CN101379386B - Portable sample analyzer system - Google Patents

Abstract

A system relating to a sample analyzer, and more specifically, to a sample analyzer that is easy to operate and reduces the risk of providing erroneous results to the user. In some cases, the sample analyzer may be a portable sample analyzer containing a disposable fluid cartridge. The operator of the analyzer does not require training.

Description

Portable Sample Analyzer Systems

This application claims the benefit of US Provisional Patent Application 60/753,293, filed December 22,2005.

This application claims the benefit of US Provisional Patent Application 60/755,014, filed December 29,2005.

This application is a continuation-in-part of US Patent Application No. 10/908,460, filed May 12, 2005, which claims the benefit of US Provisional Application 60/571,235, filed May 14, 2004.

This application is a continuation-in-part of US Patent Application Serial No. 10/908,461, filed May 12, 2005, which claims the benefit of US Provisional Application 60/571,235, filed May 14, 2004.

This application is a continuation-in-part of US Patent Application Serial No. 11/306,508, filed December 30, 2005, which is a continuation-in-part of US Patent Application Serial No. 10/950,898, filed September 27, 2004.

This application is a continuation-in-part of US Patent Application Serial No. 10/938,265, filed September 9,2004.

background

The present application relates generally to sample analyzers, and more particularly to sample analyzers that are simple to operate and reduce the risk of providing erroneous results.

Chemical and/or biological analysis is important in life science research, clinical diagnostics, and monitoring of many environments and processes. In some cases, chemical and/or biological analysis of the sample fluid is performed and/or assisted by the sample analyzer. Depending on the application, the sample fluid can be a liquid or a gas.

Many sample analyzers are fairly large devices used by professionals in laboratory settings. In order to use many sample analyzers, the collected sample must first be processed, such as diluting the sample to the desired level, adding appropriate reagents, centrifuging the sample to complete the desired separation, etc., before the prepared sample can be used in the sample analyzer. To obtain accurate results, such sample handling typically must be performed by professionals, which can add to the expense and time required to perform sample analysis.

Many sample analyzers also require operator intervention during the analysis period, such as the need to enter additional information or otherwise process samples. This can also increase the cost and time required to perform the required sample analysis. Furthermore, many sample analyzers provide only raw analytical data output, which often must be recalculated and/or interpreted by a professional to arrive at appropriate clinical or other judgments.

US Provisional Patent Application 60/753,293, filed December 22, 2005, is incorporated herein by reference. US Provisional Patent Application 60/755,014, filed December 29, 2005, is incorporated herein by reference. US Patent Application No. 10/908,460, filed May 12, 2005, is incorporated herein by reference. US Patent Application No. 10/908,461, filed May 12, 2005, is incorporated herein by reference. US Patent Application No. 11/306,508, filed December 30, 2005, is incorporated herein by reference. Continuation-in-Part of US Patent Application Serial No. 10/950,898, filed September 27, 2004, is hereby incorporated by reference. US Patent Application No. 10/938,265, filed September 9, 2004, is incorporated herein by reference.

overview

The present invention relates generally to sample analyzers, and more particularly to sample analyzers that are simple to operate and reduce the risk of providing erroneous results to the user. In some cases, the sample analyzer may be a portable sample analyzer that includes a disposable fluid cartridge.

Brief description of the drawings

Figure 1 is a perspective view of an exemplary sample analyzer and cartridge;

Figure 2 is a schematic diagram of the exemplary sample analyzer and cartridge of Figure 1;

Figure 3 is a more detailed schematic diagram showing the flow control of the sample analyzer and cartridge of Figure 2;

Figure 4 is a schematic illustration of certain features of an exemplary cartridge;

Figure 5 is a schematic diagram of a plurality of exemplary reservoirs that can be contained within a cartridge;

Figure 6 is a schematic flow diagram showing an exemplary method of analyzing a blood sample;

Figure 7 is a flowchart showing an exemplary method of obtaining various red blood cell parameters;

Figure 8 is a schematic flow diagram showing another exemplary method of analyzing a blood sample;

Figures 9a, 9b, 9c, 9d, 9e and 9f show the needle-septum interface, shaft-membrane interface and membrane-membrane interface, respectively.

Figure 9g shows a table of cavity diameters for pusher fluid, lysing solution, sphering solution and sheath fluid;

Figure 10 is a schematic flow diagram showing an exemplary method of setting up and operating a sample analyzer;

Figure 11a is a flowchart showing an exemplary method of operating a sample analyzer;

FIG. 11 b is a flow chart showing another exemplary method of operating a sample analyzer;

Figure 12 is a flowchart showing another exemplary method of operating a sample analyzer;

13 is a schematic diagram of exemplary optical measurements that can be used to aid in identifying when incorrect or unwanted fluid is present in a fluid circuit flow path;

14 is a schematic illustration of another exemplary optical measurement that can be used to aid in identifying when incorrect or unwanted fluid is present in a fluid circuit flow path;

Figure 15 is a schematic diagram of electrical measurements that can be used to aid in identifying when incorrect or unwanted fluid is present in the flow path of a fluid circuit;

Figure 16 is another schematic diagram of measurements that can be used to aid in identifying when incorrect or unwanted fluid is present in the flow path of a fluid circuit;

17 is a schematic diagram of an illustrative example that can be used to identify when one or more air bubbles or other unwanted particles are present in a sample fluid within a flow channel;

FIG. 18 is another exemplary schematic diagram that can be used to identify when one or more air bubbles or other unwanted particles are present in a sample fluid within a flow channel;

Figure 19 is a schematic diagram of an illustrative example that can be used to identify when one or more air bubbles or other unwanted characteristics are present in a sample fluid within a flow channel;

FIG. 20 shows that a pressure source can provide an exemplary pressure pulse 900 to the sample fluid in the flow channel of FIG. 19;

FIG. 21 is a schematic diagram of an illustrative example that may be useful in determining or estimating the position of a sample fluid end or distal end in a flow path of a fluid circuit;

22-23 are schematic diagrams of illustrative examples that may be used to determine when two or more fluids combine downstream of a fluid circuit;

Figure 24 is a schematic diagram of an exemplary instrument and cartridge, where the cartridge and instrument are keyed, only allowing the cartridge to be inserted into the instrument in the correct orientation;

Figure 25 is a schematic diagram of an exemplary cartridge;

26 is a schematic diagram of an exemplary cartridge containing a spring activated lancet;

Figure 27 is a schematic diagram of an exemplary cartridge with a membrane that clears air bubbles in the flow channel; and

28 is a schematic illustration of an illustrative example of a flow channel bubble trap.

detail

The present invention relates to sample analyzers, and more particularly to sample analyzers that are simple to operate and reduce the risk of providing erroneous results. In some cases, sample analyzers may be, for example, blood analyzers such as flow cytometers, blood Chemical analyzers, clinical chemistry analyzers (such as glucose analyzers, ion analyzers, electrolyte analyzers, dissolved gas analyzers, etc.), urine analyzers, or any other suitable analyzers.

If the invention meets certain requirements, it may be exempt from regulation, either by itself or by tests performed with it. The invention may be practiced to provide and/or perform tests, which may be laboratory tests and procedures, which are simple and accurate so as to provide negligible chance of erroneous results, or produce no inferable results when performed incorrectly. risk of harming the patient. One type of waiver is available from the Clinical Laboratory Improvement Amendments (CLIA) of 1988.

Figure 1 is a perspective view of a flow cytometer. The flow cytometer is described for illustrative purposes only, and it is contemplated that other types of sample analyzers can be adapted as necessary. An exemplary sample analyzer is shown generally at 10 including a housing 12 and a removable or disposable cartridge 14 . The exemplary housing 12 includes a base plate 16, a cover 18, and a hinge 20 connecting the base plate 16 with the cover 18, although this is not required. In the illustrative example, base plate 16 includes first light source 22a, second light source 22b, and third light source 22c, as well as associated optics and electronics required to operate the sample analyzer. Each light source can be a single light source or multiple light sources, depending on the application. In some cases, the overall size of the enclosure is less than 1 cubic foot, less than 1/2 cubic foot, less than 1/4 cubic foot, or less as desired. Likewise, the overall weight of the housing can be less than 10 pounds, less than 5 pounds, less than 1 pound, or less if desired.

The exemplary cover 12 includes a pressure source (eg, a pressure chamber with a controlled microvalve), a first light detector 24a, a second light detector 22b, and a third light detector 22c, each with associated optics and electronics. Each photodetector can also be a single photodetector or a multiple photodetector, depending on the application. Polarizers and/or filters are available depending on the application, if required.

Exemplary removable cartridge 14 is adapted to receive sample fluid through a sample collection port, which in the exemplary example includes a lancet 32 . In some cases, lancet 32 is retractable and/or spring loaded. Cap 38 may be used to protect sample collection port and/or lancet 32 when removable cartridge 14 is not in use.

In the illustrative example, removable cartridge 14 performs blood analysis on a whole blood sample. The lancet 32 can be used to pierce a user's finger to obtain a blood sample, which is drawn into capillary tubes in the removable cartridge 14 that have an anticoagulant coating by capillary action. The removable cartridge 14 may consist of fluid circuits, some of which are formed with a layered structure with etched channels. However, it is contemplated that the removable cartridge 14 may be constructed by any suitable means, including injection molding or any other suitable manufacturing process or method, if desired.

In use, the removable cartridge 14 may be inserted into the housing after a blood sample has been drawn into the removable cartridge 14 . In some cases, removable cartridge 14 may be inserted into the housing with lid 18 in the open position. In other cases, however, the removable cartridge 14 may be inserted into the housing by any suitable means. For example, the housing may have slots into which the removable cartridge 14 may be inserted.

Referring back to the illustrative example of FIG. 1 , removable cassette 14 may include apertures 26a and 26b that receive alignment pins 28a and 28b in base plate 16 that may assist in aligning and coupling the various parts of the instrument. The movable box 14 can also include a first transparent flow window 30a, a second transparent flow window 30b and a third transparent window 30c, which are aligned with the first, second and third light sources 22a, 22b and 22c and the first and second light sources respectively. and third photodetectors 24a, 24b and 24c.

When the lid is moved into the closed position and the system is pressurized, the lid 18 can provide control pressure to the pressure receiving ports 34a, 34b, 34c, and 34d in the exemplary removable cartridge 14 through the pressure supply ports 36a, 36b, 36c, and 36d, respectively. . Depending on the application, it is contemplated that more or fewer pressure supply and pressure receiving ports may be used. Alternatively or additionally, it is contemplated that one or more micropumps, such as electrostatically actuated meso pumps, may be provided on or in the movable cartridge 14 to provide the movable cartridge 14 with the necessary pressure to operate the fluid circuit. Some exemplary electrostatically actuated micropumps are described, for example, in US Patent Nos. 5,836,750, 6,106,245, 6179,586, 6,729,856, and 6,767,190, all of which are assigned to the assignee of the present invention and are hereby incorporated by reference in their entirety.

Once pressurized, the exemplary instrument can perform blood analysis on the collected blood sample. In some cases, blood analysis may include a complete blood count (CBC) analysis, although other types of analysis may be performed depending on the application.

To count and classify red blood cells, a portion of the whole blood sample may be split and provided to the red blood cell measurement channel of the removable cartridge 14 . The blood sample can then be diluted if desired, the red blood cells are spheroidized on the fly, and the resulting sample can be hydrodynamically concentrated to form a core that is ultimately provided to the first cytometry channel. The first cytometry channel can be positioned along the first transparent flow window 30a of the removable cartridge 14 so that fluid cells can be optically interrogated by the first light source 22a and the first light detector 24a. In some cases, a first flow sensor may be provided on the removable cartridge 14 to measure the flow rate through the first cytometric channel.

In some cases, measurement parameters may include, for example, sample flow rate (FR), measurement time (T) duration, sample dilution factor (DF), red blood cell count (N _RB ), platelet count (N _Plt ), individual cell diameters (drbc ) and each cell hemoglobin concentration (CHC). From these parameters, a number of red blood cell analysis parameters can be calculated including, for example, red blood cell count (RBC = N _RB /(DF x FR x T)), platelet count (Plt = N _plt (DF x FR x T)), mean cell hemoglobin concentration (MCHC=<CHC>), mean cell volume (MCV=(π/6)×<drbc ³ >), mean cell hemoglobin content (MCH=(π/6)×<drbc ³ ×CHC>), relative distribution width (RDW=[(π/6)×drbc ³ ]/standard deviation of MCV), hematocrit parameters (Hct=RBC×MCV) and/or hemoglobin concentration (Hb=MCHC×Hct).

In some instances, some blood samples are also directed to the absorption measurement channel. An absorption measurement channel can be positioned along the third transparent window 30c of the removable cartridge 14 so that the blood sample can be optically interrogated by the third light source 22c and the third light detector 24c. A flow sensor may be provided on the removable cartridge 14 to measure the flow rate into or through the absorption measurement channel. The absorption measurement channel may measure the absorption of incident light provided by the third light source 22c. The measured absorption level can be provided as a reading of the total or mean cellular hemoglobin concentration in the blood sample.

