Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
2000-10-25
2004-02-24
Gitomer, Ralph (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S287900, C422S051000
Reexamination Certificate
active
06696240
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to methods and apparatuses for testing analysis fluids, and more particularly to a microcuvette for analyzing one or more components of a fluid. Significant contemplated applications of the invention are in the biological sciences, especially diagnostic medicine. In this field, analysis fluids would primarily be bodily fluids, notably whole blood.
BACKGROUND OF THE INVENTION
Several dry chemistry technologies have been introduced in recent years for testing of blood specimens at the patient point-of-care (POC). Testing at the POC offers advantages of fast turnaround time, timely intervention, miniaturized and cost effective equipment, and improved patient outcomes. “Dry chemistry” means that the chemical reagents are contained within a test strip device solely in dry, but not in liquid form. Since the reagents are more stable when stored in dry form, products employing dry reagent technology usually have longer shelf life than those using liquid reagents.
In most devices, the reagents are applied to the test strip by some impregnation or coating method whereby a liquid reagent is impregnated or coated onto an integrated reagent-carrying member. The reagent member can be a bibulous material (paper), a membrane, or a reagent film. After evaporation of the reagent solvent, the dry and stable reagent is then contained within a reactive zone, signal member test field of the device. As analysis fluid makes contact with the dry reagents, the reagents are generally at least partially re-solubilized so as to react with the analyte of interest.
The most substantial application of dry technology today is in the field of self-monitoring of blood glucose (SMBG) by millions of diabetics. In this field, both photometric and sensimetric detection technologies are applied for signal quantification. A large portion of metering systems currently used by practitioners employ reflectance photometry. In these meters, light integrating a wavelength absorbed by the colored reaction product of glucose is shined onto the surface of the test field. The test field is preferably mounted on a solid state backing, usually a white plastic material. In this fashion, no light can be transmitted, so that the unabsorbed, scattered portion of the light is reflected.
In contrast to conventional photometry where absorbance of a colored or UV-absorbing reaction product is measured from reduced light transmittance in the direction of the incident light beam, reflectance is typically measured at a location angled away from the direction of incident light. As light of varying incident wavelengths is reflected in different directions, an informed choice must be made as to which ranges of incident and reflective angles to select for obtaining a signal that is most sensitively and most specifically related to concentration. Preferably, the photocurrent detector (photodiode) of the metering device is positioned at a location where unspecific scattering is at a minimum and specific reflectance is at a maximum. However, since specific and unspecific reflectance can usually not be completely spatially separated, pure signals cannot be obtained. For these reasons, measurements made in the reflectance mode do not follow Lambert Beer's law and are therefore fundamentally non-linear. This is in contrast to measurements made in the transmittance mode, which show linear signal-to-concentration responses of absorbance measurements.
Several more recent SMBG devices employ electro-sensimetric detection. The reaction current, measured by a miniature enzyme electrode, is related to glucose concentration and can be monitored amperometrically or by some other means of electrochemical detection. Most reflectance photometric and sensimetric systems employ in the first reaction step the oxygen-dependent enzymic oxidation of glucose by glucose oxidase. This reaction is specific for glucose and produces hydrogen peroxide as a reaction by-product from water and molecular oxygen. Some other systems use glucose dehydrogenase in conjunction with one or more electron acceptors.
In the reflectance photometric systems employing glucose oxidase, the generated hydrogen peroxide is reacted with peroxidase and a chromogen. The oxidized chromophore is then reflectance photometrically quantified by comparison to an on-board standard curve that relates reflectance signal to concentration. Quantification by nonlinear reflectance rather than linear absorbance photometry based on Lambert Beer's law is necessary because the law only holds for clear, non-scattering layers.
Numerous clinical evaluations of currently used glucose metering devices have generally demonstrated adequate analytical performance. However, compromised performance on some of the products, and even outright erroneous results have also been reported. Manufacturers are therefore continually striving to minimize the technical complexity of the systems, maximize operational ease, and improve reliability. Because of the vast global dimension of the SMBG market and the fast growth of diabetes in the world, these efforts have huge socioeconomic implications. At current retail prices of test strips for SMBG, a compliant insulin-dependent diabetic spends in excess of $1000 annually on test strips only, constituting a total global test strip market in excess of $2.4 billion. While this cost can generally be absorbed by citizens or reimbursement systems of the western world, it is prohibitive for most people living in countries other than the western world, where the growth of diabetes is most rampant.
Depending on measurement principle, current test systems have their intrinsic advantages and limitations. An advantage of the reflectance photometric systems is that they measure color. Potentially, this enables both visual and instrumented signal recognition. Visual interpretation can serve as a confidence check for quantitative results provided by the meter. And in markets where meters are not readily available, concentration can still be determined semi-quantitatively. Visual recognition is still well accepted as it was the only method available when SMBG started on a larger scale in the late 1970's. (A significant portion of the world market for glucose test strips is still visual at this time).
Unfortunately, the important feature of visual backup is realized only in a minority of currently marketed systems. This limitation resides in the method by which cellular component of blood is separated from plasma component. In older products, plasma was separated by soak through methods into coated bibulous materials or reagent films. Cells were then manually removed from the site of blood application by either washing or wiping them away, potentially giving rise to significant operator-induced errors. Several newer methods permit separation by means other than washing or wiping. The most frequently used are separation by porous glass fiber fleeces or membranes. In these matrices pore sizes are chosen so that cellular component is held back on the matrix surface, whereas plasma component diffuses through the separating member and into the detection member. Membranes are preferred as plasma separating materials over glass fiber fleeces because they generally absorb less blood. However, one notorious limitation of membranes is that the blood cells can clog pores. More recently, this problem has been largely overcome by using asymmetrical membranes in which pores have larger diameters on the side chosen for blood application as compared to the side dedicated to plasma retrieval.
In most current colorimetric test strips, the separating member is sandwiched against the detection member to provide for ready transfer of plasma into the reagent-impregnated detection member. The reflectance measurement is then made on the side of the test strip opposite to the side of blood application. To keep needed blood volume low, the thickness of the separation member is kept at a minimum. An adverse consequence is that the spatial separation of r
Hafellner Reinhard
Kloepfer Hans G.
Kloepfer Mary A.
Mlekusch Bernd
Roach Charles W.
Gitomer Ralph
Indiano E. Victor
Indiano, Vaughan Roberts & Filomena, P.A.
Micronix, Inc.
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