HK1179343B - Device for detecting an analyte in a bodily fluid - Google Patents

Description

Device for identifying an analyte in a body fluid

Technical Field

The invention relates to a device for detecting at least one analyte in a body fluid by means of at least one test element and preferably by means of at least one lancet with a capillary. The invention further relates to a method for identifying an analysis region of a device for detecting at least one analyte in a body fluid. Such devices and methods are used, inter alia, in diagnostics for qualitatively or quantitatively identifying one or more analytes, e.g. one or more metabolites such as blood glucose, in a body fluid such as blood or interstitial fluid.

Background

A large number of devices for detecting at least one analyte in a body fluid are known from the prior art. Test elements with at least one test chemical are generally used here. The test chemical comprises at least one identification agent which, when brought into contact with at least one analyte, carries out an analyte-specific reaction which can be identified, for example, electrochemically and/or optically.

In addition to single systems in which the taking of a body fluid sample and the analysis of a body fluid sample are carried out separately, integrated systems have recently been realized in particular. An integrated system for determining blood glucose, for example, consists of a blood-taking device and a glucose-determining device. At the time of blood acquisition, flat lancets with semi-open microcapillaries are used in several systems, wherein the capillaries typically have a width of 120 μm and a length of 4 mm. After the blood has been taken in by the puncturing process, for example in the belly finger, earlobe or forearm, the blood received in the capillary is often conveyed into the test field of the test element in such a way that the lancet is close to the test field, for example pressed against the test field. This produces an impression of the capillary, likewise approximately 120 μm wide, on a test element (for example a strip-shaped test element) which varies as a function of the blood glucose content and as a function of the formulation of the test chemical. In the optical system, the change is in each case a local color change which can be measured photometrically in reflection. The details of this process are in principle well known from the literature.

In principle, the problem arises in this case that the measurement of the color change of the test field using a non-spatially resolved sensor, i.e., for example, using a single photodiode, is problematic, since in this case the location of the gray-scale color change or color change on the test field must be detected very precisely mechanically and with small mechanical and/or optical tolerances. This can only be achieved with difficulty in the case of a movable lancet for puncturing and blood collection. If, for example, a tolerance of less than 10% of the lateral position should be achieved, the position tolerance should not exceed approximately ± 10 μm with a capillary having a width of 120 μm, which is a great mechanical challenge.

For this reason, the use of position-resolved detectors, for example CMOS cameras, has been proposed many times. US6,847,451B1, for example, describes devices and methods for determining the concentration of an analyte in a physiological sample. At least one light source and at least one detector array are used, as well as means for determining whether a sufficient amount of sample is present on a plurality of different surfaces. Furthermore, it is proposed here to use a CCD array as the detector array. Alternatives for position-resolved detection are, for example, position-resolved illumination or a mixture of such methods, for example based on line-by-line sampling.

US2004/0095360a1 describes a user interface of an image recording device and an image processing method which may be used, for example, for the analysis of biological samples, such as pregnancy tests or drug tests. For the actual image detection, a high-resolution camera sensor is used, which is designed as a color sensor. Furthermore, it is proposed here to use lines and reference lines within the test.

US7,344,081B2 describes a test result for automatically identifying a sample area of a test strip. Where an image of the bar code and an image of the at least one test strip are recorded. The color response of the test strip to the sample is determined. But in order to resolve the bar code it is inherently necessary to use a detector with a high resolution and thus a large number of pixels.

US5,083,214 describes an apparatus and method for determining suitable sampling points. The array detector scans a code in the form of a microfilm, wherein a reduction of the data to be recorded is achieved by a special type of coding. The challenge in this method is to identify moving parts and in this case, in particular, to detect information in digital form.

An active pixel image sensor row is known from DE19631086a1, which uses guard rings, protective diffusion or a combination of both techniques to prevent electrons generated at the edge of the active area from hitting the image sensor matrix. A CMOS image sensor with a plurality of active pixel rows and an optically black pixel row is known from US2007/0046803a 1. The optically black pixel rows are activated to generate a respective optically black signal upon activation of each of at least two of the active pixel rows. Both of these documents discuss particular aspects of chip design for optically sensitive chips.

However, all known solutions for image analysis of test elements have the problem that the image must be detected with a comparatively high resolution and analyzed, for example, by means of pattern recognition. A relatively high resolution here means, for example, a number of 1 million pixels, but in principle also pixel arrays with a smaller number of pixels are used. However, it is always possible to transmit still high data volumes to the peripheral electronics in a short time (for example 100 ms) and to carry out online analysis by the peripheral electronics, which, in particular in portable, for example handheld devices, limits the battery life decisively due to the high clock rate of the electronics required for this purpose and due to the large number of calculation operations. The sub-solution is suitable for pre-processing image information in a peripheral electronic device. Such a method and apparatus are described, for example, in EP1351189A1, US2005/0013494A1 or US2003/0123087A 1. Alternatively, the preprocessing portion already occurs directly on the CMOS sensor, as described, for example, in US6,515,702B1.