To count and classify white blood cells, a portion of the whole blood sample may be split and provided to the white blood cell measurement channel of the removable cartridge 14 . The blood sample can then be diluted if desired, red blood cells can be lysed in real time, and the resulting sample can be hydrodynamically concentrated to form a core that is ultimately provided to a second cytometry channel. A second cytometry channel can be positioned along the second transparent flow window 30b of the removable cartridge 14 so that fluid cells can be optically interrogated by the second light source 22b and the second light detector 24b. A flow sensor may be provided on the removable cartridge 14 to measure the flow rate through the second cytometric channel. In some cases, measured white blood cell parameters may include, for example, three (3) or (5) fractional white blood cell differentiation, total white blood cell count, and/or on-axis white blood cell volume. Other parameters may also be measured or calculated depending on the application.

Figure 1 shows an exemplary sample analyzer and cartridge assembly. However, it is contemplated that other sample analyzer configurations may be used. For example, the sample analyzer 10 and removable cartridge may be similar to that described in US Patent Application 2004/0211077 to Schwichtenberg et al., which is incorporated herein by reference.

In some cases, sample analyzer 10 is suitable for use at the point of patient care, such as a physician's office, at home, or elsewhere in the field. With the sample analyzer 10 requiring little or no specialized training for reliable use outside of a laboratory environment, the sample analyzer 10 can help streamline the sample analysis process, reduce costs and burden on medical staff, and increase analysis Convenience for many patient samples, including those requiring relatively frequent monitoring/analysis of blood.

In operation, sample analyzer 10 may receive a collected sample, such as collected whole blood, and upon activation of the analyzer, sample analyzer 10 may automatically process the sample to provide the user with information for making a clinical decision. In some examples, sample analyzer 10 may display or print out quantitative results (eg, within and/or outside predetermined ranges) so that no further calculations or interpretations are required by the user.

Figure 2 is a schematic diagram of the exemplary sample analyzer and cartridge of Figure 1 . As detailed above, in the illustrative example, substrate 16 may include multiple light sources 22, associated optics, and control and processing electronics 40 necessary to operate the analyzer. Substrate 16 may also include a battery 42, transformer, or other power source. The cover 12 is shown having a pressure source/flow control block 44 and a plurality of light detectors 24 with associated optics.

The removable cartridge 14 can receive sample fluid through a sample collection port or lancet 32 . When the pressure source/flow control block 44 is pressurized, the removable cartridge 14 can perform blood analysis on the received blood sample. In some examples, removable cartridge 14 may include a plurality of reagents 49, as described above, and a fluidic circuit for mixing the reagents with the blood sample to prepare the blood sample for analysis. Also, in some cases, removable cartridge 14 may include a plurality of flow sensors to help control and/or verify proper operation of the fluid circuit.

In some cases, blood samples are prepared (e.g., lysed, spheroidized, stained, diluted, and/or otherwise processed) and then hydrodynamically concentrated in one or more on-board cytometry channels, such as cytometry channel 50 , forming the core. In the illustrative example, cytometry channel 50 passes through a transparent flow window of removable cartridge 14, such as first transparent flow window 30a. A series of light sources 22 and associated optics in substrate 16 allow light to pass through the core fluid via flow window 30a. A series of photodetectors 24 and associated optics may also receive the core's scattered and non-scattered light via the flow window 30a. A controller or processor 40 may receive output signals from the array of detectors 24 and may differentiate and/or count selected cells present in the core fluid.

It is contemplated that the removable cassette 14 may include a fluid control block 48 to help control the velocity of at least some of the fluid in the removable cassette 14 . In the illustrative example, fluid control block 48 includes flow sensors that sense the velocity of the various fluids and report the velocity to controller or processor 40 . The controller or processor 40 may then adjust one or more control signals provided to the pressure source/flow control block 44 to achieve the desired pressure and thus the desired fluid velocity for proper operation of the analyzer.

Because blood and other biological waste fluids can transmit disease, the mobile cassette 14 may include a waste fluid reservoir 52 downstream from the exemplary cytometry channel 50 . Waste reservoir 52 may receive and store fluid in removable cartridge 14 . When the test is complete, the removable cartridge 14 of the analyzer can be removed, for example discarded in a container compatible with biological waste.

Figure 3 is a more detailed schematic showing the flow control of the Figure 2 sample analyzer and cartridge. In the illustrative example, pressure source/flow controller 44 of cap 18 provides five control pressures, including sample push (P) pressure 36a, dissolve (L) pressure 36b, spheroidize (SP) pressure 36c, sheath flow (SH ) pressure 36d and dilution (D) pressure 36e. These are for illustration only, and depending on the application, it is contemplated that the pressure source/flow controller 44 may provide more, less or a different pressure (eg, dyeing pressure to a dyeing tank). Also, it is contemplated that cover 18 may not include pressure source/flow controller 44 at all. Instead, removable cartridge 14 may include an accompanying pressure source such as a compressed air reservoir, one or more micropumps such as the electrostatically actuated micropumps described above, or any other suitable pressure source, as desired. The source and detector arrays are not shown in Figure 3.

In the illustrative example, pressure source 36a provides pressure to blood sample reservoir 62 via push flow 65, pressure source 36b provides pressure to dissolution reservoir 64, pressure source 36c provides pressure to pelletization reservoir 66, and pressure source 36d provides pressure to sheath flow Tank 68, pressure source 36e provides pressure to dilution tank 70.

In one illustrative example, each pressure source may include a first pressure chamber that receives an input pressure, and a second pressure chamber that provides a control pressure to the removable cartridge. A first valve may be located between the first pressure chamber and the second pressure chamber for controllably releasing pressure from the first pressure chamber into the second pressure chamber. A second valve in fluid communication with the second pressure chamber can controllably release the pressure of the second pressure chamber to atmosphere. This may allow the pressure source/flow controller 44 to provide control pressure to each pressure receiving port on the removable cartridge 14 . Each valve can be an array of electrostatically actuated microvalves that can be individually operated and controlled, as described in, eg, US Patent No. 6,240,944, which is incorporated herein by reference. Alternatively, each valve may be an array of electrostatically actuated microvalves pulsed with a controlled duty cycle to achieve a controlled "effective" flow rate or leak rate. Other valves can also be used if desired.

The exemplary removable cartridge 14 includes five pressure receiving ports 34 a , 34 b , 34 c , 34 d and 34 e each receiving a corresponding control pressure from a pressure source/flow controller 44 . In the illustrative example, pressure receiving ports 34a, 34b, 34c, 34d, and 34e deliver control pressures to reservoir 62, lysis 64, spheroidization 66, sheath flow 68, and dilution 70, respectively. The lysis cell 64, pelletization cell 66, sheath flow cell 68, and dilution cell 70 may be filled before the removable cassette 14 is assembled for use, while the blood reservoir 62 is filled in situ through the sample collection port or lancet 32.

As shown, flow sensors may be provided within each or selected fluid lines. Each flow sensor 80a-80e may measure the velocity of a corresponding fluid. The flow sensors 80a-80e may be thermal anemometer type flow sensors and microbridge type flow sensors. Microbridge flow sensors are described, for example, in US Patent No. 4,478,076, US Patent No. 4,478,077, US Patent No. 4,501,144, US Patent No. 4,651,564, US Patent No. 4,683,159, and US Patent No. 5,050429, all of which are incorporated herein by reference.

Alternatively or in addition, sensors 80a-80e may be used to detect one or more characteristics of the fluid, such as thermal conductivity, specific heat, fluid density, resistivity, and/or other fluid characteristics, such as to help identify or verify the fluid being passed through the flow channel. Fluid is the expected fluid or expected fluid type. This can help verify that the intended fluid is indeed being used for the flow channel for a particular analysis or operation. The controller can be programmed to detect whether the intended fluid is actually used in the flow path, and in some cases, issue a warning and/or shut down the sample analyzer.

The output signal of each flow sensor 80a - 80e may be provided to a controller or processor 40 . As shown, a controller or processor 40 may provide control signals to a pressure source/controller 44 . For example, to control the pressure applied to the blood sample, the controller or processor 40 may open the pressure source/controller 44 between the first pressure chamber and the second pressure chamber when the blood sample velocity drops below a first predetermined value. A first valve to controllably release pressure from the first pressure chamber to the second pressure chamber. Likewise, when the blood sample velocity increases above a second predetermined value, the controller or processor 40 may open the second valve, venting the pressure in the second pressure chamber. A controller or processor 40 can similarly control the rates of lysing agent, nodulizing agent, sheath flow, and diluent.

In some cases, controller or processor 40 may detect one or more changes in flow rate through the flow channel. Changes in flow rate may be due to, for example, one or more air bubbles in the flow channel, occlusion or partial occlusion of the flow channel, such as from coagulation of the blood sample, unwanted or foreign objects in the flow channel, and/or other undesirable characteristics of the flow channel. In some cases, rise time, fall time, or some other characteristic of flow rate may be used. The controller or processor 40 can be programmed to detect such characteristics of the flow rate and, in some cases, issue a warning and/or shut down the sample analyzer.

Hot gas velocity flow sensors typically include a heating element (which when energized generates one or more heat pulses in the fluid) and one or more thermal sensors (located upstream and/or downstream of the heating element to detect one or more heat pulse). The velocity of the fluid through the flow channel may be related to the time required for a heat pulse to travel from the heating element to a spaced thermal sensor.

In some cases, hot gas velocity type flow sensors may be used to detect fluid thermal conductivity and/or specific heat. Changes in the thermal conductivity and/or specific heat of the fluid may correspond to changes in the characteristics of the fluid, such as changes in the state of the fluid (clotting of the blood sample), air bubbles in the fluid, unwanted or foreign objects in the fluid, and the like. Alternatively or additionally, a hot gas velocity type flow sensor may be used to detect one or more fluid characteristics such as thermal conductivity, specific heat, etc., for example, to help identify or verify that the fluid passing through the flow channel is the intended fluid or type of fluid. This can help verify that the intended fluid is indeed being used for the flow channel for a particular analysis or operation. In some examples, it is contemplated that the controller or processor 40 may detect fluid characteristics by monitoring the thermal conductivity and/or specific heat of the fluid passing the hot gas velocity-type flow sensor. The controller or processor 40 can be programmed to detect, for example, undesirable characteristics of the fluid such as air bubbles, and/or whether the expected fluid is actually used in the flow channel, and in some cases, issue a warning and/or shut down the sample analyzer.

In some cases, an impedance sensor may be provided in fluid communication with the flow channel. A controller or processor 40 may be coupled to the impedance sensor. A change in fluid impedance may indicate a change in fluid characteristics, such as a change in fluid state (clotting of the blood sample), fluid bubbles, unwanted or foreign objects in the fluid, correct fluid type, etc. Thus, in some examples, it is contemplated that the controller or processor 40 may detect fluid characteristics by monitoring the impedance of the fluid past the impedance sensor.

A downstream valve, shown generally at 110, may also be provided. The controller or processor 40 can open/close the downstream valve 110 as desired. For example, downstream valve 110 may remain closed until the system is fully pressurized. This can help prevent blood, lysing agent, spheronizing agent, sheath flow, and diluent from flowing into fluid circuit 86 until the system is fully pressurized. Also, the downstream valve 110 can be controlled to aid in certain tests, such as zero flow tests and the like. In another example, the downstream valve 110 may be opened by mechanical action, such as when the cover is closed.

Figure 4 is a schematic illustration of certain features of an exemplary removable cartridge. An exemplary mobile cassette, shown generally at 100, may be similar to mobile cassette 14 shown and described in FIGS. 1-3. It should be understood that the removable cartridge 100 is for illustration only and that this example is applicable to many microfluidic cartridges regardless of form, function or configuration. For example, the present example can be adapted for use with removable cartridges suitable for flow cytometry, hematology, clinical chemistry, blood chemistry analysis, urinalysis, blood gas analysis, viral analysis, bacterial analysis, electrolyte measurement, and the like. It is also contemplated that any suitable material or material system (eg, glass, silicon, one or more polymers, or any other suitable material or material system) or combination of materials or material systems can be used to fabricate the removable cartridge of the present system, such as movable cartridge 100 .

The exemplary mobile cartridge 100 includes a first measurement channel 102 and a second measurement channel 104, although more or fewer measurement channels may be used as desired. In the illustrative example, first measurement channel 102 is a red blood cell measurement channel and second measurement channel 104 is a white blood cell measurement channel. The movable cartridge 100 receives the whole blood sample through the blood receiving port 106, and draws a known amount of blood into the blood sample storage capillary 108 coated with anticoagulant through capillary action. A sample pushing (P) pressure, such as sample pushing (P) pressure 36 a of FIG. 3 , is provided to a sample pushing fluid cell, such as sample pushing fluid cell 65 of FIG. 3 . When pressure is applied, the sample pushing flow is forced from the sample pushing fluid pool into the blood sample pushing channel 110

In some illustrative examples, valve 112 and flow sensor 114 may be provided within the blood sample push channel 110 circuit. Valve 112 can be controlled to open when it is desired to push a blood sample through the fluid circuit. The flow sensor 114 may measure the flow rate of the push flow of the blood sample, thereby measuring the flow rate of the blood sample through the anticoagulant-coated capillary 108 . The flow rate provided by the flow sensor 114 can be used to help control the sample push (P) pressure provided to the active cartridge 100 .

