MXPA00005419A - Capillary active test element having an intermediate layer situated between the support and the covering - Google Patents

Abstract

The invention relates to a device for collecting samples of liquid test samples for analytic elements in which the test sample is transported from a sampling location to the determination location via a capillary active canal. The capillary active canal is essentially produced by a carrier, a covering and an optional intermediate layer which lies between the covering and the support, whereby a recess is located in an area, said area constructing the canal which permits capillary liquid transport, on the edge of the analytic test element, said edge constructing the test sample feeding opening, such that the edge of the test element, said edge constructing the test sample feeding opening, is at least partially discontinuous on one side, and the area opposite the recess is open. The invention also relates to a method for accommodating a liquid test sample in an analytic element with the assistance of the inventive device.

Description

ACTIVE HAIR ELEMENT FOR TEST THAT HAS AN INTERMEDIATE LAYER SITUATED BETWEEN THE SUPPORT AND THE COVER Description of the Invention __ The invention relates to a device for removing samples of liquid samples for analytical elements in which the sample is transported in the analytical element in an active capillary channel, from a sample application opening -to the site of determination for the sample and in which the active capillary channel is essentially formed by a carrier, a cover and optionally an intermediate layer that lies between the cover and the carrier. In addition, the invention relates to a process for removing a liquid sample within an analytical element with the aid of said device. The so-called carrier-binding tests are frequently used for the qualitative or quantitative analytical determination of the components of body fluids, in particular blood. In these, the reagents are embedded in corresponding layers of a solid carrier REF: 120462 which is put in contact with the sample. If an objective analyte is present, the reaction of the liquid sample and the reagents leads to a detectable signal, in particular a color change that can be evaluated visually or with the aid of an instrument, usually by reflection photometry. The test elements or test carriers are frequently in the form of test strips which are essentially composed of an elongated carrier layer made of plastic material and detection layers which are applied to it as test fields. However, test carriers are also known, which are in the form of small quadratic or rectangular plates. Test elements for clinical diagnosis that are evaluated visually or by reflection photometry are often constructed as electrochemical and biosensing sensors such that the area of application of the sample and the detection zone are arranged one above the other on an axis vertical. This mode of construction is problematic. When the test strip loaded with the sample has to be inserted into an instrument, for example a reflection photometer, for the measurement, the potentially infectious sample material may come into contact with the parts of the instrument and may contaminate them. In addition, the volumetric dosage can only be achieved with difficulty especially in cases in which the test samples are used by untrained persons, for example in the self-control of blood sugar by diabetics. Recently, the test elements have become available, which provide a capillary channel or free space with the help of which some of the described problems can be solved. European patent EP-B-0 034 049 relates to a test element in which the sample is applied to a central sample application site, for example an opening in a cover, and is conveyed by capillary force to various detection zones that are spatially separated from the application site of the sample. In this case it is notable that a special design for the geometry of the sample application opening, which is also described in European patent EP-B-0 010 456, is emphasized as being particularly preferable. A regular hexagonal shape of the sample inlet opening in the top view is claimed to center a drop of liquid sample in the opening. This is claimed to facilitate the penetration of the sample into the active capillary channel which is perpendicular to the application opening of the sample. While in the capillary free space test elements. described, the sample is applied through an opening in the test element that is perpendicular to the capillary space, in other designs the test liquid is applied directly into the capillary free space parallel to the direction of dispersion. This is achieved in a simpler way by the test element that has an edge where the capillary clearance ends, and which is directly in contact with a sample liquid and is collected by the channel that is capable of transporting the liquid by capillary action. A frequent problem with the last test elements is that the liquid droplets that are applied to the application opening of the capillary space sample are not able to penetrate into the free space. This phenomenon can have different causes. It is conceivable that in the manufacture of such test elements the aperture for manufacturing reasons does not have the dimensions that are required for a sample droplet to enter the capillary channel for example because the aperture has been contaminated or spattered when the element Test was cut to its length, cut or die cut. Another reason may be that the hydrophobicity of the materials that are frequently used to manufacture the test elements such as for example hydrophobic plastics, deteriorate, delay or prevent the penetration of the sample into the capillary space. For example, a drop of liquid no longer enters the inside of a capillary channel or only very slowly if its internal surfaces are truly hydrophilic, but the cut edge is hydrophobic due to the materials used. The aim of the present invention was to eliminate the disadvantages of the prior art. This is achieved by the subject matter of the invention as characterized in the patent claims.