Instead of classical on-chip or off-chip pattern recognition, which separates the image into infiltrated areas, i.e. areas carrying glucose information and non-infiltrated areas, for further analysis, methods of histogram analysis are suggested. This process is described in EP1843148a 1. In this case, a frequency distribution is determined for the detected light intensity, wherein the frequency distribution has at least one first maximum caused by the non-wetted partial region and a second maximum caused by the wetted partial region. The concentration of the analyte is determined from the frequency distribution. Although histogram analysis, for example, carried out directly on a CMOS image sensor, significantly reduces the amount of data to be transmitted and analyzed, the proposed method still requires in practice significantly more than 10000 pixels when previous image preprocessing should be avoided in order to achieve a sufficiently accurate glucose measurement in this way.

The analysis and recommendations so far now impose, from the point of view of measurement technology, the requirement that the dimensions of typical measuring devices should be kept very small, which has obvious consequences in terms of flexibility of the layout of the optical arrangement. With increasing miniaturization, the lenses used to image the test spot onto the detector must have higher and higher refractive powers, which leads to increased image errors. For example, thereby making the image at the edge unclear. In order not to further threaten the image quality, it is furthermore desirable from an optical point of view to have pixels which are as small as possible. At the same time, the pixel size on the detector is generally limited to values of at least 4 μm, preferably more than 8 μm and particularly preferably more than 20 μm, due to the semiconductor processing technology of such sensors. This means that semiconductor technology generally requires as large pixels as possible, while optical device layouts require as small pixels as possible. This in turn leads to an imaging which requires magnification and thus again to a deteriorated imaging quality in a practical, cost-effective system. Furthermore, as the imaging scale increases, the requirements for positional tolerances of the test field increase in the case of conventional systems.

It is therefore the object of the present invention to specify an apparatus and a method which avoid the above-mentioned disadvantages of the known apparatuses and methods. The device should be able to be designed in particular as a portable, handheld device and should be able to reliably optically detect at least one analyte in a body fluid with high measurement accuracy using simple electronics, simple optics and low resource and energy consumption.

Disclosure of Invention

This object is achieved by a device and a method having the features of the independent claims. Advantageous developments of the invention which can be realized individually or in combination are indicated in the dependent claims.

In a first aspect of the invention, a device for detecting at least one analyte in a body fluid is proposed, which comprises at least one test element. The device can be designed, for example, as a portable device, in particular as a handheld device or a hand-held device, and can have, for example, an internal energy source, for example, an electrical energy store such as a battery and/or an accumulator. The device can be designed in particular as a portable test device.

Any type of identifiable analyte and/or body fluid parameter is considered as analyte in principle. It is particularly preferred that the analyte comprises at least one metabolite. Examples of typical identifiable analytes are glucose, cholesterol, lactate or other analytes. Combinations of analytes can in principle also be identified. Examples of body fluids include blood, interstitial fluid, saliva, urine and other body fluids.

The device comprises at least one test element. A test element generally refers to an element which is designed such that it executes at least one identifiable change by an analyte, for example as a result of contact with the analyte. For example, the test element may comprise for this purpose at least one test chemical which can carry out such an analyte-specific identification. Examples of such an identifiable change are optically identifiable changes, such as a color change, a grey value change and/or other optically identifiable changes. The test element can have, for example, at least one test field which comprises a test chemical. A test field is to be understood here as meaning, in general, a planar element which comprises at least one test chemical. However, the test field may also comprise a layer structure, wherein at least one further layer, for example a separating layer, may be applied in addition to the at least one layer comprising the test chemical. The test field may thus for example comprise a sample application face, which may for example be the surface of the test field. As the uppermost layer, a separation layer can be provided, for example, which can separate interfering components of the sample, such as red blood cells. Furthermore, the test field may comprise at least one identification layer which comprises the test chemical on its side and which may preferably be arranged below the optional separation layer. Furthermore, the test field can have a detection side from which identifiable changes can be observed. For example, the detection side may be arranged opposite to the sample application side. For example, the layer structure can be designed such that interfering components of the sample, such as red blood cells, are no longer visible from the detection side. Whereas a change of at least one property should be observable from the detection side.

The test element comprises at least one at least two-dimensional analysis region. For example, the analysis region can be arranged on the detection side of the test element, for example a test field. For example, the analysis region may be part of the detection side and, for example, be arranged on the opposite side of the test field to the sample application side. An analysis region is generally understood to be a region of the test field which is influenced by the body fluid sample in the device in an optically recognizable manner during a standard test. This may be, for example, a region in which an optically visible change occurs on the detection side when a capillary filled with the sample is pressed against the sample application side, whether by the sample itself or by an analyte-specific reaction in the test chemical of the test element. The analysis region is thus defined by the intended use of the device as the part of the test element, in particular the part on the detection side of the test field, in which the change occurs during the intended use, for example during the intended transport of the sample to the test field. In which incorrect delivery processes, for example errors in the delivery of the sample to the test element, for example spillage of the test element and/or overdosing of the sample, are excluded. In general, the test element can comprise, for example, a sample application region, to which the sample is spatially limitedly supplied when the device is used as intended, wherein the sample application region can be arranged, for example, on the sample application side of the test field. The analysis region may comprise a region opposite the sample application region, e.g. a projection of the sample application region from the sample application side to the detection side of the test field. For example, the sample application zone may have a substantially rectangular outer shape, corresponding to the outer shape of the capillary. In this case, the analysis region can also be formed, for example, substantially rectangular as a projection of the sample application region from the sample application side to the detection side.