In the illustrative example, a whole blood sample is dispensed and provided via branch 116 to red blood cell measurement channel 102 and white blood cell measurement channel 104 . In the illustrative example, valve 118 is provided in the branch line to control flow of blood sample into red blood cell measurement channel 102 and valve 120 is provided to control flow of blood sample into white blood cell measurement channel 104 .

Specifically, the erythrocyte measurement channel 102 provides the erythrocyte spheroidizing agent pressure (SP), such as the spheroidizing pressure (SP) 36 c of FIG. 3 , to the spheroidizing pool, such as the spheroidizing pool 66 of FIG. 3 . When pressure is applied, the nodulizer from the nodulizer pool 66 is forced into the nodulizer channel 124 .

In some illustrative examples, valve 126 and flow sensor 128 may also be provided within line of nodulizer passage 124 . Valve 126 can be controlled to open when it is desired to push the spherulizer into the fluid circuit. The flow sensor 128 can measure the flow rate of the nodulizer, measuring the nodulizer flow rate through the nodulizer channel 124 . The flow rate provided by the flow sensor 128 may be used to help control the spheroidizing pressure (SP) provided by the pressure source/controller 44 to the active cartridge 100 .

During normal functional operation of the exemplary mobile cartridge 100, the spheroidizer is pushed into the intersection region 130 at the spheroidizer flow rate, and the blood sample is pushed into the intersection region 130 at the blood sample flow rate. The blood sample flow rate and the nodulizing agent flow rate can be controlled by the pressure source/controller 44 of FIG. 3 .

The intersection region 130 can be configured so that the nodulizer flows around the blood sample as the two fluids flow through the intersection region 130 . In some cases, the spheroidizing agent flow rate may be higher than the blood sample flow rate, which may help improve the flow characteristics of the downstream real-time sphering-on-the-fly channel 132 and, in some cases, help form blood ribbons ( thin ribbon), completely and evenly surrounded by nodulizers. Such band flow may help the spheroidizing agent to evenly spheroidize the red blood cells as they pass through the real-time spheroidizing channel 132 . Furthermore, the length of the real-time spheroidizing channel 132 can be set in conjunction with the spheroidizing agent and blood sample flow rate so that the blood sample is exposed to the spheroidizing agent for an appropriate period of time.

Sheath flow (SH) pressure, such as sheath flow (SH) pressure 36d of FIG. 3 , may be provided to a sheath flow cell, such as sheath flow cell 68 of FIG. 3 . When pressure is applied, sheath flow is forced from the sheath flow reservoir 68 into the sheath flow channel 134 . In some illustrative examples, valve 136 and flow sensor 138 may be provided within sheath flow channel 134 line. Valve 136 is controllable to open when it is desired to push sheath flow into the fluid circuit. The flow sensor 138 can measure the flow rate of the sheath flow, and can measure the flow rate of the sheath flow passing through the sheath flow channel 134 . The flow rate provided by the flow sensor 138 may be used to help control the sheath pressure (SH) provided to the removable cassette 100 .

In an illustrative example, the sheath flow is provided to the intersection region 140 at the sheath flow rate, and a sphered blood sample is provided to the intersection region 140 at the spherized blood sample flow rate. A pressure source/controller, such as pressure source/controller 44 of FIG. 3, can be used to control the flow rate of the spheroidized blood sample and the flow rate of the sheath flow.

The intersection region 140 may be configured such that when the two fluids flow through the intersection region 140, the sheath fluid flows around the spheroidized blood sample. In some cases, the sheath flow rate is significantly higher than the spheroidized blood sample flow rate, which can help improve core formation in the downstream flow cytometry channel 142 . For example, in some flow cytometry applications, the intersection region 140 may be configured to hydrodynamically concentrate and align the spheroidized blood cells within a single row of cores so that as each red blood cell passes through the optical window region 144 of the movable cartridge 100, Both can be optically interrogated individually with the analyzer. In some cases, fluid passing through the cytometer channel 142 is directed to an accompanying waste reservoir.

Specifically to the leukocyte measurement channel 104, the leukocyte lysing agent pressure (L), such as the lysing pressure (L) 36b of FIG. 3 , is provided to the lysing agent pool, such as the lysing pool 64 of FIG. 3 . When pressure is applied, the dissolving agent of the dissolving tank 64 is forced into the dissolving agent channel 154

In some illustrative examples, valve 156 and flow sensor 158 may be provided within the line of solvent channel 154 . Valve 156 can be controlled to open when it is desired to push solvent into the fluid circuit. The flow sensor 158 may measure the flow rate of the lysate, measuring the flow rate of the lysate through the lysate channel 154 . The flow rate provided by flow sensor 158 may be used to help control the dissolution pressure (L) provided by pressure source/controller 44 to removable cartridge 100 .

During normal functional operation of the exemplary active cartridge 100, a lysate is provided to the intersection region 160 at a lysate flow rate and a blood sample is provided to the intersection region 160 at a blood sample flow rate. A pressure source/controller, such as pressure source/controller 44 of FIG. 3, can be used to control the blood sample flow rate and the lysing agent flow rate.

The intersection region 160 can be configured so that when the two fluids flow through the intersection region 160, the lysing agent flows around the blood sample. In some cases, the flow rate of the lysing agent can be higher than the flow rate of the blood sample, which can help improve the flow characteristics of the real-time lysing (lysing-on-the-fly) channel 162, and in some cases, help to form blood thin bands, completely formed by the lysing agent. and wrap it evenly. Such ribbon flow can help the lysing agent to lyse the red blood cells evenly (as the red blood cells pass through the real-time lysis channel 162). Furthermore, the length of the real-time lysis channel 162 can be set in conjunction with the lysing agent and blood sample flow rate so that the blood sample is exposed to the lysing agent for an appropriate amount of time.

Sheath flow (SH) pressure, such as sheath flow (SH) pressure 36d of FIG. 3 , may be provided to a sheath flow cell, such as sheath flow cell 68 of FIG. 3 . When pressure is applied, sheath flow is forced from the sheath flow reservoir 68 into the sheath flow channel 164 . In some illustrative examples, valve 166 and flow sensor 168 may be provided within sheath flow channel 164 line. Valve 166 is controllable to open when it is desired to push sheath flow into the fluid circuit. The flow sensor 168 can measure the flow rate of the sheath flow, and can measure the flow rate of the sheath flow passing through the sheath flow channel 164 . The flow rate provided by the flow sensor 168 may be used to help control the sheath pressure (SH) provided to the removable cartridge 100 . In some cases, the sheath flow rate through sheath flow channel 164 is the same as the flow rate through sheath flow channel 134 . In other cases, however, the sheath flow rate through sheath flow channel 164 is different from the flow rate through sheath flow channel 134 .

In the illustrative example, the sheath flow is provided to the intersection region 170 at the sheath flow rate and the lysed sample is provided to the intersection region 170 at the lysed sample flow rate. A pressure source/controller, such as pressure source/controller 44 of FIG. 3, can be used to control the flow rate of the lysed blood sample and the flow rate of the sheath flow.

The intersection region 170 can be configured so that when the two fluids flow through the intersection region 170, the sheath fluid flows around the lysed blood sample. In some cases, the sheath flow rate is significantly higher than the lysed blood sample flow rate, which can help improve core formation in the downstream flow cytometry channel 172 . For example, in some flow cytometry applications, intersecting region 170 may be configured to hydrodynamically concentrate and align leukocytes in a lysed blood sample within a single row of cores so that when each leukocyte passes through optical window 174 in movable cartridge 100 , the analyzer can perform optical interrogations one by one. In some cases, fluid passing through the cytometer channel 172 is directed to an accompanying waste reservoir.

In some cases, absorption measurement channels may also be provided. In the illustrative example, a partially lysed blood sample is provided into absorption channel 180 . A valve 182 may be provided to selectively allow a portion of the lysed blood sample to pass through an absorbent channel or region 184 . The analyzer may include a light source to illuminate the absorbing channel or region 184 and a detector to detect light not absorbed by the lysed blood sample in the absorbing channel or region 184 . The analyzer can then determine the level of absorption from which a hemoglobin measurement based on bulk absorption can be derived, and in some cases if desired, absorption channel 184 can be located downstream of cytometry channel 172 as shown in FIG. 8 . In other cases, a whole blood sample may be provided directly (eg, from branch 116) into the absorption channel. In this case, the absorption channel may include a mechanism to lyse red blood cells prior to taking the absorption measurement. While the exemplary cartridge 100 is suitable for performing a complete blood count (CBC) analysis on a whole blood sample, it is contemplated that other cartridge configurations and assay types may be used as desired.

Figure 5 is a schematic diagram of a plurality of exemplary reservoirs that may be contained within the removable cartridge. In an illustrative example, a removable cassette such as the removable cassette 100 of FIG. Waste liquid pool 52. These are for illustration only and it is contemplated that more, fewer or different reservoirs may be provided on or in the removable cartridge.

Each reservoir can be of a different size to hold the appropriate amount of fluid and/or reagents to support the desired operation of the removable cartridge. Dilution reservoir 70 may contain a dilution fluid used to dilute an incoming sample, such as a whole blood sample. In the illustrative example of FIG. 4 , the nodulizer and/or solubilizer may function as a diluent, so a separate dilution tank 70 may not be necessary or even required. Also, in some instances it may be desirable to add dye to the leukocyte channel using a staining well such as staining well 190 to support leukocyte sorting. Depending on the application, the reagents and/or fluids within the contemplated reservoir may initially be in liquid or lyophilized form.

Figure 6 is a schematic flow diagram showing an exemplary method of analyzing a blood sample using a removable cartridge. In the exemplary method, a blood sample is first collected at step 200 . Next, a blood sample is provided into the anticoagulant-coated capillary of the removable cartridge. Blood samples are then dispensed and provided into red blood cell and platelet (RBC/P) measurement channel 204 and white blood cell (WBC) measurement channel 206 .

In the RBC/P measurement channel 204, the erythrocytes are first spheroidized as shown at 212, then hydrodynamically concentrated and provided in a single row along the RBC/P cytometry channel 214 of the removable cartridge. As the cells pass through the analysis zone of the RBC/P cytometry channel 214, a light source 216, such as a vertical cavity surface emitting laser (VCSEL), shines light on individual cells. In some cases, providing an array of VCSEL devices, only the VCSELs that are directed to individual cells passing through the analysis zone of the RBC/P cytometry channel 214 are activated. Some of the incident light provided by the VCSEL is scattered and detector 218 detects the scattered light. In some cases, detector 218 may detect forward angle scattered light (FALS), small angle scattered light (SALS), and large angle scattered light (LALS).

In some cases, a laser (or other) source is focused on the RBC/P cytometry channel 214, either as an extended line source or as two separate point sources. RBCs and platelets in the RBC/P cytometry channel 214 pass through the focused light. High quality collection optics can be used to form a clear image of the cells, focusing the light on an opaque screen containing one, two or more parallel slits whose longitudinal axis is aligned with the RBC/P cytometry channel 214 The inner flow direction is perpendicular to the right angle. The interslit distance can be, for example, the expected average cell spacing within the RBC/P cytometry channel 214 . An opaque screen containing slits may be placed in front of one or more detectors 218 . As the cell image passes through the slit, the light incident on the slit is blurred, attenuating the signal reaching the detector 218, producing a pulse waveform whose width is proportional to the cell diameter. When two spaced slits are provided, the two waveforms allow calculation of cell flow velocity and thus cell size. High signal-to-noise ratios can be achieved with this technique, allowing for easy counting of events and identification of multiple cellular events. Pulse width and amplitude can also differentiate some cell types.

In some cases, both the cell and light source images are imaged on a double slit in front of detector 218 . Dual slit wells provide well-defined well geometry and high signal-to-noise ratio for counting cells. As discussed above, the signal from the slit can allow accurate measurement of cell flow velocity, which in turn can allow calculation of cell diameter.

In some cases, as shown at 220, various parameters may be measured at the time of the analysis including, for example, sample flow rate (FR), measurement time (T) duration, and sample dilution factor (DF). By monitoring the detector output and/or the corresponding scatter signal, red blood cell number (N _RB ), platelet number (N _plt ), individual cell diameter (drbc) and individual cell hemoglobin concentration can be measured.

From these parameters, as shown in 282, various red blood cell analysis parameters can be calculated, including red blood cell count (RBC=N _RB /(DF×FR×T)), platelet count (Plt=N _Plt /(DF×FR×T) )), mean cell hemoglobin concentration (MCHC=<CHC>), mean cell volume (MCV=(π/6)×<drbc ³ >), mean cell hemoglobin content (MCH=(π/6)×<drbc ³ × CHC>), relative distribution width (RDW=[(π/6)×drbc ³ ]/standard deviation of MCV), hematocrit parameter (Hct=RBC×MCV) and/or hemoglobin concentration (Hb=MCHC×Hct) .