The invention relates to a device for withdrawing samples of liquid for analytical elements, in which the sample is transported in an active capillary channel from the sample application opening to the site of determination of the sample in the analytical element, and in which the active capillary channel is essentially formed by a carrier, a cover and optionally an intermediate layer that lies between the cover and the carrier, which is characterized in that there is a notch or groove in one of the surfaces forming the channel capable of performing the liquid transport by capillarity at the edge of the analytical element that forms the sample application opening, so that one side of the edge of the device forming the sample application opening is at least partially interrupted and the opposite surface of the notch is exposed. The device according to the invention contains particularly and preferably one of such notches. However, other designs may also be made in which several and at least two notches are present together on a surface or are displaced on opposite surfaces. There are no limits to the shape of the notches, with the proviso that at least part of the edge forming the sample application opening is at least partially interrupted by the notch. Therefore triangular or polygonal shapes as well as round or elliptical shapes are possible. Irregular forms are not excluded either. The notch in a surface forming the capillary channel at the edge of the test element forming the sample application opening serves to ensure that the sample liquid can enter the capillary channel. This is achieved since the sample drop can be directly applied to one of the surfaces, whose extension forms the internal surface of the capillary, at the edge of the device that is broken by the notch that is closest to the application opening of the sample. Proper selection of the geometry and dimensions of the notch ensures that the drop of the liquid comes into contact with the active capillary zone with very high probability, regardless of the exact position of the dosage and is easily sucked into the inner part of the capillary . For example, the size of the exposed surface must be selected such that at least one site of the liquid drop applied to it comes into contact with the active capillary zone. For example, a dimension of the notch, such as its width, should be selected such that the diameter of the liquid drop is slightly larger than the selected dimension of the notch. A notch width of 1 mm has proven to be adequate for a 3 μl drop. The suction of the sample droplet inside the capillary channel is particular and preferably achieved by the area exposed by the notch which is hydrophilized, and which borders or limits directly on an active capillary zone, at least in the direction of the capillary transport channel. In this context, hydrophilic surfaces are surfaces that attract water. The aqueous samples, which also include blood, are spread perfectly on such surfaces. Such surfaces are characterized inter alia because a drop of water placed on them forms a sharp edge angle or contact angle at the interface. In contrast, an obtuse edge angle is formed at the interface between the water drop and the surface on hydrophobic surfaces, for example water repellents.