The device further comprises at least one position-resolving optical detector. For example, the detector may comprise at least one spatially resolved optical sensor, for example a sensor array with a plurality of sensor pixels, i.e. an optical single sensor. Furthermore, as will be explained in more detail below, the detector can comprise an optical arrangement which is designed to image the analysis region on an optical sensor, such as a sensor chip. The optical means may for example comprise one or more lenses and/or other imaging optics.

The detector has a plurality of pixels, for example as a component of an optical sensor, such as a sensor chip. A pixel is to be understood here in general as an image-sensitive single sensor, which can be arranged, for example, in a matrix arrangement. The detector, for example an optical arrangement of the detector, is here designed to image at least a part of the test element onto an image region. An image region is to be understood here as a subset of the sensor pixels of the detector, in particular of the optical sensor of the detector, for example a spatially coherent subset of the sensor pixels of the sensor, on which a portion of the test element is imaged, so that the sensor pixels receive image information of the imaged portion of the test element. For example, a part of the detection side of the test element, for example the test field, can be imaged on the image area. In addition to the imaged part of the test element, the detector can also be set up to image other parts of the device on the optical sensor, for example a part of the lancet and/or the capillary. It is thus possible to provide further image areas which do not contain an image of the test element but of other parts of the device.

In the case of fully or at least partially imaging the test element onto the image field, for example in the case of imaging a portion of the test field or the detection side of the test element, at least a portion of the analysis field should be imaged onto the analysis image field. The evaluation region is thus preferably at least partially a component of the part of the test element which is imaged onto the image region. The analysis image area is a diversity and/or subset and/or a portion of the image area, e.g. a coherent subset of sensor pixels of the sensor, which receives image information of the analysis area when imaging the analysis area.

It is proposed that the detector be adapted to the test element or to the device overall in such a way that a predetermined minimum number of pixels is provided for each dimension of the evaluation image area within the evaluation image area. This means that in each direction of the analysis image area, for example in the x-direction and in the y-direction, a minimum number of pixels is respectively providedN_xAnd N_y. As will be explained in more detail below, the evaluation image region can have, for example, a direction y perpendicular to the longitudinal extent of the capillary or capillary impression or of the imaging of the capillary on the evaluation image region, which is also referred to as the widthwise dimension or the widthwise side, and a coordinate x parallel to the longitudinal extent of the imaging of the capillary or of the capillary impression, which is also referred to as the longitudinal or longitudinal side. The widthwise side and the longitudinal side may in particular be substantially perpendicular to each other. The pixels are arranged in a two-dimensional matrix arrangement. The matrix arrangement has pixel rows and pixel columns. The pixel rows are arranged substantially parallel to the longitudinal direction of the analysis region and/or the analysis image region.

The analysis region can in particular be part of a test element as indicated above. In particular, in this case, it can be a part of the test field of the test element, which has at least one identification chemical for identifying the analyte, for example a part of the detection side of the test field. The device can be designed in particular such that, for the determination of the analyte, a body fluid is supplied to a sample application region of the test element, for example to the sample application side of the test field. The sample application area may, for example, be spatially limited when the device is used as intended, for example in such a way that it substantially corresponds to an impression of the capillary on the test field, for example on the sample application side, i.e. the area in which a body fluid, such as blood, is transported from the capillary to the sample application side.

The device can be designed in particular such that a body fluid, in particular blood and/or interstitial fluid, is supplied to the test element for the purpose of identifying the analyte. The transport can take place over a spatially limited sample application area on the sample application side of the test field, as indicated above. However, other embodiments are also possible in principle. The transport can be effected, for example, in such a way that the transport element is close to the test element, for example close to the sample application side of the test field. This approach may be performed until physical contact is made between the transport element and the sample application side of the test field. For example, the transport element may comprise a capillary tube, such as a capillary tube within a lancet, as shown above. Such lancets with capillary tubes are often also referred to as microsamplers. The sample application region can in particular correspond to the analysis region, for example in that the analysis region is a region of the test element in which, as described above, an optically detectable change occurs during the defined delivery of the body fluid to the sample application region. For example, the analysis region may be a region of the test field opposite the sample application region, e.g. a projection of the sample application region from the sample application side to the detection side, as long as e.g. lateral spreading effects are negligible when passing through the test field. In this way, for example, a body fluid can be transported to a sample application region on the sample application side of the test field, and detection can be carried out from the back, i.e. from the detection side, where optically detectable changes can be detected in the analysis region.

