Test elements and methods of producing the same for studying a body fluid sample

Abstract

Disclosed herein are methods of producing a test element for studying a body fluid sample. In the methods, a detection layer is covered with a polymeric spreading layer and applied to a support. The spreading layer can be produced by being sprayed onto the detection layer such that the spreading layer has a thickness of at most about 20 μm. Also disclosed are test elements produced by the methods, as well as tape cassettes incorporating such test elements.

Claims

1. A test element for detecting an analyte in a body fluid sample, the test element comprising: a support; a detection layer applied to the support; and a polymeric spreading layer covering the detection layer, wherein the polymeric spreading layer covering the detection layer is sprayed onto the detection layer to form a non-fibrous nonwoven fabric.

2. The test element of claim 1, wherein the spreading layer has a thickness selected from the group consisting of about 5 μm, about 10 μm, about 12 μm and about 20 μm.

3. The test element of claim 1, wherein the spreading layer contacts the detection layer.

4. The test element of claim 1, wherein the entire spreading layer is asymmetrical in that nominal pore sizes or diameters decrease in a direction toward the detection layer, and wherein the nominal pore sizes or diameters are about 8 μm to about 15 μm.

5. The test element of claim 1, wherein the spreading layer has a breakthrough time that is less than about one-tenth of a second.

6. The test element of claim 1, wherein the support is a tape wound into a reel in a tape cartridge.

7. The test element of claim 1, wherein the polymeric spreading layer comprises a polymer selected from the group consisting of polyethylene glycol, polyvinylalcohol, polyolefin, polyurethane, polyamide, polyimide, polyacrylate, polycarbonate, polyester, polyether, polyvinylether, polyvinylester, polyvinylalcohol and polysiloxane.

8. The test element of claim 1, wherein the spreading layer produces a mechanical stress upon the detection layer consistent with having been sprayed onto the detection layer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The advantages, effects, features and objects other than those set forth above will become more readily apparent when consideration is given to the detailed description below. Such detailed description makes reference to the following drawings, wherein:

(2) FIG. 1 shows a schematic view of an illustrative embodiment of a test element for photometric testing of a body fluid sample.

(3) FIG. 2 shows a schematic sectional view related to FIG. 1.

(4) FIG. 3 shows another illustrative embodiment of a test element.

(5) While the present inventions are susceptible to various modifications and alternative forms, exemplary embodiments thereof are shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description of exemplary embodiments that follows is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all advantages, effects, features and objects falling within the spirit and scope of the invention as defined by the embodiments described herein and the claims below. Reference therefore should be made to the embodiments and claims for interpreting the scope of the invention. As such, it should be noted that the embodiments described herein may have advantages, effects, features and objects useful in solving other problems.

DESCRIPTION OF PREFERRED EMBODIMENTS

(6) The methods and test elements now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

(7) Likewise, many modifications and other embodiments of the methods and test elements described herein will come to mind to one of skill in the art to which the invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

(8) Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which the invention pertains. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein.

(9) Moreover, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”

(10) Methods and Test Elements

(11) The test element 1 shown in FIGS. 1 and 2 is configured for photometric testing of a body fluid sample such as, for example, blood and/or interstitial fluid. Such a test element can be used to measure the concentration of glucose, lactate or other medically significant analytes.

(12) For photometric determination of the concentration of an analyte, the test element 1 contains a test field 2. The test field has a detection layer 3 that includes detection reagents, which are not necessarily shown to scale in FIG. 2. When the detection reagents are exposed to the analyte, they effect a detection reaction that leads to a color change. The intensity of the change of color in this context depends on the analyte concentration such that photometric analysis of the color change allows the analyte concentration to be determined.

(13) The detection layer 3 is covered by a polymeric spreading layer 4. The spreading layer 4 is a layer that spreads a body fluid sample applied to it. Fluid to be tested proceeds through the spreading layer 4 and then to the detection layer 3.

(14) The detection layer 3 is arranged on a support 5. In an illustrative embodiment, the support 5 is a transparent plastic film. The support 5 can be arranged on a second support 6 such as, for example, a strip of plastic or paper. The second support 6 has a recess 7 that is covered by the support 5 of the detection layer 3. In this manner, a photometric measurement can proceed through the recess of the second support 6 and the transparent first support 5. Advantageously, the spreading layer 4 has no influence on the measurement in this case.

(15) The spreading layer 4 shown in FIGS. 1 and 2 is produced by spraying a liquid, for example, by means of a pneumatic nozzle, onto the detection layer 3.

(16) Polymers are sprayed onto the detection layer 3 to form a porous spreading layer 4. It is feasible just as well to spray monomers or a mixture of monomers and polymers onto the detection layer 3 and to polymerize them on the detection layer 3. Polymers also can be cross-linked and polymerized further after being applied by spraying, but this is not obligatory.