In the exemplary WBC measurement channel 206 , red blood cells are first lysed as shown at 232 and then hydrodynamically pooled and provided in a single row along the WBC cytometry channel 234 in the movable cartridge. A light source 236 , such as a vertical cavity surface emitting laser (VCSEL), shines light on individual cells passing through the WBC cytometry channel 234 analysis zone. In some cases, an array of VCSEL devices is provided, and only VCSELs directed to individual cells passing through the WBC cytometry lane 234 analysis zone are activated. Some of the incident light provided by the VCSEL is scattered and detector 238 detects the scattered light. In some cases, detector 238 detects forward angle scattered light (FALS), small angle scattered light (SALS), and large angle scattered light (LALS). In some cases, as shown at 240, various parameters can be measured at the time of analysis including, for example, positive axis cell volume, total WBC count, and WBC five (5) fraction differential.

FIG. 7 is a flowchart showing an exemplary method of obtaining various red blood cell parameters. In the exemplary method, at step 260 a blood sample is taken. Next, the blood sample was diluted to the desired dilution factor (DF), as 264 indicated spheroidization. The diluted and spheroidized blood cells are then hydrodynamically concentrated and delivered in a single line along the RBC/P cytometry channel of the removable cartridge. A light source 216, such as a Vertical Cavity Surface Emitting Laser (VCSEL), shines light on individual cells passing through the analysis zone of the RBC/P cytometry channel. Some of the incident light provided by the VCSEL is scattered and the scattered light can be detected by a detector. In some cases, the detector detects forward angle scatter light (FALS) and small angle scatter light (SALS) for each cell. Then the processor etc. can plot the two independent scattering parameters of each cell, i.e. SALS and FALS, on the cell diameter parameter and the cell hemoglobin concentration parameter, as follows:

{S _SALSi , S _FALSi } -> (drbc _i , CHC _i )

As shown at 270 , if the scattered S _SALSi + S _FALSi intensity is not greater than the predetermined detection threshold, then control passes to step 268 . However, if the scattered S _SALSi + S _FALSi intensity is greater than the predetermined detection threshold, then control passes to step 272 . Step 272 determines if the total S _SALSi + S _FALSi is greater than a predetermined platelet threshold. If the S _SALSi + S _FALSi total is not greater than the predetermined platelet threshold, particle "i" is a platelet and control passes to step 274 . Step 274 increments the platelet count (N _Plt ) by one and control returns to step 268 .

If the S _SALSi + S _FALSi total is greater than the predetermined platelet threshold, the cells are red blood cells and control passes to step 276 . Step 276 increments the red blood cell count ( _NRBC ) by one and control passes to step 278 . Step 278 determines whether a predetermined measurement time has been reached. If not, then control returns to step 268.

Once the measured time is reached at step 278 , control passes to step 280 . Step 280 displays various measurement parameters including, for example, sample flow rate (FR), measurement time (T) duration, sample dilution factor (DF), red blood cell count (N _RBC ), platelet count (N _Plt ), individual cell diameters (drbc _i ) and each cell hemoglobin concentration (CHC _i ). From these parameters, as shown in step 282, various blood cell analysis parameters can be calculated including, for example, red blood cell count (RBC=N _RBC /(DF×FR×T)), platelet count (Plt=N _Plt /(DF×FR×T) T)), mean cell hemoglobin concentration (MCHC=<CHC _i >, mean cell volume (MCV=(π/6)×<drbc _i ³ >), mean cell hemoglobin content (MCH=(π/6)×<drbc _i ³ ×CHC _i >), relative distribution width (RDW=[(π/6)×drbc _i ³ ]/standard deviation of MCV), hematocrit parameter (Hct=RBC×MCV) and/or hemoglobin concentration (Hb =MCHC×Hct), where the symbol <X _i > refers to the average cell parameter of all cells X _i .

Fig. 8 is a schematic flow diagram showing another exemplary method of analyzing a blood sample. In this exemplary method, a blood sample is obtained and provided into a blood sample pool, as shown in step 300 . Next, the blood sample is provided into the anticoagulant-coated capillary of the removable cartridge and diluted. The blood samples are then dispensed and provided into red blood cell and platelet (RBC/P) measurement channel 304 and white blood cell (WBC) measurement channel 340 .

In the RBC/P measurement channel 304, red blood cells are first spheroidized as shown at 306 and then hydrodynamically concentrated and provided in a single row along the RBC/P cytometry channel 308 of the removable cartridge. A first light source 310 such as a vertical cavity surface emitting laser (VCSEL) and associated optics provides a focused beam of light onto individual cells passing through the analysis zone of the RBC/P cytometry channel 308 . In some cases, providing an array of VCSEL devices, only the VCSELs directed to individual cells passing through the analysis zone of the RBC/P cytometry channel 308 are activated.

As individual cells/particles pass through the focused incident beam, some light is blocked, scattered or blocked, which can be detected with a detector (not shown). When two or more light sources are focused at differently spaced points on the RBC/P cytometry channel 308, the leading and/or trailing source of each cell can be detected. By measuring the time it takes the cells to traverse the distance from one focal point to the next, the flow rate and thus the cell velocity can be determined. Once the cell velocity is determined, the length of time the cell blocks, scatters or blocks the light beam can be correlated to cell size and/or cell volume.

In some examples, the analyzer may provide another light source 314 and associated optics. The associated optics of the light source 314 can collimate the light and measure off-axis scatter such as SALS and FALS scatter. As noted above, SALS and FALS scattering measurements such as red blood cell count ( _NRBC ) 316 , platelet count ( _NPlt ) 322 , individual cell diameter (drbc _i ), cell volume 318 and individual cell hemoglobin concentration 320 (CHC _i ) can be measured with SALS and FALS. From these parameters, as discussed above, various blood cell analysis parameters can be calculated including, for example, red blood cell count (RBC= _NRBC /DF×FR×T)), platelet count (Plt=N _Plt /(DF×FR×T)) , mean cell hemoglobin concentration (MCHC=<CHC _i >, mean cell volume (MCV=(π/6)×<drbc _i ³ >), mean cell hemoglobin content (MCH=(π/6)×<drbc _i ³ × CHC _i >), relative distribution width (RDW=[(π/6)×drbc _i ³ ]/standard deviation of MCV), hematocrit parameter (Hct=RBC×MCV) and/or hemoglobin concentration (Hb=MCHC× Hct), where the symbol <X _i > refers to the average cell parameter of all cells X _i .

In an exemplary WBC measurement channel 340 , the red blood cells are lysed and the dye injected as shown at 342 as appropriate. The cells are then hydrodynamically concentrated and delivered in a single row along the WBC cytometry channel 344 of the removable cartridge. A light source 346 such as a Vertical Cavity Surface Emitting Laser (VCSEL) shines light on individual cells passing through the WBC cytometry channel 344 analysis zone. In some cases, an array of VCSEL devices is provided, and only VCSELs directed to individual cells passing through the analysis zone of the WBC cytometry channel 344 are activated.

As individual cells/particles pass through the focused incident beam, some light is blocked, scattered or blocked, which can be detected with a detector (not shown). When two or more light sources are focused on differently spaced points on the WBC cytometry channel 344, the leading and/or trailing sources of individual cells can be detected. By measuring the time it takes the cells to traverse the distance from one focal point to the next, the flow rate and thus the cell velocity can be determined. Once the cell velocity is determined, the length of time the cell blocks, scatters or blocks the light beam can be correlated to cell size and/or cell volume.

In some examples, a light source 350 and associated optics and/or polarizers may be provided. Optics associated with light source 350 can collimate the light and measure off-axis scatter such as SALS, FALS and LALS scatter, as shown at 354 . As noted above, SALS, FALS, and LALS can be used to scatter measurements such as white blood cell count (N _WBC ) 352 and help differentiate white blood cells, as shown at 356 . In some cases, one or more polarizers are provided to polarize the light provided by the light source, and the level of polarization extinction/rotation detected by the detector can be used to help distinguish leukocytes, although this is not required in all instances.

In an illustrative example, cells exiting WBC cytometry channel 344 may be provided to total absorption channel 360 . A light source 362 may shine light on cells present in the absorption channel 360, and a detector 364 may detect light not absorbed by resident cells. The uptake channel 360 can thus be used to measure the total uptake level of the resident cells. Absorption levels may, for example, measure the overall or mean cellular hemoglobin concentration of a blood sample. The hemoglobin channel can have optics for re-zeroing, auto-focusing and/or calibration. The light source 362 may be an LED with an output signal near the center of the absorption peak, so no filter may be required. The curvette can be used to receive and hold the sample for evaluation of hemoglobin. Humidity and temperature sensors may be located on the card to indicate the current and historical card conditions under which these parameters were measured. The time for the card to heat up or cool down may indicate the temperature before operation is initiated. Monitoring of such conditions can be related to the materials and solutions on the card. Mastering these conditions can eliminate or significantly reduce the chance of delamination of the card or cassette structure as a safety measure.

Contamination-free transfer and movement of fluids can be achieved through the interfaces shown in Figures 9a-9f. Once the reagents are stored in the reagent cartridge of the instrument, there is a problem of compressibility of the fluid in the supply lines from the reagent reservoir to the fluid interface. In order to achieve high fidelity fluid flow control, this problem should be minimized. The compressibility may be due to gas bubbles, either from dissolved gas arising from the solution as the temperature changes or from air diffusing through the gas-permeable walls of the supply line. One way to solve this problem could be to pump the bubbling solution, such as a reagent, from the instrument fluid interface into a valve that can go to the kit waste tank, eg replacing it with fresh fluid. Once the air bubbles have been reabsorbed or flushed to waste, the valve can be turned again to bring the fluid/air level back to the fluid interface. Another immediate concern may be the potential for contamination of the instrument by blood samples after the liquid level is restored to near the fluid interface. Several solutions are available for controlling the flow of blood samples and reagents while not requiring exposure for contact control.

In the needle-septum interface shown in Figures 9a and 9b, the needle 1201 can pierce the septum 1202, delivering fluid stored on the instrument to the channel 1203 and card 1204. A flow sensor and controller can be located on the instrument. When the needle 1201 is taken out at the end of the measurement, the septum 1202 is self-sealing, and the card is leak-tight and easy to handle. While this method works well for directing the reagents stored by the instrument to the card 1204, the sample blood is already present on the card and once the needle penetrates the septum 1202, it will come into contact with the blood. The curved-tipped needle 1201 may be specially designed to pierce the septum without coring.

During operation, contamination of the needle 1201 can be minimized, which can be overcome in several ways. During the measurement, push the flow to flush the inside of the needle. At the end of the measurement, the outside of the needle 1201 can be wiped with the septum 1202 when the needle is taken out. The small size of needle 1201 can limit the amount of blood retained on its tip surface area. The instrument's thermal sterilization process of the needle tip can be a very rapid heating/cooling cycle due to the small size and geometric similarity of the needle to the heat transfer pin. The sterilization process can be proved experimentally. Also, a valve that normally opens when power is off prevents any backflow of fluid into the instrument.

Mention may be made of the axis-membrane interface of Figures 9c and 9d. In this method, the long and thin sample loop can be replaced by a cylindrical sample reservoir sealed at one end with an elastic membrane 1206 . Membrane 1206 may be located on molded case 1207 over sample reservoir 1208. To dispense the sample, a lead screw rotated by a microstepping motor is pushed against the membrane. This could be a syringe pump in essence, with the shaft 1205 pushing against the membrane 1206 instead of pushing a piston inside the syringe barrel. An advantage of this approach is that the physical barrier film 1206 can eliminate contamination issues.

The method may include finding zero displacement of the shaft 1205 (ie only contacting the membrane 1206) after the card is installed in the instrument. The volume change response of the sample reservoir may be non-linear with axis displacement and requires calibration. The shaft 1205 tip can be designed for displacement efficiency. The reality may be that the shaft at full stroke can deliver 80% of the sample in the reservoir. Membrane 1206 needs to be recessed enough so that a finger cannot accidentally press/actuate the membrane and dispense the sample.

The membrane-membrane interface can be shown in Figures 9e and 9f. In this method, the sample can still be stored in a cylindrical reservoir sealed at one end with an elastic membrane. Displacement of the membrane 1206 can be caused by an actuator 1211 having a membrane 1212 closing its tip. If the two membranes 1206 and 1212 are already in contact, pumping the drive fluid 1213 to the tip of the driver 1211 deforms both the membranes 1212 and 1206, moving an equal volume of fluid in the sample cell 1208.

Some advantages of this approach may be apparent. Flow sensor technology can be used to control the flow rate of the draw solution 1213 and ultimately the sample flow rate. Because the actuation is fluid driven, membranes 1206 and 1212 are naturally easily deformable to provide high displacement efficiency. This method also eliminates contamination issues by isolating the blood sample behind a physical membrane.

The method may include finding zero displacement after installing the card in the instrument so that the membranes 1212 and 1206 just touch without moving any blood sample. The volume change response of the sample reservoir 1208 may vary slightly from the volume change of the driver membrane 1212, requiring calibration. The membrane 1206 on the card must be recessed enough so that a finger cannot accidentally press/actuate the membrane 1206 and dispense the sample.

The sample loops of Figures 9e and 9f are not elongated channels but shallow cylindrical chambers. Membrane 1212 is in good initial contact with 1206 (ie, no air is trapped between them), and the volume of draw fluid 1213 developed can deflect the membrane by a repeatable amount (calibrable).