The edge angle which is a result of the surface tensions of the test liquid and the surface to be examined is a measurement of the hydrophilicity of a surface. Water, for example, has a surface tension of 72 mN / m. If the value of the surface tension of the observed surface is much lower than this value, for example greater than 20 mN / m, then the wetting is poor and the resulting edge angle is obtuse. Such a surface is termed as hydrophobic. If the surface tension approaches the value that is found for water, then the humidification is good and the edge angle is sharp. In contrast, if the surface tension is the same as or higher than that of the value found for water, then the drop runs and there is a total diffusion of the liquid. It is no longer possible to measure a bank angle. The surfaces that form a sharp edge angle with water droplets or on which a total dispersion of a drop of water is observed, are termed as hydrophobic. The ability of a capillary to suck a liquid depends on the wetting capacity of the canal surface with the liquid. This means, for aqueous samples, that a capillary must be manufactured from a material whose surface tension reaches almost 72 mN / m or exceeds this value. The sufficiently hydrophilic materials for the construction of a capillary which rapidly sucks the aqueous samples are for example glass, metal or ceramic. However, these materials are not suitable for use in test carriers since they have some severe disadvantages such as the risk of breakage in the case of glass or ceramic or the change in surface properties over time in the case of numerous metals. The sheets or sheets of plastic or molded parts are therefore usually used to manufacture test elements. As a rule, the plastics used hardly exceed a surface tension of 45 mN / m. In a relative sense, even with the most hydrophilic plastics such as polymethyl methacrylate (PMMA) or polyamide (PA) it is only possible - if there is a possibility - to build slow suction capillaries. Capillaries made of hydrophobic plastics such as for example polystyrene (PS), polypropylene (PP) or 'polyethylene (PE) essentially do not suck the aqueous samples. Consequently it is necessary to equip the plastics used as a construction material for the test elements, with active capillary channels with hydrophilic properties, for example, to hydrophilize them. • In a preferred embodiment of the analytical test element according to the invention, at least one, but preferably two and especially and preferably two opposing surfaces that form the internal surface of the channel capable of transporting the liquid by capillary action, are hydrophilized . At least the exposed surface opposite the notch is most preferably hydrophilized. If more than one surface is hydrophilized then the surfaces can be made hydrophilic using the same or different methods. Hydrophilization is particularly necessary when the materials forming the active capillary channel, in particular the carrier, are themselves hydrophobic or only very slightly hydrophilic, because they are, for example, non-polar plastic compounds. Non-polar plastics such as for example polystyrene (PS), polyethylene (PE), polyethylene terephthalate (PET) or polyvinyl chloride (PVC) are advantageous as carrier materials because they do not absorb the liquids that are to be examined and in this way the sample volume can be effectively used by the detection layer. The hydrophilization of the capillary channel surface makes it possible for a polar, preferably aqueous liquid sample to easily enter the capillary channel and be quickly transported to the sample determination site. In this context, the site of determination is understood as that site or that zone to which the sample must be transported in the analytical element, in order to achieve the desired result. If the analytical element is for example a test carrier to be evaluated optically or photometrically, the sample determination site is the detection zone of the test carrier in which a reaction with a color change is observable. If the analytical element is an electrochemical sensor, the sample determination site is understood as an integrated electrode inside the sensor, which is capable of performing the desired electrochemical detection reaction. If the analytical element does not serve itself to detect an analyte in a sample, but is, for example, only used for volume dosing or taking a certain amount of sample material, the sample determination site can simply be a mark on the analytical element up to which the capillary free space has to be filled, in order to measure for example a certain minimum volume of sample. Ideally, the hydrophilization of the surface of the capillary channel is achieved by the use of a hydrophilic material in its manufacture which, however, can not by itself suck the sample liquid or only to a negligible degree. In cases where this is not possible, a hydrophobic or only a very slightly hydrophilic surface can be hydrophilized by suitable coating with a stable hydrophilic layer which is inert to the sample material, for example by the covalent bond of hydrophilic polymers, preferably a plastic surface by applying layers containing wetting agents, or by coating the surfaces with nanocomposites by means of sol-gel technology. In addition, it is also possible to achieve increased hydrophilicity by thermal, physical or chemical treatment of the surface. Hydrophilization is very special and preferably achieved by the use of thin layers of oxidized aluminum. These layers are either applied directly to the desired components of the test element, for example by vacuum coating the workpieces with metallic aluminum and subsequently oxidizing the metal, or by using sheets or metal foils or metal coated plastics. for the construction of test carriers that also have to be oxidized to achieve the desired hydrophilicity. In this case the metal layer thicknesses from 1 to 500 nm are suitable. The metal layer is subsequently oxidized to form the oxidized form in which case above all the oxidation in the presence of water vapor or by boiling in water have proven to be especially suitable methods in addition to the electrochemical, anodic oxidation. The oxide layers formed in this way are between 0.1 and 500 nm, preferably between 10 and 100 nm in thickness, depending on the method. Larger layer thicknesses of the metal layer, as well as the oxide layer, can in principle be realized in practice, but do not show any additional advantageous effect. A second subject of interest of the invention relates to a process for removing a sample of liquid, in particular a body fluid such as blood, plasma, serum, urine, saliva, sweat, etc., with the aid of a device according to the invention. to the invention. In this process the sample of the liquid is first contacted with the device at the edge of the opening of the sample application which is interrupted by the notch. The sample liquid is transported to the internal part of the device by the capillary forces in the channel, which is able to carry out the liquid transport by capillarity, so that it can reach its site of determination. The invention is elucidated in more detail by figures 1 and 2 and by the following examples. Figure 1 shows a particularly preferred embodiment of the device according to the invention. A schematic top view of the device according to the invention is shown in Figure 1A. Figures IB to 1G each show cross-sectional views along lines A-A '(IB), B-B' (IC), C-C (ID and 1G), D-D '(IE) and E-E' (IF) respectively. Figure 2 shows a detailed enlarged perspective of the region of application of the sample of the device according to the invention. The numbers in the Figures denote: 1 carrier 2 detection element 3 capillary channel 4 sample application opening 5 notch for application of the sample 6 ventilation opening 7 cover 8 cover sheet of the free space 9 intermediate layer 10 support sheet Various views (Figures IA to 1F) of a particularly preferred embodiment of the device according to the invention are shown schematically in Figure 1. It is intended that the views shown give a three-dimensional impression of the device according to the invention. An intermediate layer (9) is mounted on a carrier (1) for example in the form of a double-sided adhesive tape. In the area of the capillary channel (3) the intermediate layer (9) has a gap that determines the length and width of the channel (3). Its height is given by the thickness of the intermediate layer (9). On the side of the capillary channel (3) which is opposite the carrier (1), a cover (7), for example a sheet or sheet of plastic, is located adjacent to the detection element (2), for example a membrane impregnated with the reagent A sheet or cover sheet (8) of the free space is provided to ensure capillary continuity between the detection element and the cover. This can be hydrophilized to make possible a rapid transport of the sample from the sample application opening (4) towards the ventilation opening (6), which marks the opposite end of the capillary channel. An additional advantage of hydrophilization is that a drop of sample liquid can be applied directly to a hydrophilic surface in the notch area (5) which is surrounded on several sides of the boundary by the active capillary zone (3). This leads to a rapid penetration of the liquid droplet inside the test element. The capillary zone (3) extends from the sample application opening (4) towards the opposite end of the detection element (2) and thus ensures that the sample liquid can make contact with the entire area of the detection element. (2) and in this way a homogeneous distribution of the sample on the detection element (2) is carried out. The opening (4) for application of the sample and the ventilation opening (6) limit the capillary active region (3) in the direction of capillary transport. Figure 1G shows how the intermediate layer (9) can be covered by a support sheet (10) in order to cover the areas of the adhesive tape that are exposed. However, the ventilation opening (6) must not be covered. When the shown device is used, its sample application opening (4) is brought into contact for example with a drop of blood located on the tip of a finger. In this context, it is not important if the drop of blood comes into contact with the device according to the invention containing the opening (4) for application of the sample from above, for example on the flat side of the carrier (1) or from the front, for example, from the front side of the test element. This largely rules out an erroneous sample application that could for example be expected from users who use them for conventional test strips that have to be dosed from above. When the device according to the invention is used, the drop of blood comes into contact with the exposed surface which is optionally hydrophilized and simultaneously with the capillary channel (3) through the notch (5) in the carrier (1) . The capillary channel is filled with the sample until it is filled from the opening (4) for application of the sample to the ventilation opening (6). After this the device is removed from the patient's finger which ensures that only the sample that is present in the capillary channel (3) is available for the detection element (2). In this way overdosing is excluded. The defined height of the capillary channel provides a defined layer thickness of the sample on the detection element. An enlarged detail of a perspective view of the application area of the sample of a particularly preferred embodiment of the test element according to the invention is shown in Figure 2. The notch (5) in the carrier (1) facilitates the penetration of a sample liquid from the sample application opening (4) into the active capillary zone (3) which in the present case is formed by the carrier (1), the intermediate layer (9) and the cover (7). In addition to the form shown, the notch may also have any other desired shape serving the purpose according to the invention. Among others, semicircular, triangular or polygonal shapes are possible and the use of one or several adjacent stepped notches is possible.