As indicated above, the device may comprise in particular at least one lancet element having at least one capillary. For example, the device may comprise a drive device, by means of which a puncturing movement of the lancet element can be driven, including for example a forward movement (puncturing movement) and a return movement. The body fluid may be received in the capillary during the puncturing process and/or during the return movement. The device can then be designed in particular to receive a body fluid by means of a capillary and to deliver the body fluid to a test element, in particular to a test field having at least one identification chemical, by bringing the capillary close to the test element. This transport can take place, for example, to a sample application region on the sample application side of the test element, in particular of the test field. The approach of the capillary to the test element, for example to the sample application side of the test field, can be carried out in particular by means of at least one actuator. Thus, for example, an actuator can be provided which brings the capillary, which is at least partially filled with body fluid, close to the test field, for example close to the sample application side, until the transport takes place. For example, the capillary may be pressed against the sample application side of the test field. However, in principle, a contactless approach is also possible, for example an approach over such a short distance that the sample transport from the capillary to the sample application side takes place, for example, by capillary and/or adhesive forces between the lancet and the test field. Alternatively or in addition to the actuator, however, the device can also be designed in other ways for bringing the capillary into proximity with the test element. For example, the lancet or capillary can be guided during the retraction movement of the lancet such that it describes a spatial trajectory in which the sample application side of the test element, for example a test field, is approached. For example, a curved guide for a lancet can be provided, in which the lancet describes a curved track, by means of which the lancet or capillary is pressed against and/or close to the test field. Various other embodiments or combinations of the above and/or other embodiments for bringing a capillary close to a test element are also possible.

As already mentioned, the analysis region can be in particular a region of the test element in which an optically detectable change occurs as a result of the body fluid being transported onto the test element. The change can be caused by the body fluid itself or, to a greater or lesser extent, by at least one analyte contained in the body fluid and, for example, by its reaction with at least one test chemical. As already mentioned, the analysis region can thus be in particular a part of the test field, for example also on the detection side, which can be opposite the sample application side of the test field, for example in such a way that the analysis region corresponds to the projection of the sample application region on the sample application side when the device is used as intended. For example, the analysis region may be a region in which a visually identifiable change, for example a change in color and/or a change in grey value, occurs due to the sample. In particular, the analysis region can be an image of the capillary from the sample application side to the detection side or a partial region of the projection.

The capillary can in particular have a width of 50 to 200 μm, in particular 90 to 150 μm, particularly preferably approximately 120 μm. Alternatively or additionally, the capillary tube may in particular have a length of at least 1mm, in particular at least 2mm, and preferably a length of 2 to 4 mm. Typically, the capillary has a depth of 20 to 150 μm, for example 50 to 120 μm. But other dimensions of the capillary are in principle also possible.

The device can be set up in particular to automatically recognize the analysis region. For this purpose, the device may have an evaluation device, for example, which may be completely or partially integrated in the detector, but which may also be arranged completely or partially externally. The analysis device may for example comprise one or more data processing devices. Alternatively or additionally, however, the evaluation device can also be designed in a simpler manner and can, for example, comprise one or more comparators and/or other electronics in order to compare the signal of the detector, for example the optical sensor and/or the signal of one or more pixels of the optical sensor, with one or more threshold values. Alternatively or in addition to the task of identifying the analysis area, the analysis device may also have other tasks, for example a task of performing data reduction, a task of identifying a workflow that is not in accordance with the specification, a task of preprocessing image data or the like.

In the automatic identification of the analysis region, different methods can be used. In a first method variant, use is made of an evaluation region which preferably can represent the projection of the capillary onto the detection side of the test element. In this first method variant, therefore, a pattern recognition method can be used, in which the lancet and/or the capillary of the device is recognized. The device can thus be set up, for example, such that the capillary projects beyond the test element, so that not only an image of the detection side of the test element is recorded by means of the detector, but also a sub-region of the lancet and/or capillary in which the lancet and/or capillary is not located on the sample application side of the test element. For example, as described above, a test field can be provided having a sample application side with a lancet having a capillary adjacent thereto; and has an opposite detection side, which is observed by the detector. If a lancet with a capillary protrudes from the side of the test field, the detector preferably records the lancet and the part of the capillary which is not optically masked by the test field. The pattern recognition method can in particular be designed such that an extrapolation of the lancet and/or capillary to the test element is identified as the evaluation region. Examples of said first method variant are set forth in more detail below.

