box branch The analysis type held, box specificity calibration parameter (if any), the timing parameters of analysis, analysis input pressure and/or Flow velocity etc..In some cases, bar code 1124 may also provide the software that instrument when being analyzed with box uses.Bar shaped is not provided Code 1124 or in addition to providing bar code 1124, may also provide RFID label tag, and instrument may include the machine of reading RFID label tag Tool device.RFID label tag may include the above-mentioned similar information on bar code 1124.
Temperature can also influence the performance of some reagents, in some cases, it is possible to provide maximum temperature indicator 1126 and/or Minimum temperature indicator 1128.Minimum temperature indicator 1128 can be similar to the freezing indicator purchased from JP Labs.By JP The freezing indicator use that labs is provided can be easy to the label form for adhering to box or other containers.When the temperature of freezing indicator Degree less than water it is below freezing when, it produces irreversible color change, and such as blueness becomes red.Instrument may include that detecting freezing refers to Show that the optics of the color of agent 1128 is ask and visit device, if reagent has been exposed to the temperature less than minimum temperature, sample analyser may Without analyzing and/or not providing result, in some cases, it can be possible to provide error message or error code.
Equally, maximum temperature indicator 1126 can be similar to the temperature indicator purchased from JP Labs.It is predetermined when reaching some During temperature (or temperature range, usually above room temperature), there is color change in these indicator.When heated, they are from without discoloration Into it is red, from colourless become green, become red etc. from blueness.The oil of commercially available acquisition can be easy to add these indicator In black instrument such as relief printing plate (flexo) and intaglio plate (gravure).Instrument may include that the optics of the color of detection temperature indicator 1126 is ask Device is visited, if reagent has been exposed to the temperature higher than maximum temperature, sample analyser may be without analyzing and/or not providing As a result, in some cases, it can be possible to provide error message or error code.
It may also provide humidity and/or moisture indicator.Humidity and/or moisture indicator can be similar to purchased from JP Labs' Those.Color change can be occurred by being all exposed to humidity and/or moisture indicator after moisture.Under home humidity, face Color changes the time needed can from a few minutes to several weeks.
Exemplary cartridge 1120 may also include time marker 1130.In some instances, box 1120 can packed In be shipped to user.The environment of control can be provided around box 1120 by packing.Before use, user must be from the package Box 1120 is taken out, so that box 1120 is exposed to environment.Time marker 1130 can be started when the pack is opened, it is predetermined reaching Changeable colour or the detectable condition of offer after period.Time marker 1130 can be similar to the persond eixis purchased from JP Labs Device.
Instrument may include that the optics of the color of detection time indicator 1130 is ask and visit device, if after the period expires, sample divides Analyzer may be without analyzing and/or not providing result, in some cases, it can be possible to provide error message or error code.This can be User specifies and opens box packaging, blood or other samples are mounted in the scheduled time that box 1120 and all instruments are analyzed.This Can help to reduce user sample is waited mounted in box 1120 and then before being analyzed too long so as to allow sample solidification, be dried Or change the chance of feature.
When taking out box 1120 from packaging, time marker can not be started, but a band 1132 or other materials are carried For on the sample input port 1134 of box 1120.Can be covered with a band 1132 or other materials time marker 1136 it On.Before sample is loaded into box, user must remove band 1132 or other materials, time marker is exposed to ring Border simultaneously starts time marker.After predetermined amount of time, the changeable colour of time marker 1136 or the detectable condition of offer.
Instrument may include that the optics of the color of detection time indicator 1136 is ask and visit device, if had timed out, sample analyser May be without analyzing and/or not providing result, in some cases, it can be possible to provide error message or error code.This can be to use Person specifies from sample input port and removes band 1132 or other materials, enters blood or other samples mounted in box 1120 and with instrument The scheduled time of row analysis.This can help to reduce user sample is waited mounted in box 1120 and then before being analyzed it is too long So as to the chance for allowing sample to solidify, being dried or changing feature.