Example 1 Manufacture of the analytical test element according to the invention A double-sided adhesive tape with a thickness of 100 μm is glued on a sheet of 350 μm thick polyethylene terephthalate (Melinex®, ICI, Frankfurt am Main, Germany) covered with an aluminum layer 30 nm thick, which was completely oxidized with water vapor. The sheet has a length of 25 mm and is 5 mm wide. A hollow in the form of a central notch of 1 mm in width of 2 mm in length is located on one of the short sides. The adhesive tape has a punched hole 2 mm wide and more than 15 mm long that defines the dimensions of the capillary channel. The length of the punched hole is selected to be slightly larger than the desired length of the active capillary channel, which is determined by its cover in order to ensure ventilation of the channel during filling with the sample liquid. A detection film 3 mm long and 5 mm wide is glued on the side of the adhesive tape that provides ventilation at a distance of 1 mm from the end of the punched hole. A film is used as the detection film, as is known from German Patent Application No. P 196 29 656.0. The detection film is specific for the detection of glucose. A cover layer 12 mm long and 5 mm wide is glued on the region of the adhesive tape which is still open between the notch-shaped recess and the detection film, so that the cover layer and the Detection film limit one with the other. The cover layer is composed of a sheet of polyethylene terephthalate 150 μm thick provided on one side with adhesive on which is glued a sheet of polyethylene terephthalate 6 μm thick (both from: Hostaphan®, Hoechst, Frankfurt am Main, Germany) coated with a layer of oxidized aluminum 30 nm thick, on the side facing the capillary channel. In this case the thinner sheet extends approximately 500 μm beyond the thicker sheet on the side facing the detection film. When the cover layer is mounted on the adhesive tape care must be taken that the protruding end of the thinner sheet is placed between the detection element and the thicker sheet of the cover layer. In order to cover areas of the adhesive sheet that are still exposed, they are covered with a Melinex® sheet of 175 μm thickness, however without covering the functional areas. The test element obtained in this way has a capillary channel of 15 mm in length, 2 mm in width and 0.1 mm in height. The channel can collect 3 μl of sample liquid. An area of 3 mm x 2 mm of the detection film is wetted by the sample.