In a second variant of the method or apparatus, which may alternatively or additionally be used, a signal variation method may be employed. In the signal change method, a change in the signal of an optical sensor of the probe is monitored. In this case, the region of the test element in which the optically detectable change occurs by the delivery of the body fluid onto the test element is identified as the analysis region. As indicated above, the optically detectable change can be a change caused by the body fluid itself, for example in such a way that the body fluid itself causes a darkening and/or a change in the gray level and/or a change in the color in the analysis region on the detection side of the test element, for example the test field. Alternatively or additionally, however, these optical changes can also be caused by the analyte to be identified itself. In both cases, the position of the analysis region can be determined by means of a signal variation method. For example, the analysis region may be identified and defined by identifying inhomogeneities caused by capillary edges of optically identifiable variations (e.g. discoloration and/or darkening and/or grey value changes).

This aspect of the proposed invention can also be implemented independently of the remaining aspects of the device. In a parallel aspect, a method for identifying an analysis region of a test element is thus proposed, in particular using the device described above or below. However, the use of other types of devices is also conceivable in principle. Generally, at least one lancet element having at least one capillary is used in the method (e.g., according to the above description). The body fluid received in the capillary is transported to the test element, for example to the sample application side of the test field of the test element. Furthermore, at least a part of the test element, for example a part of the detection side of the test field of the test element, is imaged onto an image region, for example an image region of an optical sensor of the detector, by means of at least one spatially resolved optical detector (for example according to the above description). In this case, at least a part of the analysis region of the test element is imaged onto the analysis image region. The method is carried out in such a way that the analysis region is automatically identified according to a method selected from the group consisting of: a pattern recognition method, wherein in the pattern recognition method a lancet and/or a capillary is recognized, wherein an extrapolation of the lancet and/or the capillary to the test element is identified as an analysis area; signal change method, wherein the region of the test element in which an optically detectable change occurs by the delivery of a body fluid onto the test element is identified as an analysis region. The latter method variant can be carried out, for example, by means of a simple comparison method, for example, by monitoring a pixel, a plurality of pixels or all pixels of the optical sensor of the detector, comparing the signal of the pixel with a previously recorded signal and, for example, comparing the signal change with a threshold value. If the signal change exceeds a predetermined threshold value, it can be concluded, for example, that wetting has occurred and that the associated pixel is arranged in the evaluation region or in the evaluation image region. For further possible embodiments, reference is made to the above description.

The detector can be designed in particular such that the detector or the optical sensor of the detector has a total number of maximally 1000 pixels, preferably maximally 500 pixels, particularly preferably maximally 256 pixels. For example, a probe having a longitudinal side and a lateral side may be employed. As defined above, the longitudinal side can be defined in particular as the x-direction, which is arranged in the normal case, i.e. parallel to the capillary when the device is used as intended, or parallel to the imaging of the capillary in the image area. Accordingly, the lateral side can be oriented perpendicular to the capillary or perpendicular to the imaging of the capillary and can be defined, for example, as the y-direction. The detector can be designed in particular such that it has at least 3 pixels, preferably a maximum of 100 pixels, in particular 20 to 50 pixels and particularly preferably 32 pixels, in the direction of the lateral side. The detector can furthermore have at least 1 pixel, preferably 2 to 20 pixels, in particular 5 to 10 pixels and particularly preferably 7 pixels in the direction of the longitudinal side, i.e. in the x direction. However, other embodiments are also possible in principle. It is particularly preferred that the detector is designed such that at least 3 pixels, in particular 5 to 30 pixels and particularly preferably 10 pixels, are arranged in the analysis region, i.e. in a region in which the optically detectable change is detectable when the device is used as intended and, for example, when a body fluid is transported onto the test element as intended.

The analysis region can in particular have, as described above, a longitudinal side and a lateral side, in particular a longitudinal side parallel to the imaging orientation of the capillary or the capillary on the image region and a lateral side perpendicular to the capillary or its imaging orientation. The widthwise side may be defined as the y-direction as described above and the longitudinal side may be defined as the x-direction, wherein these directions are preferably substantially perpendicular to each other, e.g. with a deviation of not more than 5 °. Thus, pixels of the same y coordinate may be referred to as pixel rows and pixels of the same x coordinate may be referred to as pixel columns. The detector can be designed in particular such that at least 3 pixel rows, in particular 3 to 10 pixel rows, are arranged in the analysis region in the direction of the lateral side. Alternatively or additionally, the detector can be designed such that at least one pixel column, preferably at least 3 pixel columns, in particular 3 to 10 pixel columns and particularly preferably 7 pixel columns, are arranged in the direction of the longitudinal side.

These pixels may in particular have an elongated pixel geometry. Here, an elongated pixel geometry is to be understood as a geometry in which the pixels have a larger extension in one dimension than in the other dimension. For example, a pixel may have a greater length in the x-direction than in the y-direction. Thus, for example, the analysis region can have a longitudinal side and a lateral side, in particular a longitudinal side oriented parallel to the capillary and a lateral side oriented perpendicular to the capillary. The pixels can in particular have a length in the longitudinal direction, i.e. for example in the x direction, and a width in the direction of the lateral sides, preferably in the y direction. The length can preferably exceed the width. In particular, the length can be at least 1.3 times, in particular at least 1.7 times or at least 2 times and particularly preferably 2.3 times the width. Such a pixel geometry has proven particularly suitable in practice for elongated capillaries with typical dimensions, for example the capillary dimensions shown above, in order to reliably detect the analysis region and to analyze optically identifiable changes. The length of the pixels can be, for example, 10 to 300. mu.m, preferably 50 to 100 μm and particularly preferably 70 μm. The width can be, for example, from 5 to 200. mu.m, preferably from 10 to 100. mu.m and particularly preferably 30 μm.