In some cases, box may include to help the spring driving lancet by blood sample collection in box.For example, Figure 26 Display includes the exemplary cartridge 1150 of spring driving lancet 1152.Spring driving lancet 1152 may include to make lancet It is inclined to the spring or other biased elements 1153 of extension bit 1154.Release mechanism 1156 and spring driving lancet can be made 1152 connect so that lancet is locked in into punctured bit 1158.When user starts release button or handle 1160, machinery dress is discharged 1156 releasable spring driving lancets 1152 are put, lancet can be moved to extension bit 1154 from punctured bit 1158 suddenly.Such as User's finger withstands box 1150 when fruit starts release button or handle 1160, then spring driving lancet 1152 is pierceable makes User's skin, suction out appropriate amount blood.Spring driving lancet 1152 (can not show with the sample collection capillary in box 1150 Show) it is in fluid communication, therefore in some instances, blood sample can be directly delivered in the sample collection capillary of box 1150.Spring Driving lancet 1152, release mechanism 1156 and release button or handle 1160 can be similar to be purchased from Becton, Dickinson and Company BDTM Lancet Device。
Or sample can be delivered to the sample of box from the finger of such as puncture by pipette (may use anti-coagulants coating) In product input or capillary.Sample can be shifted and is introduced into box with syringe.Can all alcohol swabs before piercing, cutting or cut finger Piece wipes finger and prepared.The lancet for being carved with set depth can be used, such as the lancet 1152 of box 1150 in Figure 26.
In some cases, with reference to figure 27, movable and/or disposable cassette 1200 may include the machine for removing bubble in fluid Tool device.In some cases, when bubble passes through under the perforated membrane for forming part flow channel wall, flow channel can be removed Bubble in middle liquid stream.In figure 27, show that alveolate liquid just flows along flow channel 1170.Film 1172 makes flow channel 1170 separate with draft chamber 1174.The pressure of draft chamber 1174 keeps below the pressure of flow channel 1170.In some cases, Film is hydrophobic membrane, is such as purchased from Millipore Corporation, Billerica, Mass FluoroporeTM、MitexTMOr DuraporeTMFilm.MitexTMFilm is prepared with PTFE, and aperture is 5 or 10 microns.FluoroporeTMFilm is used with HDPE carriers Prepared by PTFE, aperture is 1 or 3 micron.DuraporeTMFilm is prepared with Kynoar, 0.1,0.22 and 0.45 micron of aperture. Hydrophobic membrane can generally maintain higher differential pressure without enabling flow through water transfer membrane leakage.
Pressure differential between flow channel 1170 and draft chamber 1174 forces the gas of bubble 1180 through film 1172 and outside Exhaust outlet 1182, the bubble in the downstream liquid of film 1172 is caused to significantly reduce (preferably bubble-free).Then the liquid of bubble-free can To flowing down, such as 1184 displays, further handled by the fluid circuit on movable and/or disposable cassette.
Although in order to obtain the gas flow rate of bubble 1180 of the identical from capture, larger aperture compares small-bore needs Smaller pressure differential, but larger aperture can not both maintain big pressure differential and not allow liquid to pass through.Estimation has 1 micron openings Film should be able to maintain that 1PSI pressure differential, surface energy and pore geometry feature depending on liquid and film.
Figure 28 is the illustrative examples schematic diagram of the bubble grabber 1191 in the side wall of flow channel 1185.Bubble 1187 can Moved into along fluid 1193 in one or more grabbers 1191, assemble and melt with the bubble 1189 in grabber Close；Or bubble 1191 becomes the starting bubble 1189 in grabber.Grabber can become shaped like three in flow channel wall Angle hook-type, when bubble by when can be trapped and can not be flowed back to from grabber in fluid.In addition to the triangle of display, catch Obtain device shape and can also be rectangle, hemispherical etc..
In some instances, sample analyser can have the electronic equipment and/or software of control each part of sample analyser. In some cases, although sample analyser can be powered by line voltage distribution, there can be backup battery under powering-off state.Electronics Equipment may also include clock chip (sometimes with backup battery), to maintain correct time and date.Correct time and day Phase can be used for such as compare can from reagent pack or box on bar code reading the reagent term of validity, to determine reagent whether still It can so use.
