Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
1997-03-18
2001-03-06
Housel, James C. (Department: 1641)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S007920, C435S007950, C435S805000, C435S810000, C435S969000, C435S970000, C435S975000, C436S518000, C436S531000, C436S807000, C436S810000, C422S051000, C422S051000, C422S067000, C422S073000, C422S105000, C422S105000
Reexamination Certificate
active
06197494
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to disposable reagent-containing elements which can be used in conjunction with an electronic instrument for performing diagnostic assays (medical diagnostics). It also relates to a method for performing diagnostic biological assays employing the use of a disposable reagent-containing element.
2. Discussion of the Background
Many analytical techniques have been developed for chemical, biochemical and biological assays. Procedures that use a discrete fluid sample for the analysis of a single analyte are traditionally characterized as wet chemical techniques or dry chemical techniques. In recent years both types of techniques have been automated to reduce costs and simplify procedures. Wet chemical methods, typified by the Technicon® autoanalyzers, utilize batches of reagent solutions, pumps and fluid controls, coupled with conventional sensors such as radiometric (e.g.: fluorescent, calorimetric, or nephelometric) electrochemical (e.g.: conductometric, polarographic, or potentiometric) and others, such as ultrasonic, etc. sensors. These techniques are characterized by large equipment, and are generally expensive. They are complicated, and require a skilled operator.
Decentralized testing, particularly in medical applications, has been achieved with a variety of simpler systems often based on cuvettes for optical determination but sometimes based on dry chemistry-based “reagent strip” technology. Generally, a reagent strip is an absorbent structure containing a reagent which self-meters an applied sample and develops or changes color to indicate the extent of reaction. Although self metering, some reagent strips, however, require pipetting of sample to achieve maximum accuracy and precision. A reagent strip is employed either by itself or in conjunction with a simple instrument to read the color intensity or hue and translate the results into a numerical value which is displayed. Unlike a cuvette or test tube, mixing or convection cannot be sustained in a reagent strip after the sample has entered, and once having entered, the sample cannot be removed from within without destroying the integrity of the strip. In one application, reagent strip technology is used extensively in the home by diabetic patients who test themselves daily to determine blood sugar levels.
In a more general example of “reagent strip” technology, Eastman Kodak has introduced a system of dry chemistry, claiming to overcome many of the traditional weaknesses of dry chemical methods. The Kodak technique utilizes flat, multi-layered sheets arranged in sequence. The top layer receives a liquid sample which passes downward undergoing separation and reactions in a pre-arranged sequence. The sheet is designed to accept a small volume of liquid and distribute it uniformly over a reproducible area. The area is less than the total area of the multi-laminar sheet. Each layer of the sheet is essentially homogenous in a direction parallel to the surface. Once the sample has spread radially (a rapid process), the components of the liquid can move downward at rates that are essentially the same in any plane that is parallel to the surface. In this way uniform reactions, filtrations, etc. can occur.
The analyte is detected in the multi-layered sheets by radiometric or electrochemical methods which are carried out in a thermostated environment. This permits the use of kinetic and static measurements to detect analyte concentrations in a liquid sample.
Radiation is caused to enter this assembly in a path which is traverse to the several layers. The radiation is modified by the analyte or by a component or product of the analyte. For example, the exciting radiation may be partially absorbed by the analyte or by a component or product of the analyte. The modified radiation may be reflected back transversely through the laminar assembly, typically from a reflective layer, adjacent or nearly adjacent to a thin layer where color is formed. Thus, reflectance can be monitored (as opposed to transmission only through the color producing layer). Reflectance, as expressed by Kubelka-Monk theory, consists of optical density absorbance and scattering components and is more sensitive than transverse colorimetry through a thin, turbid layer. Reflectance, however, may be a more difficult technique to standardize and to interpret data from than colorimetry.
Conventional colorimetry has not been practiced with reagent strips because the color producing layers are generally thin and not transparent. The path of the exciting radiation is thus very short (with large light losses due to opacity) and is determined by the thickness of the layer in which the exciting radiation encounters the substance which is excited. Since this dimension must be very small to permit rapid measurement, e.g., 10 &mgr;m to 100 &mgr;m, the degree of modification of the exciting radiation is quite small. This limits the applicability of this technique to analyses in which the analyte (or the product of the analyte) interacts very strongly with the exciting radiation, otherwise a very sensitive detecting apparatus has to be used. This method has been shown to be useful for measuring analytes in blood that exist at relatively high concentrations, e.g., glucose, BUN, cholesterol and albumin.
Other analytical methods have been developed that utilize rapidly reversable chemical reactions to continuously monitor analyte concentrations in biological fluids, or industrial effluent streams, or ponds, lakes and streams. For example, several methods have been proposed to measure the oxygen level in blood of critically ill patients.
Reagent strip technology, however, possesses salient drawbacks and limitations. For example, once a sample is added to a reagent strip and permeates the porous structure of the strip, the sample cannot be removed or washed out without destroying the integrity of the strip. For example, immunoassays are extremely difficult to perform with reagent strips, in part because separation of free and bound antigen (or antibody) molecules from a mixture of both cannot be readily achieved in a conventional porous or layered structure. This limits possible immunoassay applications to certain special cases of reactions, for example certain homogenous reaction sequences. Incubation with mixing, a step common to a variety of assays, cannot be performed easily in conventional reagent strip formats since they rely on diffusion and initial capillary action only for mixing.
Technologies have not yet been developed to cause or to control forced convection for a specified period of time within the porous structure of a reagent strip after the sample has entered and permeated the porous strip structure. In conventional reagent strips, the strip is an absorbant matrix in which mixing is extremely difficult and limited. It addition, reagent strips almost exclusively use reflectance as a photometric method to quantitatively determine the extent of a color reaction. There are no reagent strips known to the inventor which can be read via light transmission/absorbance colorimetry, nephelometry, fluorescence, chemiluminescence, or evanescent wave technology. Fluorescence measurement is possible in reagent strips, but difficult to achieve. Electrochemistry has been used successfully.
As discussed above, a large number of types of medical tests are carried out by trained medical to laboratory personnel. These tests must be performed accurately and reproducibly with a minimum amount of error since they are used as aids in diagnosing and treating medical ailments. To aid laboratory personnel in performing these tests accurately on a large number of samples in a relatively short period of time, auxiliary equipment, which is often expensive, is frequently used. Most of these tests are performed on a macro scale and thus require considerable quantities of both sample and reactants. They also require varying degrees of sample preparation. These and other reasons are major contributors to the generally re
Cardiovascular Diagnostics Inc.
Housel James C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ryan V.
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