(17) In some embodiments, monomers or polymers for forming the spreading layer 4 can be sprayed onto the detection layer 3 as an emulsion. In this instance, a phase inversion proceeds in droplets of the emulsion or upon impact on the detection layer 3. The monomers or polymers contained in the emulsion then can form the spreading layer 4, for example, as a membrane or a nonwoven fabric, and become cross-linked. In other embodiments, a solution, such as a polymer solution, is sprayed to form the spreading layer.

(18) Regardless of whether an emulsion or a solution is applied by spraying, the molecules that then form the spreading layer 4 are sprayed together with a liquid that evaporates subsequently. The liquid can be a polar organic liquid such as, for example, an alcohol. It also is contemplated that aqueous liquids may be used, although the detection layer 4 might possibly be affected adversely by aqueous liquids. For this reason, polar organic liquids are preferred.

(19) The spreading layer 4 can be produced from, for example, cellulose, modified cellulose, in particular hydroxypropylcellulose, cellulose nitrate or cellulose acetate, polyethylene glycol, polysulfone, polyethersulfone, polyolefin, polyurethane, polyamide, polyimide, polyacrylate, polycarbonate, polyester, polyether, polyvinylether, polyvinylester, polyvinylalcohol, polysiloxane or a mixture thereof containing one or more of the polymers. Substituted polymers of these classes are feasible just as well, such as, for example, polytetrafluoroethylene, and polymer mixtures such that copolymers are produced upon application by spraying.

(20) The spreading layer 4 advantageously can be sprayed directly onto the detection layer 3. In this manner, the spreading layer 4 contacts the detection layer 3 (i.e., touches against it). In some embodiments, the spreading layer 4 can have a thickness of about 5 μm to about 10 μm, or even up to about 20 μm. As used herein, “about” means within a statistically meaningful range of a value or values such as a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature or volume. Such a value or range can be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.

(21) The distance between the surface of the spreading layer 4 and the detection layer 3 being small is advantageous in that a body fluid sample applied to the spreading layer 4 can reach the detection layer 3 very quickly. The breakthrough time (i.e., the time for fluid applied to the spreading layer 4 to reach the detection layer 3) is less than one-tenth of a second. The thickness of the spreading layer 4 being low also is advantageous in that only very little fluid remains in the spreading layer 4 such that a very large fraction of the sample quantity is available for the detection reaction in the detection layer 3. Quantities as small as about 0.5 μm therefore are sufficient for determining the analyte concentration.

(22) In some embodiments, a hydrophilic substance can be embedded in the spreading layer 4 such as, for example, a surfactant or other surface-active substance. The hydrophilic substance can be applied either by spraying together with the spreading layer or by being incorporated into the spreading layer 4 in a subsequent manufacturing step.

(23) The spreading layer can have a nominal pore diameter of less than about 5 μm and typically of no more than about 2 μm. Alternatively, the nominal pore diameter can be of no more than about 1 μm or can be about 0.5 μm. In this manner, the spreading layer 4 can be used to remove, by filtration, sample components that interfere with the detection reaction or the analysis thereof such as, for example, blood cells. The porosity of the spreading layer 4 even can be asymmetrical in that the pore size decreases toward the detection layer 3.

(24) Application of the spreading layer 4 by spraying can be used to produce layers with improved spreading behavior so that the surface area wetted by applying about 0.5 μl of a body fluid sample such as blood is twice as large as on a hydrophobic surface.

(25) The test element shown in FIGS. 1 and 2 can be provided in the form of a test strip. For example, and as shown in FIG. 3, a test element for photometric testing of a body fluid sample can differ from the embodiment described above in that the support 5 is a tape that can be arranged such that it is reeled up into a tape cartridge 10. A tape cartridge 10 of this type allows a large number of body fluid samples to be tested. The improved adhesion and low thickness of a spreading layer applied by spraying are particularly advantageous for tape cartridges of this type since they make it easier to reel-up the support tape.

(26) As further shown in FIG. 3, the support 5, which is provided as a tape, has multiple test fields 11 that each include a detection layer and a spreading layer covering the detection layer (i.e., can be made up like the embodiment according to FIGS. 1 and 2). The tape cartridge 10 has a housing 12, in which a bulk supply roll 13 is arranged on which the support 5 bearing unspent test fields 11 is reeled up in the form of a tape. Spent test fields are reeled up onto a drive reel 14 together with the support 5. Reeling-up the drive reel simultaneously reels-off the bulk supply reel such that the test fields 11 can be moved sequentially to a housing opening for use.