There may be force variations in the membrane interface. The compliance introduced by the elastic membrane should be small, since typical elastomers such as silicone rubber and Neoprene usually have a Poisson's ratio in the range of 0.45-0.50 and are almost incompressible. Basically, elastomers are deformable but not compressible; they change shape easily but not their volume. Therefore, the membrane-membrane interface, where the hard materials of the plastic housing and the actuator limit the shape change of the elastomer, should not exhibit significant kinetic consequences from the low compliance of the elastomer.

The deflection of the membrane 1206 cannot dispense all of the sample or reagent contained within the reservoir. The deployment ratio can be characterized by displacement efficiency. An efficiency of ε = 80% should be considered reasonable. If also assuming a ratio of membrane deflection to chamber diameter (e.g., δ = 1/3), the displacement volume can be approximately

V _disp =εδ(π/4)d ³

The diameter of the reservoir can be estimated as follows

d=((4V _disp /(εδπ)) ^1/3 .

The table in Figure 9g lists the reservoir diameters sufficient to store the sample push flow and each reagent, assuming that the assay will be run for 4 minutes, half the time measuring RBC and half the time measuring WBC. The size of the on-card reagent reservoirs for the spheroidizing and sheathing solutions can be based on an adequately sized card.

There are significant advantages to supplying reagents from the needle-septum interface of a reagent storage cartridge contained within the instrument. Blood samples can be controlled through a membrane-type interface or a needle-septum interface if a small sterile mechanism is provided on the instrument.

Figure 10 is a schematic flow diagram showing an exemplary method of assembling and operating a sample analyzer. In an illustrative example, a blood analysis cartridge may be used and analyzed as shown at 351, a control cartridge may be used and analyzed as shown at 370 to help verify the performance of the analyzer, and/or a calibration cartridge may be used and analyzed as shown at 380 to Helps calibrate the analyzer. The blood analysis cartridge can be installed every time for blood analysis. A control box may be mounted on the analyzer as shown at 372 and run periodically as shown at 374 eg once a day to verify that the analyzer is getting accurate results. As indicated at 376, the instrument may display a flag indicating whether the measurement is within range. This flag can depend on whether the measurement is in the normal, low or high range. As shown at 380 , the calibrator may be mounted on the calibration box as shown at 382 and operated as shown at 384 . The instrument may adjust the calibration coefficients as indicated at 386 to match the calibration. A calibration card can be installed in the analyzer to recalibrate the analyzer at a lower frequency than the control card, eg, every 3 months. Calibration may include passing a precision bead flow through the flow channel before or after operation, eg, to calibrate the pulse width, to provide particle size information passing through the channel.

Each cartridge can hold all necessary fluids and/or components to function accordingly. This way, little training is required to operate and/or maintain the analyzer and still obtain accurate results. Offers sample analyzers with removable and/or disposable cartridges that can be reliably used by untrained personnel outside of a laboratory setting, helping to streamline the sample analysis process, reducing cost and medical staff burden, Increased ease of analysis of many patient samples, including those requiring fairly frequent blood monitoring/analysis. The system can indicate if reagents and/or sample fluids are spoiled, stale, contaminated, incorrect or inappropriate or unacceptable. The final activity of the system may include not performing an analysis, not providing a result, providing an error flag, etc.

When a blood analysis cartridge is used as shown at 351, a blood sample may be collected and placed in the blood analysis cartridge, as shown at 353 and 355. The blood sample can be sucked into the blood analysis box by capillary action or manual pump as needed. The blood analysis cartridge can then be loaded into the analyzer instrument. In an illustrative example, the analyzer can then self-align the blood analysis cartridge and corresponding parts of the analyzer (eg, light source/light detector, etc.), as shown at 357 . Next, one or more buttons can be pressed to initiate the blood analysis process. In some cases, simply loading the cartridge into the analyzer without pressing a button or the like can cause the analyzer to begin the alignment and blood analysis process.

Cards can run as 358. Once the analyzer is driven, the analyzer can perform various tests. For example, the analyzer can close all valves on a blood analysis card and apply pressure to various fluid inlets on the card. The analyzer can then measure the flow rate through one or more flow sensors on the card. Flow should be zero since all valves are closed. However, if the flow sensor indicates a non-zero flow rate, the analyzer can recalibrate the flow sensor back to zero flow. This can help increase the accuracy of flow sensor measurements. The analyzer checks for and begins purging air bubbles as needed. Alternatively or additionally, the analyzer can check for coagulation of the blood in the removable cartridge, for example by measuring the flow rate of the blood sample under the applied pressure (e.g. with a flow sensor), and if the flow rate is too low relative to the applied pressure, it can be determined that the blood sample has solidification. If blood clotting is found, the analyzer can display a message indicating that the measurement failed.

The analyzer can then implement the blood analysis cartridge timing scheme. The blood analysis cartridge timing scheme may be similar to that shown and described in US Patent Application Serial No. 10/932,662, filed September 2, 2004, assigned to the assignee of the present invention, and incorporated herein by reference. The specific timing scheme of the blood analysis cartridge may depend on the specific design of the blood analysis cartridge. The analyzer also verifies the presence of stable core fluid in any cytometry channel on the blood analysis cartridge and, if present, identifies the location of the core fluid.

The blood analysis cartridge can then, for example, lyse the red blood cells in the portion of the blood sample that will be used to measure white blood cells, spheroidize the erythrocytes in the portion of the blood sample that will be used to measure red blood cells, form a core fluid within any cytometry channel on the blood analysis cartridge, and/or exert Any other desired functionality. The analyzer can provide light to selected areas of the blood analysis cartridge, such as any cytometry channel, and detect light passing through the selected areas.

In this way, the analyzer can count and classify the particles in the sample, such as white blood cells, red blood cells, platelets, etc., and then display, print, sound or mark the blood analysis results for the user. In some instances, the analyzer displays or prints quantitative results (eg, within and/or outside predetermined ranges) so that no further calculations or interpretations are required by the user. The measurement can be considered complete, as shown at 361, and the result is displayed. Finally, the analyzer's blood analysis cartridge can be removed and disposed of as shown at 363 .

When the control operation is to be performed as shown in 370, a control box can be used. In some cases, control runs may be performed on a regular basis, such as once a day or once a week. A control box may contain a control sample with known characteristics. Therefore, when the control samples are analyzed by the analyzer, known results should be obtained. In an exemplary method, a control box is housed within the analyzer, as shown at 372 . Next, the analyzer is started, as shown in 374 , and the analyzer performs analysis and displays the results, as shown in 376 . In some instances, the analyzer displays or prints quantitative results (eg, within and/or outside predetermined ranges) so that no further calculations or interpretations are required by the user. Finally, the analyzer's control box can be removed and disposed of. If the results of the control run are outside a predetermined range, a calibration run, such as calibration run 380, may preferably be performed.

The calibration box may be used when a calibration run of the 380 display is to be performed. In some cases, calibration runs may be performed periodically, such as once a month, or as needed. Calibration cartridges may include calibration samples with known characteristics. Therefore, when the calibration samples are analyzed by the analyzer, known results should be obtained. In an exemplary method, a calibration cartridge is loaded into the analyzer, as shown at 382 . Next, the analyzer is started, as shown at 384, and multiple results are obtained. By comparing the expected results with those obtained during the calibration run, the analyzer can automatically adjust one or more calibration factors in memory to recalibrate the analyzer so that on the next run, the analyzer will produce the expected or desired results, e.g. 386 show.

Figure 11a is a flowchart showing an exemplary method of operating a sample analyzer. The exemplary method is generally shown at 400 and entered at step 402 . Control passes to step 404, where a blood sample is provided into a disposable fluid cartridge. Control then passes to step 406 where the disposable fluid cartridge is inserted into the blood sample analyzer. Control then passes to step 408 . Step 408 starts the blood sample analyzer, and step 410 obtains blood analysis results from the blood sample analyzer without requiring any interaction from the blood sample analyzer user. Control then passes to step 412, where the step is exited.

11b is a flowchart showing another exemplary method of operating a sample analyzer. The exemplary method is shown generally at 500 and begins at step 502 . Control passes to step 504 where a blood sample is provided to a disposable fluid cartridge. Control then passes to step 506 where the disposable fluid cartridge is inserted into the blood sample analyzer. Control then passes to step 508 . Step 508 starts the blood sample analyzer, and step 510 obtains blood analysis results from the blood sample analyzer without any interaction from the blood sample analyzer user. Control then passes to step 512 . Step 512 determines whether the blood analysis results are within a predetermined range. As noted above, in some examples, the analyzer may display or print out quantitative results (eg, within and/or outside predetermined ranges) so that no further calculations or interpretations are required by the user. Control then passes to step 514, where the step is exited.

Figure 12 is a flowchart showing another exemplary method of operating a sample analyzer. The method is generally shown at 600 and entered at step 602 . In an exemplary method, a blood analysis cartridge may be used and analyzed as shown at 604, a control cartridge may be used and analyzed as shown at 620 to help verify the performance of the analyzer, and/or a calibration cartridge may be used and analyzed as shown at 640 to Helps calibrate the analyzer. The blood analysis cartridge can be installed every time blood analysis is performed. The control box may be loaded into the analyzer on a regular basis such as once a day to verify that the analyzer is producing accurate results. The calibration kit can be placed in the analyzer less frequently, such as once every 3 months, to recalibrate the analyzer, or as needed.

Each cartridge type can contain all necessary fluids and/or components to function accordingly. This way, the analyzer can be operated and/or maintained without extensive training to obtain accurate results. Offers sample analyzers with removable and/or disposable cartridges that can be used reliably outside of a laboratory setting with little or no specialized training, helping to streamline the sample analysis process, reducing cost and medical Staff burden, increasing convenience for sample analysis of many patients, including patients requiring fairly frequent blood monitoring/analysis.

In the exemplary method of FIG. 12 , control passes to step 604 when a blood analysis cartridge is used. In step 606, a blood sample is provided to a disposable fluid cartridge. Control then passes to step 608 where the disposable fluid cartridge is inserted into the blood sample analyzer. Control then passes to step 610 . Step 610 starts the blood sample analyzer, and step 612 obtains the analysis result from the blood sample analyzer.

Control passes to step 620 when a control box is used. Step 620 passes control to step 622, where the control cartridge is inserted into the blood sample analyzer. Control then passes to step 624 . Step 624 starts the blood sample analyzer, and step 626 uses the control fluid cartridge to obtain control analysis results. Control then passes to step 628. Step 628 determines whether the control analysis results are within expected control limits. If the control assay results are not within the expected range, the results obtained by the blood analysis cartridge should not be trusted. In some cases, the sample analyzer can be recalibrated with a calibration cartridge, and then another control cartridge can be used to verify the operation/calibration of the sample analyzer.

Control passes to step 640 when a calibration cartridge is used. Step 640 passes control to step 642 . Step 642 inserts the calibration cartridge into the blood sample analyzer. Control then passes to step 644 . Step 644 starts the blood sample analyzer, and step 646 uses the calibration fluid cartridge to obtain calibration analysis results. Control then passes to step 648. Based on the results of the calibration analysis, step 648 adjusts the analyzer as needed.

In some cases, the sample analyzer can be a fully automated instrument, an all-in-one and/or self-contained test instrument. The sample analyzer accepts and analyzes directly unprocessed samples such as capillary blood (finger prick), venous whole blood, nasal swabs or urine. Alternatively or additionally, the sample analyzer may require only basic non-technology dependent sample operations, including any decontamination operations. Likewise, the sample analyzer may only require basic non-technology-dependent reagent operations, such as "mixing reagent A and reagent B", and may not require operator intervention during the analysis step. In some cases, the sample analyzer may include or provide instructions (and in some cases, when the confirmatory test is clinically appropriate, the sample analyzer may include or provide materials for obtaining and shipping a sample for the confirmatory test).

Sample analyzers can be supplied with a Quick Reference Instructions Guide. The Quick Reference Guide provides a quick reference for operating the sample analyzer. In use, the user can refer to the Quick Reference Guide if they have any questions about how to operate the sample analyzer.

In some cases, quick reference guides may include self-explanatory images or diagrams that illustrate various steps, sometimes from sample collection through analysis. In one illustrative example, the quick reference guide includes only images or diagrams and no words or a minimal number of words. This helps users who are not fluent in a specific language, such as English, to operate the sample analyzer effectively. In one illustrative example, the quick reference guide may show and/or describe the steps of: removing the disposable cartridge from the package; The marker changes color after being exposed to air for a predetermined period of time; blood is drawn from the patient; the drawn blood is provided to the cartridge; the cartridge is installed in the instrument; the instrument is run and results are received; the cartridge is removed from the instrument and the cartridge is discarded. This is just an example.

It is contemplated that the instrument housing may include pockets for quick reference guides and the like. When in use, the user can flip open the quick reference guide in the pocket for reference. Alternatively, the quick reference guide may be secured to the sample analyzer housing with a screw-type clip or the like, which may allow the user to flip through the pages of the quick reference guide during use. In another illustrative example, the quick reference guide may be affixed to the removable cartridge, or may be printed on the packaging containing the removable cartridge. In yet another illustrative example, the quick reference guide can be printed on a leaflet that can be affixed to a wall or the like near the sample analyzer.