If powered off during analysis, and without backup battery is provided, then electronic equipment and/or software can termination analysis, no Result is sent, in some cases, error message or error code are sent to user.
The various light sources and detector of electronic equipment and/or software and sample analyser can be connected.In some instances, Electronic equipment and/or software can before sample analysis, afterwards and/or periodically or the whole fortune for checking light source and photodetector OK.For example, electronic equipment and/or software can before sample analysis, afterwards and/or periodically or the one or more inspections of whole checking Survey the light whether device is detecting respective sources offer.
Besides or furthermore, the scrambling of box can be identified after box inserting instrument but before analysis program starts (irregularities), such as the crack of optical window or the dust of optical window or chip.This can be for example, by starting One or more light sources pass light through optical window and with one or more detectors detect optical signature (reflection, scattering, FALS, SALS, LALS etc.) complete.If optical window includes crack, dust or chip on optical window or has and other do not advise Then feature, then these atypical characteristics can produce on the detector it is expected outside optical signature.If electronic equipment and/or soft Part finds such atypical characteristic, then sample analyser may without analyzing and/or not providing result, in some cases, Error message or error code may be provided.Sordid optics can be cleaned with cotton piece.
If flow sensor in sample analyser be present, a certain electronic equipment and/or software can before analysis, it Flow sensor output is monitored afterwards or during analysis, to prove the flow velocity of prompting within the required range or meet required distribution map.Such as Fruit electronic equipment and/or the flow velocity of software discovery prompting within the required range or do not meet required distribution map, then sample analysis Instrument may be without analyzing and/or not providing result, in some cases, it can be possible to provide error message or error code.
In some cases, sample analyser may include certain built-in self-test (BIST) level.For example, in test pattern Under, some or all of electronic equipment storage element (such as register) together selectivity can be connected in series of scans chain, Wherein test vector can be continuously scanned in chain type register.In some cases, electronic equipment input and output can wrap Include the scratchpad register that only logic is inserted in test pattern.The functional clock cycle can be started, wherein by test vector bit (bits) logic circuit (logic) being released through between register, result is obtained by register.Then result can continuously be swept Register is described, compared with expected results.This can test sample analyzer comprehensively electronic equipment.
Many such test vectors can be implemented to realize required fault coverage.In some cases, fault coverage can As needed be more than 50% logic circuit, more than 60% logic circuit, more than 80% logic circuit, more than 90% logic circuit, More than 95% logic circuit or more than 99% logic circuit.After test, electronic equipment can be gone back to functional mode, can be again Start the normal functionality operation of sample analyser.Sample analyser can at regular intervals as 1 time per hour, 1 time a day, weekly 1 time, monthly 1 time or as needed with any other required interval automatically into test pattern.
In some cases, according to purposes, by electronic equipment and/or Software for Design and/or test, there is provided between mean failure rate Every the time (MTBF) be more than 5,000 hours, more than 8,000 hours, more than 10,000 hours, more than 50,000 hours, be more than 100,000 hours or more.
In some instances, can by sample analyser by internet be connected to it is remote one or more.Carried when so For when, test result can be delivered to far be used for for a long time store and/or further analysis (if desired).It is additionally, it is contemplated that remote Ground may include that the remote diagnosis of sample analyser and/or the diagnostic software of maintenance can be carried out.In some cases, far can be certainly The hardware or software of dynamic upgrading sample analyzer.
Analyzer can be connected by wireless communication connection with other positions or place.Radio contact can provide with internet or Other networks similar function and feature.Wireless communication connection may conform to the consensus standard of associated communication community or industry.
This analyzer can be hematology analyzer and immunoassay apparatus.
Card Rejections and other mistakes can be sent to far.It is abnormal high far to can determine that whether specific sample analyser occurs Mistake.Abnormal high mistake can prompt sample analyser failure or marginality (marginal) hardware component to be present, can far send Maintenance personal's maintenance/change the part before user pinpoints the problems.It can also be prompted in the high mistake of the exception of particular location The user of the position may need more to train.Such training can be from far being dispatched into lab assistant.Can by box and Instrument Design is also operable into untrained personnel.
