Quality control device for use in an analytical instrument

Abstract: Novel methods and devices are provided involving at least one chamber, at least one capillary (12), and at least one reagent (16) involved in a system providing for a detectable signal. As appropriate, the devices provide for measuring a sample, mixing the sample with reagents, defining a flow path, and reading the result. Of particular interest is the use of combinations of specific binding pair members which result in agglutination information, where the resulting agglutination particles may provide for changes in flow rate, light patterns of a flowing medium, or light absorption or scattering. A fabrication technique particularly suited for forming internal chambers in plastic devices is also described along with various control devices for use with the basic device.

Description: BACKGROUND OF THE INVENTION Field of the Invention This invention is related to quality control devices for use in testing devices having internal chambers into which fluids are drawn. Background of the Invention In the development of the diagnostics field, there has been explosive growth in the number of substances to be determined. For the most part, the medical field has looked to clinical laboratories for these determinations. The clinical laboratories have been dependent upon expensive sophisticated equipment and highly trained technical help to fulfill the manifold needs of the medical community. However, in a highly automated clinical laboratory, there is substantial need to perform one or a few assays on a stat basis with minimum equipment. There is also an expanding need for having analytical capabilities in doctors' offices and in the home. There is a continuing need to monitor the level of drug administered to people with chronic illnesses, such as diabetics, asthmatics, epileptics, and cardiac patients, as it appears in a physiological fluid, such as blood. Tests of interest include prothrombin time, potassium ion, and cholesterol. Determining red-blood-cell count is also a common test. In the case of diabetic patients, it is necessary to determine sugar level in urine or blood. Numerous approaches have been developed toward this end, depending to varying degrees on instrumental or visual observation of the result. Typical of these are the so called "dip-stick" methods. These methods generally employ a plastic strip with a reagent-containing matrix layered thereon. Sample is applied to the strip and the presence or absence of a analyte is indicated by a color-forming reaction. While such devices have proven useful for the qualitative determination of the presence of analytes in urine and can even be used for rough quantitative analysis, they are not particularly useful with whole blood because of the interferring effects of red blood cells, nor are they useful for making fine quantitative distinctions. Accordingly, there remains a need for the development of methods and devices capable of analyzing whole blood and other complex samples rapidly with a minimum of user manipulations. Brief Description of the Relevant Literature Powers et al ., IEEE Trans. on Biomedical Engr. (1983) BME-30-228, describes detecting a speckle pattern for determining platelet aggregation, as does Reynolds, Light Scattering Detection of Thromboemboli , Trans. 11th Annual Mtg. of the Soc. for Biomaterials, San Diego, CA, April 25-28, 1985. Reynolds and Simon, Transfusion (1980) 20 :669-677, describes size distribution measurements of microaggregates in stored blood. Of interest in the same area are U.S. Patent Nos. 2,616,796; 3,810,010; 3,915,652; 4,040,742; 4,091,802; and 4,142,796. U.S. Patent No. 4,519,239 describes an apparatus for determining flow shear stress of suspensions in blood. Ab Leo sells the HemoCue TM device for measuring hemoglobin. Also, see U.S. Patent No. 4,088,448, which describes a cuvette for sampling with a cavity which is defined in such a manner as to draw into the cavity a sample in an amount which is exactly determined in relation to the volume of the cavity by capillary force. A device used to transport liquids by capillary flow is described in U.S. Patent 4, 233,029. SUMMARY OF THE INVENTION The present invention relates to quality control devices for use in an analytical instrument in which a defined chamber or channel is prepared within the internal space of a solid device. The instruments typically call for the use of capillary force to draw a sample into the internal chambers of a plastic device. Such capillary flow devices, particularly capillary flow devices designed for a constant flow rate, typically include at least one capillary acting as a pump, usually for controlling the volume of the sample and the time period for reaction, a chamber, an inlet port, a vent, and a reagent in proximity to at least one surface of the device. The capillary and chamber provide for capillary flow due to surface action and for mixing of the assay medium with the reagent. The reagent is part of a detection system, whereby a detectable result occurs in relation to the presence of an analyte. The device and the corresponding method can be used with a wide variety of fluids, particularly physiological fluids, for detection of drugs, pathogens, materials endogenous to a host. An optical measurement is being made, which requires the selection of a transparent material. Analytical instruments in which the present invention can be used are described in detail in the parent patent EP-B-212 314, incorporated herein by reference for the disclosure of these instruments. According to the invention a quality control device is provided for use in an analytical instrument which utilizes an analysis cartridge containing an internal chamber in which said analysis occurs, said analysis cartridge being insertable into a location in said instrument so that light generated in said instrument passes through said chamber and is detected by a light detector in said instrument, which comprises: a control cartridge, wherein said control cartridge is insertable in said location; a liquid crystal cell located in said control cartridge so as to interpose between said light source and a light detector in said analytical instrument; and a polarizing filter located between said light source and said light detector so as to allow passage or block passage of light between said light source and said light detector when voltage applied to said liquid crystal is modulated. The polarizing filter can be located in the control cartridge. Another possible location for this polarizing filter is the analytical instrument. The control cartridge can further comprise a power supply and a control circuit capable of modulating voltage supplied to said liquid crystal cell. The actual device containing the capillary channels and other chambers is typically a flat cartridge that is inserted into an instrument which makes the various electronic measurements. Reference is made to the parent patent EP-B-212 314 for a detailed description thereof. An useful control device according to the invention is some means for simulating blood flow through a capillary channel in order to determine whether the electronic apparatus into which the cartridge is being inserted is fully operational. Numerous means of accomplishing this result are available, but one useful technique not believed to be previously used in any similar manner is described below. As described in detail in the parent patent EP-B-212 314, one useful technique for measuring blood flow is to detect the presence of the speckled pattern that results from the interaction of particles and coherent light. Any technique that simulates blood flow when such a detection system is being used will need to simulate the speckled pattern of light. Since the detector and the coherent light source are typically located in a close spatial relationship directly opposite each other so that insertion of the capillary device will result in light from the coherent light source passing directly through a channel in the device to the detector, simulation of blood flow requires insertion of some device into the electronic apparatus that can modulate the light beam. While this could be accomplished using a second device that could, for example, produce modulated light, a useful technique is to include electronics and modulating devices directly in the capillary device so that each capillary cartridge can be used to determine the operating characteristics of the electronic apparatus containing the coherent light source and detector immediately prior to actual measurement being taken. However, this requires that the speckled pattern generator be such that it will not then interfere with the actual measurement. One means of accomplishing these results is to include a liquid crystal display-type apparatus at the location where measurement is being made. The liquid crystal material is selected so as to rotate polarized light that passes through it, the typical means by which liquid crystals operate. Polarizer filters will be present, either in the cartridge itself or in the electronic apparatus into which the cartridge is inserted that will result in the passage of light through the polarizing filters when the liquid crystal device is turned off. However, when the liquid crystal device is activated by application of a voltage, light passage will be blocked. Typically, when the liquid crystal device is activated, it rotates the polarization of the laser beam, thereby reducing the passage of a light and generating light amplitude fluctuations, which are detected as being equivalent to the moving speckled pattern generated by passing coherent light through the thin film of particle-containing fluid that would normally flow down the capillary channel. A low viscosity liquid crystal material having a high refractive index change (thereby enabling rapid fluctuations) is desirable. A typical design uses a crystal oscillator and a chain of binary counters from which the liquid crystal display driver signals are derived as well as the time base for the measurements to be taken. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a block diagram of an electronic circuit suitable for use in an electronic capillary cartidge device to simulate the passage of blood through a capillary in a control cycle. Figure 1 shows electronic circuitry that can be utilized to simulate the passage of blood through a capillary flow device. The circuitry includes a crystal-controlled oscillator in which 220 represents the crystal and 222 represents the oscillator. The signal from the oscillator drives two frequency dividers (224 and 226) that will generate the output signals for a driver 228 of a liquid crystal display cell 230. Cell 230 is biased by an oscillating signal having a specific rate of oscillation, for example 128Hz. The cell will therefore rotate its polarization at the rate of 128Hz. Polarizer 231 in combination with cell 230 therefore operate to alternately block and pass light as a result of the rotating polarization. Two more dividers (232 and 234) drive a logical AND gate (236) whose output will go to a logic circuit low at defined intervals, for example, approximately every 20 seconds. When the output goes to a logical low, the output of a logical OR gate (238) will reset the dividers, thereby stopping the process. Accordingly, modulating signals for the liquid crystal display cell 230 are generated for the set time period, 20 seconds in the above example. The device is provided with a start switch 240. When switch 240 is closed, the reset signal is cleared, and the process is restarted. The oscillator, dividers, logic gates, and liquid crystal display driver can be implemented in CMOS technology using standard techniques of electronic fabrication. An CMOS device can be readily powered through more than 10,000 cycles when powered by a coin-type lithium battery. EXAMPLE : Electronic Cartridge An electronic cartridge capable of simulating the flow of whole blood through a capillary was prepared using a 32768Hz crystal-controlled oscillator to drive two 1-16th frequency dividers that generated the input signals for a driver of a liquid crystal display cell prepared in accordance with the electronic diagram set forth in Figure 1. This cell was biased by a 2048Hz signal modulated at 128Hz intervals. The cell therefore rotated its polarization at the rate of 128Hz. Two more dividers drove a logical AND gate whose output was to a logic low every 20 seconds. At this point, the output of a logical OR gate reset the dividers, stopping the process. Accordingly, the LCD was powered and modulating for a 20-second interval. A start switch was provided to clear the reset signal and restart the process. The oscillators, dividers, logic gates, and LCD driver were implemented in CMOS technology and powered by a coin-type lithium battery. The electronic cartidge has a life of more than 10,000 cycles.