In some cases, to further reduce the risk of erroneous results, one or more fail-alarm and/or fail-safe mechanisms may be provided. For example, in one illustrative example, a sample analyzer can help detect if a user is providing the wrong sample type. For example, if the sample analyzer is set to perform a white blood cell count on a whole blood sample, the sample analyzer can help detect whether the sample provided by the user is not blood.

In one illustrative example, the sample analyzer may perform an analysis, and if one or more output parameters are outside a predetermined range, the sample analyzer may not provide a result and/or issue an error message or error code. For example, if the sample analyzer is a flow cytometer used to count white blood cells on a whole blood sample, and the sample analyzer does not count any white blood cells (or a small number of white blood cells), the sample analyzer may not provide results, in some cases , providing an error message or error code.

In some instances, one or more optical measurements can be used to help identify the presence of incorrect fluid in a flow channel, such as when a user provides an incorrect sample, or when reagents are not provided to the correct flow channel of a fluid cartridge hour. Figure 13 shows one such optical measurement. In Fig. 13, a sample fluid 700 is present within a channel 702 defined, for example, by channel walls 704 of the fluid cartridge. In the illustrative example, channel walls 704 have a refractive index " _nw " and the sample fluid has a refractive index " _ns ". A light source 706 provides an incident beam (sometimes a collimated beam) at an angle to one of the channel walls 704 . A detector 708 is placed to detect light 710 reflected from the channel wall/sample interface. The amount of light reflected from the channel/sample interface to the detector 708 will depend on the relative refractive indices of the channel walls " _nw " and the sample fluid " _ns ". When the desired sample fluid 700 is present in the channel 702, a desired reflection amount or reflection signal can be determined. When an incorrect sample type or incorrect reagent or other incorrect sample fluid is provided to the flow channel 700, the " _nic " refractive index of the incorrect sample fluid can cause the detector 708 to measure a different reflected signal of the light 710 . Such changes may indicate the presence of incorrect sample fluid in the flow channel 702 . Alternatively or additionally, such changes may indicate the presence of air bubbles, blood clots, or other unwanted particles or other characteristics of the sample fluid. When so detected, the sample analyzer may not provide a result and, in some cases, may issue an error message or error code to the user.

Figure 14 shows another optical measurement that can be used to help identify when incorrect or unwanted fluid is present in a flow channel. In Figure 14, a sample fluid 720 is present within a flow channel 722 defined, for example, by channel walls 724 of the fluid cartridge. In the illustrative example, channel walls 724 have a refractive index " _nw " and the sample fluid has a refractive index " _ns ". A light source 726 provides an incident beam (sometimes a collimated beam) at an angle to one of the channel walls 724 . A detector 728 is positioned to detect light 730 passing through the channel 722 and sample fluid 720 .

In this illustrative example, channel 722 is made sufficiently thin to allow optical tunneling through channel 722 and sample fluid 720 when the sample fluid refractive index " _ns " is within a desired range. If the sample fluid refractive index " _ns " is below the desired range, the light will not pass through the channel 722, but will be reflected. If the sample fluid refractive index "n _s " is higher than the desired range, then light will tend to pass through the channel 722 and the sample fluid 720, so this example may be most suitable for detecting samples with a refractive index " _ns " smaller than the desired range (such as Blood) has an incorrect refractive index for the sample fluid. Alternatively or additionally, this illustrative example may be used to detect the presence of air bubbles, blood clots or other unwanted particles or other characteristics of the sample fluid as desired. When so tested, the sample analyzer may not provide a result, and in some cases, may provide an error message or wrong code.

FIG. 15 is another illustrative example that may be used to identify when incorrect or unwanted fluid is present, for example, in a flow channel of a fluid cartridge. In this illustrative example, sample fluid 750 is provided in flow channel 752 defined by channel walls 754 . In an illustrative example, two or more electrodes 760 are provided on one or more channel walls 754, and in some examples, two or more electrodes 760 may be formed on one or more plastic sheets in a stacked Shaped or fixed together to form the fluid circuit of the fluid box. Two or more electrode assemblies can be extended into or along the flow channel 752 on the fluid cartridge to connect with the desired drive circuit.

The power supply 758 can provide a signal between the electrodes 760 and the resistance between the electrodes through the sample fluid 750 can be measured. This measures the resistivity of the sample fluid 750 in the channel 752 . When an incorrect sample fluid is present in the flow channel 752, the resistivity of the incorrect sample fluid may be outside the expected range. Resistivity outside the expected range may also indicate the presence of air bubbles, blood clots or other unwanted particles or other characteristics of the sample fluid. When so detected, the sample analyzer may not provide a result, and in some cases, may provide an error message or wrong code.

In some cases, power supply 758 may provide a low potential AC signal (e.g., less than 10V peak-to-peak, less than 5V peak-to-peak, less than 3V peak-to-peak, less than 1V peak-to-peak, less than 0.5V peak-to-peak, or less than 0.1V peak - peak) to limit the electrochemical reaction of the sample fluid 750 caused by the electrode 760. Electrochemical reactions may, for example, introduce gas bubbles or the like into sample fluid 750, which may be undesirable in some circumstances.

In addition to or instead of using resistivity measurements described above, it is contemplated that capacitance measurements may be used. In this illustrative example, capacitance between two or more electrodes may be measured through sample 750 . When an incorrect sample fluid is provided to the flow channel 752, the capacitance result of the incorrect sample fluid may be out of the expected range. Capacitance outside the expected range may also indicate the presence of air bubbles, blood clots or other unwanted particles, or other characteristics of the sample fluid. When so tested, the sample analyzer may not provide a result, and in some cases, may provide an error message or wrong code.

FIG. 16 is another illustrative example that may be used to identify when incorrect or unwanted fluid is present in, for example, a flow channel of a fluid cartridge. In this illustrative example, sample fluid 770 is provided in flow channel 772 defined by channel walls 774 . In the illustrative example, pH sensor 776 is provided in fluid communication with sample fluid 770 . The pH sensor 776 can detect the pH of the sample fluid 770 and report a signal to the controller 780 . When an incorrect sample fluid is provided to the flow channel 772, the pH of the incorrect sample fluid may be outside the expected range. A pH level outside the expected range may also indicate the presence of air bubbles, blood clots or other unwanted particles or other characteristics of the sample 770 . When so detected, the sample analyzer may not provide a result, and in some cases, may provide an error message or wrong code.

17 is an illustrative example that can be used to identify when one or more air bubbles or other unwanted particles are present in a sample fluid in a flow channel. In this illustrative example, sample fluid 800 resides in flow channel 802 defined, for example, by channel wall 804 of the fluid cartridge. A light source 806 provides an incident beam (sometimes a collimated beam) at an angle to one of the channel walls 804 . A detector 808 is positioned to detect light 730 scattered by air bubbles or other unwanted particles present within the sample fluid 800 in the flow channel 802 . If, for example, the sample fluid 800 is free of any air bubbles, the light will pass through the sample fluid without scattering and the detector 808 will detect no signal (or a low signal). When the detector 808 finds a light scatter signal above a certain threshold, indicating that the sample fluid 800 in the flow channel 802 has one or more air bubbles or other unwanted particles, the sample analyzer may not provide a result, in some cases , which may provide an error message or error code.

FIG. 18 is an illustrative example that may be used to identify when one or more air bubbles or other unwanted particles are present in a sample fluid in a flow channel. In this illustrative example, sample fluid 820 resides in flow channel 822 defined, for example, by channel wall 824 of the fluid cartridge. An ultrasonic transducer 826 and an ultrasonic receiver 828 are provided adjacent to the flow channel 822 . In some cases, an ultrasonic transducer 826 is provided on one side of the flow channel 822 and an ultrasonic receiver 828 is provided on the opposite side. In other cases, the ultrasonic transducer 826 and the ultrasonic receiver 828 are provided on the same side of the flow channel 822 . In either case, ultrasonic receiver 828 may be used to detect scattering of the ultrasonic signal from ultrasonic transducer 826 by air bubbles or other unwanted particles in fluid sample 820 . When so tested, the sample analyzer may not provide a result, and in some cases, may provide an error message or wrong code.

FIG. 19 is another illustrative example that may be used to identify when one or more air bubbles or other unwanted characteristics are present in a sample fluid in a flow channel. In this illustrative example, sample fluid 850 is located within flow channel 852 defined, for example, by channel wall 854 of the fluid cartridge. A flow sensor 856 is provided in fluid communication with the flow channel 852 for sensing the flow rate of the sample fluid 850 . The flow sensor may be, for example, a flow sensor of the hot gas velocity type and/or a flow sensor of the microbridge type. Microbridge flow sensors are described, for example, in US Patent No. 4,478,076, US Patent No. 4,478,077, US Patent No. 4,501,144, US Patent No. 4,651,564, US Patent No. 4,683,159, and US Patent No. 5,050,429, all of which are incorporated herein by reference.

Pressure source 860 may provide variable pressure to sample fluid 850 in flow channel 852 . Controller 862 may receive a flow rate signal from flow sensor 856 and, in some cases, may control pressure source 860 . In one illustrative example, to detect air bubbles in the sample fluid, controller 862 may cause pressure source 860 to suddenly change the pressure applied to sample fluid 850 . The resulting change in flow rate of sample fluid 850 can then be monitored with flow sensor 856 .

FIG. 20 is a graph showing exemplary pressure pulses 900 that may be provided by pressure source 860 to sample fluid 850 within flow channel 852 of FIG. 19 . The flow rate shown at 902 can be obtained with little or no air bubbles in the sample fluid 850 . When the pressure pulse 900 suddenly increases, the flow rate 902 increases more rapidly from the lower flow rate value 904 to the higher flow rate value 906, and when the pressure pulse 900 suddenly decreases, it decreases rapidly from the higher flow rate value 906 to the lower flow rate value 904 . However, when bubbles are present in the sample fluid 850, the resulting flow rate 908 (shown in dashed lines) may increase more gradually from a lower flow rate value 904 to a higher flow rate value 906 when the pressure pulse 900 suddenly increases, and when the pressure pulse 900 suddenly decreases, resulting The flow rate 908 may decrease more gradually from the higher flow rate value 906 to the lower flow rate value 904 . Air within the bubbles may, for example, increase the compressibility of the sample fluid 850, thus causing a more gradual increase and decrease in flow rate. The presence of air bubbles in the sample fluid 850 can be detected by monitoring the change in flow rate as the applied pressure changes. If the change in flow rate is found to be sufficiently reduced, the sample analyzer may not provide a result and, in some cases, may provide an error message or error code.

The desired pressure source 860 may be a suitable pressure source, including a conventional pump, a compressed air source, or any other suitable pressure source as desired. In some cases, pressure source 860 may be a high frequency pressure source such as a piezoelectric vibrator, an ultrasonic transducer, or any other type of high frequency pressure source. In some cases, high frequency pressure sources can be used in conjunction with conventional pumps or other pressure sources, allowing parallel operation. That is, when analyzing a sample fluid, a conventional pump or other pressure source 860 may be used to actually move the sample fluid through the flow channel 852 of the fluid cartridge. A high frequency pressure source may not be used to move the sample fluid appreciably along the flow channel, but may be used to generate high frequency pressure pulses on the sample fluid to detect certain parameters of the sample fluid including, for example, the presence of air bubbles, the compressibility of the sample fluid, and the like. The compressibility of the sample fluid can be used to help determine if the sample fluid 850 in the flow channel 852 is the expected sample fluid type, if not the sample analyzer may not provide a result, and in some cases, may provide an error message or code.

In any event, in some cases, when the high frequency pressure source is run simultaneously or in parallel with a conventional pump or other pressure source, the sample fluid can be monitored in situ while the fluid circuit is processing the sample.

In some cases, the pressure pulses can be used to determine or estimate the position of the sample fluid end or distal end in the flow channel of the fluid circuit. Figure 21 shows one such illustrative example. In Fig. 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 . A pressure transducer (eg, a pressure source) 1008 and a pressure receiver (eg, a pressure sensor) 1010 are shown in flow connection with the sample fluid 1004 at known locations relative to the flow channel 1000 . Pressure transducer 1008 may generate pressure pulses in sample fluid 1004 . The pressure pulse propagates along the sample fluid 1004 to the tip 1012 . Some energy of the pressure pulse will be reflected back to the pressure receiver 1010 by the tip 1012 of the sample fluid 1004 . The distance of the current position of tip 1012 from pressure transducer 1008 and/or pressure receiver 1010 is related to the time required for a pressure pulse to propagate along sample fluid 1004 to tip 1012 and back to pressure receiver 1010 . Thus, by measuring the time required for a pressure pulse to propagate to tip 1012 and back to pressure receiver 1010, the position of tip 1012 along flow channel 1000 can be determined.