(27) The tape cartridge 10 can include a chamber for the bulk supply reel 13. The drive reel 14 can be arranged outside the chamber of the bulk supply reel 13. In this manner, the bulk supply reel 13 with the sensitive detection reagents of the unspent test fields 11 is protected from detrimental ambient influences and, in particular, from moisture in spent test fields. The support 5, which is provided as a tape, can be guided on its path from the bulk supply reel 13 to the drive reel 14 by means of tape guiding elements 15 that define the tape transport pathway.

EXAMPLES

(28) The invention will be more fully understood upon consideration of the following non-limiting examples, which are offered for purposes of illustration, not limitation.

(29) Efficient spreading layers have been obtained, for example, as follows:

(30) Bionate 80A UR (an aliphatic polyurethane, from DSM Biomedical Materials; Geleen, NL) was dissolved in tetrahydrofuran (an aliphatic ether, from Sigma-Aldrich; Steinheim, GER) at a concentration between 3-6% (m/m). To this solution, Tween 20 (a surfactant, polyoxyethylene(20)-sorbitan-monolaurate, alternative name poly(oxy-1,2-ethandiyl)-monododecanoic acid sorbitylester, from Sigma-Aldrich) or DONS (dioctylsulfosuccinate sodium salt, alternative name bis(2-ethylhexyl)-sulfosuccinate sodium salt, from Sigma-Aldrich) was added in an amount corresponding to about 3-5% (m/m) of the polymer content. The solution then was sprayed through a pneumatic rotary jet nozzle at a spraying pressure between about 2-4 bar. The consumption of polymer solution during the spraying process was about 2 ml/min.

(31) The test element with the detection layer to be coated was arranged at a distance of 5 cm to 15 cm (e.g., about 10 cm) below the spray nozzle. The process was carried out at room temperature in a common laboratory ventilation hood (without controlling temperature and humidity). The polymer layer thus applied by spraying dried within a few seconds to form a film that adhered firmly to the detection layer.

(32) The spraying process was carried out with either a static test element or a moving test element. For coating the moving test element, the test element was fixed in place on a cylinder, and the cylinder was rotated below the spray nozzle (e.g., at about 100-120 rpm). The spreading layers applied in both static and mobile manner showed an efficient spreading effect.

(33) The layer thickness of the sprayed spreading layer was varied by selecting the spraying time. A spraying time of about 2 seconds produced spreading layers with a layer thickness in the range of about 2-5 μm. At a spraying time of about 10 seconds, the layer thickness of the spreading layer was in the range of about 8-10 μm. Longer spraying times allowed the layer thickness to be adapted according to need to values of, for example, 20 μm, 40 μm or even 100 μm.

(34) The efficiency of the spreading layer was checked by dripping different volumes of blood ranging from 0.05 μl to 2.0 μl onto the uncoated detection layer versus the spreading layer-coated detection layer. For example, a 0.5 μl droplet of blood had a diameter of about 1.5 mm on an uncoated detection layer and did not spread on the hydrophobic surface. There remained a dome-shaped blood residue with a contact angle of about 40°. In contrast, the 0.5 μl droplet of blood had a diameter of about 2.8 mm to about 3.1 mm on the detection layer coated with the spreading layer sprayed onto it and spread completely (i.e., no residual blood remained visible (contact angle 0°)). Accordingly, the sprayed spreading layer increased the surface of the detection layer that was wetted by blood by about four-fold. The very efficient improvement of the spreading behavior was detected regardless of the layer thickness of the spreading layer (i.e., was evident with thin spreading layers in, e.g., the range of about 2-5 μm) as well as with thicker spreading layers (in the range of about 20-40 μm).

(35) Moreover, it was found that the spreading behavior improved through the sprayed-on spreading layer regardless of the blood volume for blood volumes in the relevant range of 0.05-2 μl. The thickness of the layer was determined through optical digital microscopy (incident light) using one cross-section each of the coated test elements. This was tested using a Keyence VHX-1000 microscope as the measuring device. The efficiency of the spreading layer was determined in a corresponding manner, namely by optical digital microscopy (incident light) of the wetted region of a test element after the application of a blood sample. The contact angles were determined using a Kruss DAS 100 contact angle measuring device (Kruss GmbH; Hamburg, Del.).

(36) All of the patents, patent applications, patent application publications and other publications recited herein are hereby incorporated by reference as if set forth in their entirety.

(37) The present invention has been described in connection with what are presently considered to be the most practical and preferred embodiments. However, the invention has been presented by way of illustration and is not intended to be limited to the disclosed embodiments. Accordingly, one of skill in the art will realize that the invention is intended to encompass all modifications and alternative arrangements within the spirit and scope of the invention as set forth in the appended claims.

LISTING OF REFERENCE NUMBERS

(38) 1. Test element 2. Test field 3. Detection layer 4. Spreading layer 5. Support 6. Second support 7. Recess 10. Tape cartridge 11. Test field 12. Housing 13. Bulk supply reel 14. Drive reel 15. Tape guiding element