The pixels are arranged in a two-dimensional matrix arrangement. The matrix arrangement has rows and columns of pixels, for example as described above. So that the rows can be oriented parallel to the x-direction and the pixel columns can be oriented parallel to the y-direction, for example. The pixel rows are arranged substantially parallel to the longitudinal direction of the analysis region, for example substantially parallel to the imaging of the capillary or a longitudinally extending axis of the imaging of the capillary in the image region. "substantially parallel" is to be understood here to mean, in particular, a deviation from perfect parallelism of less than 5 °, in particular a deviation of less than 2 ° and particularly preferably a deviation of 1 ° or less, in particular 0 °. The longitudinal direction of the analysis region, i.e. for example the longitudinal extension axis of the capillary and/or the imaging of the capillary in the image region, can thus be arranged substantially parallel to the pixel rows. This embodiment of the device, in particular in combination with the above-described very long pixels, leads to a particularly efficient analysis of the analysis region with the smallest possible number of pixels, the possibility of using a large pixel area and nevertheless a reliable analysis of a large number of pixels in the analysis region.

The detector can in particular have a position-resolving optical arrangement as already described above. The position-resolving optical device may have, for example, one or more lenses and/or other optical imaging systems. Furthermore, the spatially resolving optical arrangement can have further optical elements with non-imaging properties, for example diaphragms or the like. Furthermore, filters, mirrors, other types of optical deflection elements or other optical elements may be provided, for example.

The spatially resolving optical device can be designed in particular to image the analysis region onto the analysis image region with a magnification of 3:1 to 0.5:1, preferably with a magnification of 2:1 to 0.8:1, particularly preferably with a magnification of 1.1:1 to 0.9:1 and ideally 1: 1. A magnification of 3:1 means here that the analysis image area is 3 times the analysis area. Ideally, the optical device is therefore designed such that it has practically no magnification, but the size of the evaluation image area corresponds substantially to the size of the evaluation area.

As described above, the determination of the analysis area is based on a prescribed infiltration (Benetzung). For example, the analysis region may comprise an impression of the capillary or a projection of the capillary onto the detection side. In addition to the intended wetting, in which case, in addition to the unavoidable inhomogeneities in the region of the capillary edge, the transfer of the body fluid from the capillary to the test element, for example to the sample application side, different transport errors and/or wetting errors can occur. So that for example the capillary may be insufficiently filled so that too little body fluid is transported to the sample application side. However, this case of incomplete filling and/or incomplete transfer of the body fluid onto the test element is only one of a plurality of error cases. This situation may then arise, for example, in the following cases: an inappropriate puncture location into the body tissue is selected so that too little body fluid is received by the microsampler, for example during the puncture procedure and/or sampling procedure. The opposite may also occur. In this case, for example, the entire lancet can be wetted with body fluid or blood, which is then transported to the test element, so that, for example, a body fluid overflow of the test element occurs. This can also lead to errors, for example, by virtue of the fact that no non-wetted regions are available in the image region, i.e. regions outside the analysis region which can be used as reference values and/or "blank values", as will be explained in more detail below, for characterizing the discoloration or optical change of the test element.

It is therefore particularly preferred that the device is designed to characterize, in particular evaluate, the wetting of the test element with a body fluid. This characterization can be carried out, for example, by providing an evaluation device, for example an evaluation device having the above-described features, which evaluates the signals of the optical sensors of the detector. The analysis device can, for example, characterize the wetting in such a way that a defined wetting, i.e. a defined transport of the body fluid to the test element, is distinguished from one or more error situations. For example, a defined successful delivery of the body fluid onto the test element can be distinguished from a case of an overflow, in which the body fluid is delivered to the sample application side of the test element even outside the boundary of the capillary, and from a case of an under-dose, in which the sample application side is not completely wetted with body fluid even in the actual analysis region. The characterization can be carried out in particular in such a way that the device is set up to compare a plurality of pixels in at least one dimension with one another. For example, pixels adjacent in at least one direction, for example in a direction parallel to the longitudinal sides of the analysis region, can be compared with one another. In particular, two or more adjacent pixels of a pixel row oriented parallel to the analysis region can be compared. In particular, the signals of the pixels in the analysis area can be compared to identify whether the pixels which actually should indicate wetting actually show such wetting. In this way, for example, an underdosage, for example, an incomplete filling by a capillary and/or an incomplete transfer of the body fluid to the test element, can be detected. On the other hand, it is possible to identify: pixels which should not actually indicate wetting, i.e. pixels outside the analysis area, actually detect wetting, so that, for example, an overflow and/or overdose can be detected. The characterization can be carried out, for example, in such a way that a comparison of neighboring pixels from a pixel row which is arranged substantially parallel to the longitudinal direction of the analysis region is carried out, wherein, for example, a threshold method can be used. So that for example a difference of the signals of neighboring pixels can be formed and compared with at least one threshold value. If the difference exceeds at least one threshold value, it can be concluded, for example, that there is insufficient infiltration and/or insufficient dosage and/or other errors. In this case, the longitudinal direction of the analysis region is preferably oriented substantially parallel to the edge of the capillary and/or the capillary channel of the capillary. The capillary tube is preferably, as described above, brought into close proximity to the test element for the purpose of transporting body fluid, for example pressed against the test element. Thus, based on a comparison with adjacent pixels of this pixel row oriented parallel thereto, an erroneous transport of an erroneously filled capillary and/or body fluid can be recognized, for example, based on an incomplete and/or gapped filling of the capillary.