Flow channel 1002 is similar to flow channel 1000, but ends at a greater distance along the flow channel. Therefore, assuming sample fluid 1006 is the same as sample fluid 1004 , the time required for the pressure pulse to propagate to tip 1014 and back to pressure receiver 1018 will be greater than the time required for flow channel 1000 . Also, the amplitude of the reflected pressure pulse received by pressure receiver 1018 may be weaker than the amplitude of the pressure pulse received by pressure receiver 1010 . Thus, monitoring the amplitude may provide another way to estimate or determine the position of tips 1012 and 1014 along flow channels 1000 and 1002, respectively.

22-23 illustrate exemplary methods of determining when two fluids have joined in a fluid circuit. In many sample analyzers, different fluids are initially provided in different flow channels. However, in a fluid circuit, the various fluids are often mixed. For example, although the blood sample and spheroidizing agent may initially be provided in separate flow channels, they are then mixed together somewhere downstream in the fluid circuit. When and how the various fluids are concentrated can be important to the overall function of the sample analyzer as disclosed in US Patent Application Serial No. 10/932,662, assigned to the assignee of the present invention and incorporated herein by reference.

To help determine when two or more fluids have converged downstream of the fluid circuit, a pressure transducer may be used to generate a pressure pulse in at least one of the fluid samples. For example, referring to FIG. 22 , a pressure transducer 1030 , such as a pump, piezoelectric vibrator, ultrasonic transducer, or any other type of pressure transducer, can generate pressure pulses in sample fluid 1032 in first flow channel 1034 . A pressure receiver 1036 (eg, a pressure sensor, an ultrasound receiver, etc.) may be in fluid communication with the sample fluid 1040 of the second flow channel 1042 . The first flow channel 1034 and the second flow channel 1042 may converge at a flow channel 1044, as best shown in FIG. 23 .

Referring again to FIG. 22 , the pressure pulse generated in the first sample fluid 1032 by the pressure transducer 1030 may propagate along the first sample fluid 1032 but may not extend appreciably to the end or distal end of the first sample fluid 1032 1046. In the illustrative example, flow channel 1044 shown in FIG. 22 is initially filled with air or other gas and then replaced by sample fluid 1032 and 1040 as sample fluid 1032 and 1040 are pushed along their respective flow channels 1034 and 1042 . Before the sample fluids 1032 and 1040 are concentrated, the pressure receiver 1036 is unlikely to receive significant pressure pulses or significantly dampened pressure pulses from the pressure transducer 1030 .

One or more pressure sources (not shown), such as pumps, etc., can be activated to move the sample fluids 1032 and 1040 along their respective flow channels 1034 and 1042 until the sample fluids 1032 and 1040 converge, as better shown in FIG. 23 . When this occurs, the pressure pulse generated by pressure transducer 1030 can now propagate more freely to pressure receiver 1036 . Thus, by monitoring when the pressure receiver 1036 begins to receive or receives less attenuated pressure pulses from the pressure transducer 1030, it can be determined when the sample fluids 1032 and 1040 have converged.

In some cases, pressure transducer 1030 can generate a sequence of pressure pulses (sometimes at a fairly high frequency) in the sample fluid, which can be coupled with a pump or pump that actually moves sample fluid 1032 and 1040 along flow channels 1034, 1042, and 1044 of the fluid circuit Other stressors operate simultaneously or in parallel. Thus, the pressure transducer 1030 can be used to monitor the sample fluid of the fluid circuit in situ, and more specifically monitor when the sample fluids 1032 and 1040 are pooled downstream.

In some cases, the sample analyzer is not on a horizontal plane when analyzing, which can affect the operation of the sample analyzer. To detect this condition, it is contemplated that the sample analyzer may include a level sensor. In an illustrative example, the level sensor can be a Micro Tilt sensor (D6B) available from Omron Corporation. Other level sensors may include ball sensors with electrical outputs. Using the level sensor, the sample analyzer can determine if the sample analyzer is level enough for analysis. If the sample analyzer is not level enough, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or wrong code.

Another method of checking the adequacy of the sample analyzer involves depressurizing one or more flow channels containing the fluid and measuring the flow rate of the fluid in the one or more flow channels. If the sample analyzer is not level enough, gravity can cause the flow rate in one or more flow channels to exceed the expected range. If the flow rate is outside the expected range, the sample analyzer may be considered insufficient and the sample analyzer may not analyze and/or provide no results, and in some cases, error messages or codes.

In some cases, bumping or moving the sample analyzer during analysis may affect sample analyzer operation. To detect this, it is contemplated that the sample analyzer may include shock and/or vibration sensors. In one illustrative example, the shock and/or vibration sensor may be a Shock/Vibration sensor (D7E-2) available from Omron Corporation. Using shock and/or vibration sensors, the sample analyzer can determine if the sample analyzer has been bumped or moved. If the sample analyzer has been jolted sufficiently, the sample analyzer may require the user to run a control or calibration card before starting to verify that the sample analyzer is functioning correctly. In some cases, the sample analyzer may determine if the sample analyzer was bumped or moved during analysis. If the sample analyzer has been sufficiently bumped while analyzing, the sample analyzer may not provide a result and, in some cases, may provide an error message or wrong code.

In some cases, a sample analyzer can include an instrument and removable and/or disposable cartridges. Because user behavior is sometimes unpredictable, it may be necessary to confirm that the cartridge is correctly inserted into the instrument before starting an analysis. One method of implementation is to design the cartridge and instrument so that the cartridge can only be inserted into the instrument in the correct orientation. For example, FIG. 24 shows cartridge 1100 received by a slot of instrument 1102 (arrow 1104 ). Exemplary cartridge 1100 includes a recess 1106 on the upper surface of cartridge 1100 . The instrument includes corresponding protrusions 1108 adapted to extend into the grooves 1106 when the cartridge 1100 is inserted in the correct orientation relative to the instrument 1102 . If the cartridge 1100 is inserted upside down, the grooves 1106 and protrusions 1108 will not align, preventing the cartridge 1100 from being fully inserted into the slot of the instrument 1102 . Likewise, if end 1112 of cartridge 1100 is inserted into a slot in instrument 1102 , groove 1106 and protrusion 1108 will not align and will prevent cartridge 1100 from being fully inserted into the slot in instrument 1102 . This is just one example of locking the cartridge 1100 into the instrument 1102 so that the cartridge 1100 can only be inserted into the instrument 1102 in the correct orientation.

The orientation of the cartridge relative to the instrument can be confirmed by any means, especially if the cartridge is not locked to the associated instrument. For example, in some instances, one or more pressure ports may extend between the instrument and the cartridge when the cartridge is properly inserted into the instrument. The instrument applies pressure to one or more pressure ports and checks to see if the desired fluid is found. If the instrument pressure port does not interface with the cartridge pressure port, the desired fluid may not be found. If the desired flow rate is not found, the sample analyzer may not perform an analysis and/or provide no results, and in some cases, an error message or error code.

In another example, a cartridge may include one or more optical windows or other optical structures. If the cartridge is properly loaded into the instrument, the instrument can optically interrogate the location of one or more optical windows or other optical structures. If the expected optical response is not detected, the cartridge may not be properly oriented and the sample analyzer may not perform the analysis and/or provide no results, and in some cases, an error message or wrong code.

In some cases, a sample analyzer may require one or more reagents for the desired sample analysis. It may be necessary to determine whether the correct reagents are present and are performing well. In one illustrative example, the reagents can be delivered in containers, which can include barcodes or other codes that identify various parameters of the reagents. Various parameters may, for example, identify reagent type, date of manufacture, reagent expiration date, and other parameters. The sample analyzer may include a barcode reader or other code reader to read various parameters. The sample analyzer can then determine, for example, whether the reagents are the correct reagents for the desired sample analysis, whether the reagents are past a specified expiration date, or the like. If the reagents are not the correct reagents for the desired analysis or perform poorly, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide error messages or codes.

In some cases, reagents may be stored on removable and/or disposable cartridges. Disposable cartridge 1120 shown in FIG. 25 includes three chambers 1122a, 1122b, and 1122c, each of which is used to store specific reagents required for an assay to be performed with cartridge 1120. Shown has a barcode 1124 attached to the box 1120 . Once the cartridge is properly inserted into the appropriate instrument, the instrument can read the barcode to determine if the reagent is the correct reagent for the desired sample analysis, if the reagent is past its specified expiration date, etc.

Barcode 1124 may also identify various parameters related to cartridge 1120 . For example, the barcode 1124 can identify the cartridge, the type of assay the cartridge supports, cartridge-specific calibration parameters (if any), timing parameters for the assay, input pressure and/or flow rate for the assay, and the like. In some cases, the barcode 1124 may also provide software used by the instrument when analyzing with the cartridge. Instead of or in addition to barcode 1124, an RFID tag may be provided, and the instrument may include a mechanism to read the RFID tag. The RFID tag may include similar information as described above with respect to the barcode 1124 .

Temperature may also affect the performance of some reagents, and in some cases a maximum temperature indicator 1126 and/or a minimum temperature indicator 1128 may be provided. The minimum temperature indicator 1128 can be similar to the freeze indicator available from JP Labs. Freeze indicators offered by JP labs come in the form of tags that can be easily attached to boxes or other containers. When the temperature of the freezing indicator falls below the freezing point of water, it produces an irreversible color change, eg blue to red. The instrument may include an optical interrogator that detects the color of the freeze indicator 1128. If the reagent has been exposed to temperatures below the minimum temperature, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or error code.

Also, the highest temperature indicator 1126 can be similar to the temperature indicator available from JP Labs. These indicators change color when a certain predetermined temperature (or temperature range, usually above room temperature) is reached. When heated, they change from colorless to red, colorless to green, blue to red, etc. These indicators can be readily incorporated into commercially available ink tools such as flexo and gravure. The instrument may include an optical interrogator that detects the color of the temperature indicator 1126. If the reagent has been exposed to a temperature above the maximum temperature, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or error code.

Humidity and/or moisture indicators may also be provided. Humidity and/or moisture indicators can be similar to those available from JP Labs. The humidity and/or moisture indicator may change color after total exposure to moisture. Under normal ambient humidity, the color change can take anywhere from a few minutes to several weeks.

The example case 1120 may also include a time indicator 1130 . In some examples, cassette 1120 may be shipped to the user in a sealed package. The airtight packaging can provide a controlled environment around the cassette 1120. Before use, the user must remove the cartridge 1120 from the packaging, thereby exposing the cartridge 1120 to the environment. The time indicator 1130 can be activated when the package is opened, change color or provide a detectable condition after a predetermined period of time has elapsed. Time indicator 1130 may be similar to the time indicator available from JP Labs.

The instrument may include an optical interrogator that detects the color of the time indicator 1130, and if the time period expires, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or wrong code. This allows the user to specify a predetermined time for unpacking the cartridge, loading the blood or other sample in the cartridge 1120, and analyzing it with the instrument. This can help reduce the chances of a user loading a sample in the cartridge 1120 and then waiting too long before performing an analysis allowing the sample to freeze, dry out, or change characteristics.

When the cartridge 1120 is removed from the package, the time indicator may not be activated, but a strip 1132 or other material may be provided over the sample input port 1134 of the cartridge 1120 . Time indicator 1136 may be covered with a strip 1132 or other material. Before loading the sample into the cartridge, the user must remove the strip 1132 or other material, then expose the time indicator to the environment and activate the time indicator. Time indicator 1136 changes color or provides a detectable condition after a predetermined period of time has elapsed.

The instrument may include an optical interrogator that detects the color of the time indicator 1136, and if the time is up, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or wrong code. This allows the user to specify a predetermined time when the strip 1132 or other material is removed from the sample input port, blood or other sample is loaded into the cartridge 1120, and analyzed by the instrument. This can help reduce the chances of a user loading a sample in the cartridge 1120 and then waiting too long before performing an analysis allowing the sample to freeze, dry out, or change characteristics.

In some cases, the cartridge may include a spring-push lancet to help collect the blood sample within the cartridge. For example, FIG. 26 shows an exemplary cartridge 1150 including a spring-pushed lancet 1152 . The spring-push lancet 1152 may include a spring or other biasing element 1153 that biases the lancet toward the extended position 1154 . A release mechanism 1156 can be coupled to the spring-operated lancet 1152 to lock the lancet in the retracted position 1158 . When the user activates the release button or handle 1160 , the release mechanism 1156 can release the spring-operated lancet 1152 and the lancet can suddenly move from the retracted position 1158 to the extended position 1154 . If the user's finger rests against the cartridge 1150 when the release button or handle 1160 is actuated, the spring-loaded lancet 1152 can pierce the user's skin and draw out an appropriate amount of blood. Spring-push lancet 1152 can be in fluid communication with a sample collection capillary (not shown) in cartridge 1150 , so in some examples, a blood sample can be delivered directly into the sample collection capillary of cartridge 1150 . Spring-push lancet 1152, release mechanism 1156, and release button or handle 1160 may be similar to the BD ^™ Lancet Device available from Becton, Dickinson and Company.

Alternatively, the sample may be delivered from, for example, a pierced finger through a pipette (possibly coated with an anticoagulant) into the sample input or capillary of the cartridge. Samples can be transferred and introduced into the cartridge with a syringe. Use an alcohol swab to prepare your finger before pricking, cutting, or cutting it. A lancet engraved with a set depth can be used, such as lancet 1152 of box 1150 in FIG. 26 .