Example 2 Measurement of blood glucose concentration with the help of the test element of example 1 The sample application side of the test element of Example 1 is placed on a drop of sample liquid. The capillary of the test element is automatically filled with the sample within 2 seconds. If glucose is present in the sample, a development of color in the detection film is visible after a few seconds. The end point of the reaction is reached after approximately 30 to 35 seconds. The color obtained can be correlated with the glucose concentration of the sample and evaluated either visually or by reflection photometry. It is noted that in relation to this, date the best method known to the applicant to carry out the said invention, is that which is clear from the present description of the invention.

Claims (8)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A device for removing samples of liquid samples for analytical elements, in which the sample is transported in an active capillary channel from the sample site to the determination site and in which the active capillary channel is essentially formed by a carrier, a cover and optionally an intermediate layer lying between a second cover and the carrier, wherein a notch is located on one of the surfaces forming the channel capable of carrying out the capillary transport of the liquid at the edge of the analytical element forming the opening of the liquid. the application of the sample, so that one side of the edge of the test element forming the sample application opening is at least partially discontinuous and the surface opposite the notch is exposed.

2. The device according to claim 1, characterized in that at least two notches are located next to one another.

3. The device according to claim 1, characterized in that the notches are staggered on opposite sides.

4. The device according to any of claims 1 to 3, characterized in that at least one of the surfaces forming the internal surface of the channel capable of performing the liquid transport by capillarity, is hydrophilized.

5. The device according to claim 4, characterized in that the exposed surface opposite the notch is hydrophilized.

6. The device according to any of claims 4 or 5, characterized in that the hydrof ilization is achieved by the use of a hydrophilic material or by coating a less hydrophilic material with a hydrophilic layer.

7. The device according to claim 6, characterized in that a layer of oxidized aluminum is used for hydrophilization.

8. A process for the removal of a liquid sample in an analytical element, with the aid of a device as claimed in claims 1 to 1, characterized in that the liquid sample is brought into contact with the analytical element at the edge of the sample. sample application opening broken by the notch, and transported by capillary forces within the channel capable of capillary transport of the liquid.