As indicated above, the detector can be designed in particular as a compact detector. The detector can thus in particular have a detector component, in particular a detector chip, wherein, for example, the evaluation device can be integrated completely or partially in the detector component, in particular the detector chip. The evaluation device can be set up to carry out an image evaluation of the image region and/or evaluation of the image region in full or in part. The detector chip can be designed in particular as an application-specific integrated circuit (ASIC).

The device can be set up in particular to recognize a null value. The blank value here characterizes the optical properties of the image area and/or of the evaluation image area without wetting the test element with body fluid. The identification of the null value can be carried out, in particular, again using an evaluation device, which can be integrated completely or partially in the detector. The device may in particular be set up to determine a null value according to one or more of the methods described below.

In a first variant of the method in which the device, in particular the analysis device, is set up for execution, a recording of a temporal image sequence can be carried out. A temporal image sequence is to be understood here as a plurality of image information of the optical sensor, which are images recorded at different, successive times, for example at intervals of 100 ms. The analysis region may be determined from the temporal image sequence, for example by means of one or more of the methods described above. At least one, preferably a plurality of pixels arranged in the evaluation region can be identified, and at least one starting value of a pixel is determined from the temporal image sequence and used as a null value. In other words, the analysis region can first be determined from the temporal image sequence and then one or more starting values can be determined from the recorded image sequence for one or more pixels within the analysis region, which starting values can then be used as null values, which corresponds to a "rewind" of the film of the image sequence. The advantage of this method is that a null value can be determined for each pixel to be analyzed, which null value corresponds exactly to this pixel.

Alternatively or additionally, a method may be used in which starting values of all pixels of an image area or at least one starting value of a plurality of pixels of the image area are stored. The analysis region can then be determined from the temporal image sequence of pixels. Pixels outside the analysis area can be discarded, so that in this way data reduction can be performed. At least one starting value of the pixels within the analysis area can then be used as a null value. This method variant offers the advantage of a significant data reduction, since pixels outside the analysis region can already be discarded as soon as it is clear where the analysis region is located within the image region when the temporal image sequence is recorded, so that it is no longer necessary to store the image sequence of the entire image region, but rather only the image sequence of the pixels of the analysis region.

In a third method which can again be used alternatively or additionally, the analysis region can be determined, for example, by means of one or more of the methods described above. At least one pixel outside the analysis region, i.e. the pixel onto which the region of the test element outside the analysis region is imaged, can then be used as a null value. This method variant offers the following advantages: only a small amount of data needs to be stored. The determination of the null value can be carried out, for example, exclusively and solely by means of images after the analyte reaction, without the need to store a history or a time image sequence. In principle, however, other methods for determining one or more null values can also be used. The proposed device and the proposed method have a number of advantages over the known devices and methods. According to the invention, an advantageous alternative to the use of a conventional image sensor having more than 10000 pixels is thus provided, as can be used for histogram analysis, for example, according to EP1843148a 1. The invention is based on the recognition, in particular, that, on the one hand, it is desirable to have a positional resolution of at least approximately 10 pixels per capillary width in a manner that is equivalent to the image of the capillary on the image region. On the other hand, however, the invention is based on the recognition that the optical imaging quality in small, highly integrated and cost-sensitive devices, in particular hand-held devices, is strongly impaired by the lack of space. At the same time, the present invention correctly treats the following facts: as large pixels as possible are advantageous in terms of semiconductor technology, since an optical sensor with as large pixels as possible, for example with the pixel geometries and/or pixel sizes described above, enables a comparatively high fill factor of the optical sensor.

So that in particular optical devices with 1:1 imaging can be used according to the invention. In one or more of the above-described variants, it is possible in particular to increase the area per pixel and to reduce the number of pixels accordingly, using the above-described device. As the number of pixels decreases, for example to the above-mentioned number of pixels of the optical sensor, a reduction of the data volume and of the effort for analyzing the data occurs, so that an improvement can be achieved at all the above-mentioned critical boundary conditions of the device. At the same time, the pixel geometry can be adapted to the identification method and implementation, for example by forming the pixels in a rectangular manner, wherein the pixel geometry can be adapted in particular to the geometry of the analysis region (for example the measurement spot) which is caused, for example, by the capillary geometry.