Claims: A quality control device for use in an analytical instrument which utilizes an analysis cartridge containing an internal chamber in which said analysis occurs, said analysis cartridge being insertable into a location in said instrument so that light generated in said instrument passes through said chamber and is detected by a light detector in said instrument, which comprises: a control cartridge, wherein said control cartridge is insertable in said location; a liquid crystal cell located in said control cartridge so as to interpose between said light source and a light detector in said analytical instrument; and a polarizing filter located between said light source and said light detector so as to allow passage or block passage of light between said light source and said light detector when voltage applied to said liquid crystal is modulated. The quality control device of claim 1, wherein said polarizing filter is located in said control cartridge. The quality control device of claim 1, wherein said polarizing filter is located in said instrument. The control device according to any of the claims 1-3, wherein said control cartridge further comprises a power supply and a control circuit capable of modulating voltage supplied to said liquid crystal cell.

Inventors: ALLEN JIMMY D, COBB MICHAEL E, GIBBONS IAN, HILLMAN ROBERT S, OSTOICH VLADIMIR E, WINFREY LARA J, ALLEN, JIMMY D., COBB, MICHAEL E., GIBBONS, IAN, HILLMAN, ROBERT S., OSTOICH, VLADIMIR E., WINFREY, LARA J.
Applicants: BOEHRINGER MANNHEIM CORP, BOEHRINGER MANNHEIM CORPORATION
Application year: 1986
Main classification: G01N21
IPC codes: G01N21, B29C45, B01F5, G01N33, B01F3, B01F13, G01N15, B01L3, B29C59, G01N35, B29C65, B01F1