Far can also statistical analysis from multiple sample analysers mistake and/or BIST results, identify in sample analysis Sample analyser part, software or the other regions that can strengthen in instrument later release.
As needed, can be by sample analyser or the temperature of surrounding, humidity and other ambient parameters, and impact, incline Oblique and other sensing data periodic detections and transmission are to far.
In this manual, certain situation can assume that or foretell property, but state in another manner or tense.
Although describing the present invention at least one illustrative examples, those skilled in the art are reading this explanation It will be clear that many changes and modification after book.Therefore the appended claims explained as broadly as possible with prior art are intended to include All such changes and modification.

Claims (10)

1. a kind of sample analyser, the sample analyser includes：
Shell；
The box that can be removed in the shell and from the shell is arranged on, the box includes：
At least one flow channel, at least one flow channel include the body at least the first wall, the second wall and the passage Product, wherein second wall is oppositely arranged and spaced apart with the first wall with the first wall；With
On first wall and extend into the first electrode of at least one flow channel, so as to the first electrode with Flow through the fluid contact of at least one flow channel；With
On second wall and extend into the second electrode of at least one flow channel, so as to the second electrode with Flow through the fluid contact of at least one flow channel；With the signal source for being connected to the first electrode and the second electrode, the letter The voltage and current that can be measured across the signal of at least one flow channel is combined in number source with first and second electrode Feature；With
The controller being arranged in the shell, the controller are configured to receive from united with first and second electrode The output signal of the signal source, the output signal indicate voltage and electricity across the signal of at least one flow channel Feature is flowed, when the voltage and current feature measured by first and second electrode and the signal source is in the fluid When outside particular range, the controller does not provide result, provides error message or provides error code.
2. the sample analyser of claim 1, wherein：
The resistivity of the volume is indicated across the voltage and current feature of the signal source of the electrode；
Resistivity in the particular range indicates suitable fluid be present in the volume；
Resistivity not in the particular range indicates incorrect reagent to be present in the fluid, bubble be present and/or not Acceptable characteristic of fluid；And
The resistivity in the particular range does not cause the sample analyser not provide analysis result or instruction mistake.
3. the sample analyser of claim 1, wherein：
The resistance of the volume is indicated across the voltage and current feature of the signal source of the electrode；
Resistance in the particular range indicates correct fluid be present in the volume；
Incorrect fluid reagent be present in resistance instruction fluid not in the particular range, bubble, and/or volume be present In fluid unacceptable feature；And
The resistance in the particular range does not cause the sample analyser not provide analysis result or instruction mistake.
4. the sample analyser of claim 1, wherein：
The electric capacity of the volume is indicated across the voltage and current feature of the signal source of the electrode；
Electric capacity in the particular range indicates suitable fluid be present in the volume；
Not in the particular range electric capacity instruction fluid in exist incorrect reagent, exist bubble, incorrect fluid, And/or unacceptable characteristic of fluid；And
The electric capacity in the particular range does not cause sample analyser not provide analysis result, the incorrect fluid of instruction or refer to Show mistake.
5. the sample analyser of claim 1, further includes the time marker associated with the box, wherein event causes Time marker works.
6. the sample analyser of claim 5, wherein：
In the box is originally located in and packed；And
The event is to take out the box from the packaging, and the event starts time timing of the time marker to consumption.
7. the sample analyser of claim 6, if wherein the time of consumption is more than the acceptable time, the box is inserted After instrument, card and instrument composition sample analyser, the sample analyser can be without analyzing, not providing result and/or providing Mistake indicates.
8. the sample analyser of claim 1, further comprising spring driving lancet, it is configured to blood sample being transported into institute State in box, wherein the lancet is inclined to extension bit and lancet is locked in retraction position until release by release device.
9. the sample analyser of claim 1, the bubble grabber being further contained at least one flow channel.
10. the sample analyser of claim 9, wherein the bubble grabber includes perforated membrane as at least one flowing A part for the wall of passage, to discharge bubble from passage when bubble passes through.
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