In some cases, referring to FIG. 27, the removable and/or disposable cartridge 1200 may include a mechanism to remove air bubbles from the fluid. In some cases, air bubbles may be removed from the flow in the flow channel as they pass under the porous membrane forming part of the flow channel wall. In FIG. 27 , liquid is shown flowing along flow channel 1170 with bubbles. Membrane 1172 separates flow channel 1170 from plenum chamber 1174 . The pressure of the plenum chamber 1174 remains lower than the pressure of the flow channel 1170 . In some cases, the membrane is a hydrophobic membrane, such as Fluoropore ^™ , Mitex ^™ or Durapore ^™ membranes available from Millipore Corporation, Billerica, Mass. Mitex ^™ membranes are made of PTFE with pore sizes of 5 or 10 microns. Fluoropore ^™ membranes are made of PTFE with HDPE support and have a pore size of 1 or 3 microns. Durapore ^™ membranes were prepared from polyvinylidene fluoride with pore sizes of 0.1, 0.22 and 0.45 microns. Hydrophobic membranes are generally capable of maintaining higher pressure differentials without fluid leakage through the water-transporting membrane.

The pressure differential between flow channel 1170 and plenum 1174 forces the gas of bubbles 1180 to pass through membrane 1172 and outer vent 1182, resulting in significantly less (preferably no) bubbles in the liquid downstream of membrane 1172 . The bubble-free liquid can then flow down, as shown at 1184, for further processing by the fluid circuit on the removable and/or disposable cartridge.

Although a larger pore size requires a smaller pressure differential than a smaller pore size to achieve the same gas flow rate from trapped gas bubbles 1180, the larger pore size cannot maintain a large pressure differential without allowing liquid to pass through. It is estimated that a membrane with 1 micron pores should be able to sustain a pressure difference of 1 PSI, depending on the surface energy of the liquid and the membrane and the pore geometry.

FIG. 28 is a schematic illustration of an illustrative example of a bubble trap 1191 on the sidewall of the flow channel 1185 . Bubbles 1187 may move along the fluid 1193 into one or more traps 1191, collect and fuse with gas bubbles 1189 already in the traps; or the gas bubbles 1191 may become initial bubbles 1189 in the traps. The trap can be deformed like a triangular hook in the wall of the flow channel, and when air bubbles pass through, they can be trapped and cannot flow back from the trap into the fluid. In addition to the triangle shown, the catcher shape can be rectangular, hemispherical, etc.

In some examples, a sample analyzer may have electronics and/or software that control various components of the sample analyzer. In some cases, although the sample analyzer may be powered by line voltage, it may have a battery backup in the event of a power outage. Electronic devices may also include clock chips (sometimes with battery backup) to maintain accurate time and date. The exact time and date can be used, for example, to compare reagent expiration dates, which can be read from, for example, a barcode on the reagent packaging or cartridge, to determine if the reagent is still usable.

If power is lost during analysis and no battery backup is provided, the electronics and/or software may terminate the analysis without issuing results and, in some cases, issue an error message or error code to the user.

Electronics and/or software can be interfaced with the various light sources and detectors of the sample analyzer. In some examples, the electronics and/or software can check the operation of the light source and light detector before, after, and/or periodically or throughout sample analysis. For example, electronics and/or software may verify that one or more detectors are detecting light provided by a corresponding light source before, after, and/or periodically or throughout sample analysis.

Alternatively or additionally, cartridge irregularities, such as cracks in the optical window or dust or debris in the optical window, can be identified after the cartridge is inserted into the instrument but before the analytical procedure begins. This can be done, for example, by activating one or more light sources to pass light through the optical window and using one or more detectors to detect optical features (reflection, scattering, FALS, SALS, LALS, etc.). If the optical window contains cracks, dust or debris on the optical window, or has other irregularities, these irregularities can produce unexpected optical features on the detector. If the electronics and/or software detect such irregularities, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, error messages or codes. Dirty optics can be cleaned with a cotton pad.

If a flow sensor is present in the sample analyzer, some electronics and/or software can monitor the flow sensor output before, after, or during analysis to demonstrate that the indicated flow rate is within the desired range or conforms to the desired profile. If the electronics and/or software find that the indicated flow rate is not within the desired range or conforms to the desired profile, the sample analyzer may not perform the analysis and/or provide no results, and in some cases, may provide an error message or error message. code.

In some cases, the sample analyzer may include certain built-in self-test (BIST) levels. For example, in the test mode, some or all storage elements (such as registers) in the electronic device can be selectively connected together in a series of scan chains, wherein the test vectors can be continuously scanned in the chained registers. In some cases, the inputs and outputs of the electronic device may include test registers that are only logically inserted in test mode. A functional clock cycle may begin in which the test vector bits are released through the logic between the registers from which the results are fetched. The result can then be continuously scanned out of the register and compared with the expected result. This fully tests the electronics of the sample analyzer.

Many such test vectors can be implemented to achieve the desired fault coverage. In some cases, fault coverage may be greater than 50% logic, greater than 60% logic, greater than 80% logic, greater than 90% logic, greater than 95% logic, or greater than 99% logic, as desired. Once tested, the electronics can be returned to the functional mode and normal functional operation of the sample analyzer can be resumed. The sample analyzer may automatically enter test mode at regular intervals such as hourly, daily, weekly, monthly, or at any other desired interval as desired.

In some cases, depending on the application, the electronic equipment and/or software are designed and/or tested to provide a mean time between failures (MTBF) of greater than 5,000 hours, greater than 8,000 hours, greater than 10,000 hours, greater than 50,000 hours, greater than 100,000 hours, or above.

In some examples, the sample analyzer can be connected to a remote location or locations via the Internet. When so provided, the test results can be delivered remotely for long-term storage and/or further analysis, if desired. Additionally, it is contemplated that the remote location may include diagnostic software that enables remote diagnostics and/or maintenance of the sample analyzer. In some cases, the hardware or software of the sample analyzer can be automatically upgraded remotely.

Card declines and other errors can be sent remotely. Remotely, it can be determined whether a particular sample analyzer is experiencing abnormally high errors. An abnormally high error can indicate a failed or marginal hardware component of the sample analyzer, which can be dispatched remotely to repair/replace the component before the user notices the problem. An unusually high error at a particular location may also indicate that the user at that location may need more training. Such training may be dispatched to laboratory personnel from remote locations. Cassettes and instruments can be designed to be operated by untrained personnel.

The remote can also statistically analyze errors and/or BIST results from multiple sample analyzers, identifying sample analyzer components, software or other areas that can be enhanced in subsequent releases of the sample analyzer.

Temperature, humidity, and other environmental parameters in or around the sample analyzer, as well as shock, tilt, and other sensor data, can be periodically detected and sent to remote locations as needed.

In this specification, some circumstances may be hypothetical or prophetic in nature, but stated in another manner or tense.

While the invention has been described with respect to at least one illustrative example, many alterations and modifications will become apparent to those skilled in the art upon reading this specification. It is therefore intended that the appended claims be interpreted as broadly as possible from the prior art to cover all such changes and modifications.

Claims (17)

1. sample analyser, described sample analyser comprises:

Instrument with line of rabbet joint; With

The box that comprises flow channel, this box are used for inserting the line of rabbet joint;

When box inserts the line of rabbet joint near the light source of box; With

When box inserts the line of rabbet joint near the detecting device of box; And

Wherein:

Flow channel comprises conduit wall;

Conduit wall has first refractive index;

Sample fluid in the flow channel has second refractive index;

Light source is in the passage that illumination is gone into to flow; With

Detecting device is for detection of the light of first and second refractive index interfaces reflection.

2. the analyser of claim 1, wherein:

The light indication fluid refracting rate that detecting device detects; With

If the fluid refracting rate is not in specified scope, then sample analyser can not analyzed, do not provided result, the incorrect fluid of indication and/or error flag is provided.

3. the analyser of claim 1, wherein conduit wall is enough thin, so that the Δ between first and second refractive index allows the optics tunnelling when being within the satisfactory scope of fluid.

4. the analyser of claim 1, if wherein the fluid refracting rate is not in specified scope, then fluid may be incorrect sample or sample, has incorrect reagent, bubble, clot and/or pollutant.

5. the analyser of claim 1, wherein:

Detecting device is for detection of by conduit wall and fluid and pass conduit wall and arrive the outer light of passage;

Arrive the refractive index of the light indication fluid of detecting device; And

If the refractive index of fluid is not in the specified scope of appropriate samples fluid, then sample analyser may not analyzed, do not provided result, the incorrect sample fluid of indication and/or error flag is provided.

6. sample analyser, described sample analyser comprises:

Instrument with the line of rabbet joint and detecting device;

Box, described box are used for inserting in the line of rabbet joint, and described box has flow channel, and described box comprises first transparency window, second transparency window and the 3rd transparency window;

Aim at first light source, secondary light source and the 3rd light source that arrange respectively with described first transparency window, second transparency window and the 3rd transparency window, this transparency window is used for transmitting energy from this light source;

The ultrasonic transducer that contiguous described flow channel provides;

The ultrasonic receiver that contiguous described flow channel provides;

Pressure source;

Wherein said ultrasonic receiver is for detection of the scattering that is caused the ultrasonic signal that described ultrasonic transducer sends by the bubble in the fluid sample or other unwanted particle.

7. the analyser of claim 6, wherein:

Light source is used for providing light, the angled flow channel that passes through of the wall of described light and flow channel;

Detecting device is for detection of the scattered light intensity from flow channel;

There are unwanted particle or bubble in the fluid of the intensity indication flow channel of a certain scope;

If detect the intensity of a certain scope, then analyser can not provide the result maybe can provide error flag.

8. the analyser of claim 6, wherein:

Have in the reflected ultrasound energy indication flow channel of a certain scope intensity and have bubble or other unwanted particle;

If ultrasonic receiver receives the reflected ultrasound energy of a certain scope intensity, then analyser will not provide the result and/or error flag will be provided.

9. the analyser of claim 6, wherein:

Pressure source is used for a certain pressure variation is put on the flow channel sample fluid;

Detecting device is the flow sensor that is arranged in flow channel, is used for the flow velocity of monitoring flow channel;

Flow sensor monitoring sample fluid flow velocity, and pressure source changes a certain pressure the fluid that puts in the flow channel;

The compressible amount of the change in flow indication sample fluid of the time per unit for a certain pressure changes; And

There is bubble in the compressible amount indication sample fluid of specified scope.

10. the analyser of claim 9, wherein pressure source is high-frequency impulse piezoresistive pressure source.

11. the analyser of claim 9, if there is bubble in the sample fluid in the indication flow channel, then analyser will not provide the result and/or error flag will be provided.

12. the analyser of claim 6, wherein:

Pressure source is the pressure transducer that transmits pressure pulse in the sample fluid of flow channel, is positioned at the moving passage of longshore current with respect to the primary importance of sample fluid end;

Detecting device is the pressure receiver that receives the pressure pulse of fluid end reflection, is positioned at the second place of the moving passage of longshore current; And

The moving passage of longshore current transmits pressure pulse to the duration that receives between the reflected impulse and indicates described end along the position of flow channel with respect to first and second positions.

13. the analyser of claim 6, wherein:

Pressure source is the pressure transducer that transmits pressure pulse in the first fluid of first flow channel;

Detecting device is the pressure receiver that receives from the pressure pulse of second fluid in second flow channel;

Have terminal first fluid and be positioned at first flow channel;

Have the second terminal fluid and be positioned at second flow channel; And

If pressure pulse is produced in first fluid by pressure transducer, then the end one of first and second fluid is joined, and pressure receiver just tangible pressure pulse signal will occur.

14. the sample analyser of claim 6, described sample analyser also comprises:

Lay respectively at the one or more flow sensors in the flow channel;

If the flow velocity of one or more flow sensor indications exceeds the flow velocity desired extent, then analyser can be considered to not measure up, and then analyser may not analyzed, do not provided the result and/or error flag will be provided.

15. the sample analyser of claim 6, described sample analyser also comprises:

Lay respectively at the one or more flow sensors in the flow channel;

If the flow velocity of one or more flow sensor indications exceeds the flow velocity desired extent, then the fluid in the flow channel can be considered to incorrect, and then the result may not analyzed, do not provided to analyser, can indicate incorrect fluid, and/or error flag will be provided.

16. the sample analyser of claim 6

Wherein:

Described box comprises one or more flow channels;

It is coupled that one or more flow channels have at least one flow sensor separately,

Before analyzing operation, simultaneously and/or monitor each flow sensor output afterwards;

Check that each flow sensor exports to determine that it is whether in desired extent and/or flow distribution figure;

If a flow sensor output is regarded as not in desired extent and/or profile of flowrate, then sample analyser may not analyzed, and the result is not provided, and/or error flag will be provided.

17. the sample analyser of claim 6, described sample analyser also comprises:

Be positioned at the flow sensor of flow channel;

If have the passage step-down of fluid, flow sensor can be measured the rate of flow of fluid that the gravity level causes;

The level of flow velocity indication analyser;

If the analyser level is not in specified scope, then analyser may not analyzed, and the result is not provided, and/or error flag will be provided.

Images