In summary, the following embodiments are considered to be particularly advantageous within the scope of the invention:

embodiment 1: device for identifying at least one analyte in a body fluid, comprising at least one test element having at least one two-dimensional analysis region, and further comprising at least one spatially resolved optical detector having a plurality of pixels, wherein the detector is designed to image at least a part of the test element onto an image region, wherein at least a part of the analysis region is imaged onto an analysis image region, wherein the detector is adapted to the test element such that a predetermined minimum number of pixels is provided for each dimension within the analysis image region, wherein the pixels are arranged in a two-dimensional matrix arrangement, wherein the matrix arrangement has pixel rows and pixel columns, wherein the pixel rows are arranged substantially parallel to the analysis region and/or to the longitudinal direction of the analysis image region.

Embodiment 2: the device according to the former embodiment, in which the analysis region is part of a test element, is configured such that a body fluid is supplied to the test element for the purpose of identifying the analyte.

Embodiment 3: the device according to one of the above embodiments, wherein the device comprises at least one lancet element having at least one capillary.

Embodiment 4: the device according to the preceding embodiment, wherein the device is designed to receive a body fluid by means of a capillary, wherein the device is also designed to deliver the body fluid onto the test element by bringing the capillary close to the test element.

Embodiment 5: the device according to the former embodiment, wherein the analysis region is a region of the test element in which the optically identifiable change occurs by the delivery of the body fluid onto the test element.

Embodiment 6: apparatus according to one of the first three embodiments, wherein the capillary has one or more of the following dimensions:

a width of 50 to 200 μm, in particular 90 to 150 μm and particularly preferably 120 μm;

a length of at least 1mm, in particular at least 2mm and preferably a length of 2 to 4 mm.

Embodiment 7: the device according to one of the above-described embodiments, wherein the device is set up to automatically recognize the analysis region.

Embodiment 8: the device according to the preceding embodiment, wherein the device is set up to identify the analysis region according to a method selected from the group consisting of:

a pattern recognition method, wherein the device comprises at least one lancet element and/or at least one capillary, wherein the lancet element and/or the capillary of the device is recognized in the pattern recognition method, wherein an extrapolation of the lancet element and/or the capillary onto the test element is identified as an analysis area; and

a signal change method, in which a region of the test element is identified as an analysis region, in which region an optically detectable change occurs by the delivery of a body fluid onto the test element.

Embodiment 9: the device according to one of the above-described embodiments, wherein the detector has a total number of maximally 1000 pixels, preferably maximally 500 and particularly preferably maximally 256 pixels.

Embodiment 10: the device according to one of the above-described embodiments, wherein the detector has a longitudinal side and a broadside, in particular a longitudinal side oriented parallel to the capillary of the device and a broadside oriented perpendicular to the capillary, wherein the detector has at least 3 pixel rows, preferably a maximum of 100 pixel rows, in particular 20 to 50 pixel rows, in the direction of the broadside, wherein the detector furthermore has at least 1 pixel column, preferably 2 to 20 pixel columns, in particular 5 to 10 pixel columns and particularly preferably 7 pixel columns, in the direction of the longitudinal side.

Embodiment 11: the device according to one of the above-described embodiments, wherein preferably at least 3 pixels, in particular 5 to 30 pixels and particularly preferably 10 pixels are arranged in the analysis region.

Embodiment 12: the device according to one of the above-described embodiments, wherein the analysis region has a longitudinal side and a broadside, in particular a longitudinal side oriented parallel to the capillary of the device and a broadside oriented perpendicular to the capillary, wherein the detector is configured such that at least 3 pixel rows, in particular 3 to 10 pixel rows, are arranged in the direction of the broadside within the analysis region, and wherein the detector is further configured such that at least 1 pixel column, preferably at least 3 pixel columns, in particular 3 to 10 pixel columns and particularly preferably 7 pixel columns are arranged in the direction of the longitudinal side.

Embodiment 13: the device according to one of the above-described embodiments, wherein the pixels have an elongated pixel geometry, wherein the analysis region has a longitudinal side and a broadside, in particular a longitudinal side parallel to the capillary orientation of the device and a broadside perpendicular to the capillary orientation, wherein the pixels have a length in the direction of the longitudinal direction, and wherein the pixels have a width in the direction of the broadside, wherein the length exceeds the width, preferably at least 1.3 times, in particular at least 1.7 times or at least 2 times and particularly preferably 2.3 times the width.

Embodiment 14: the device according to one of the above-described embodiments, wherein the detector has a spatially resolving optical arrangement, wherein the spatially resolving optical arrangement is designed to image the evaluation region onto the evaluation image region with a magnification of 3:1 to 0.5:1, preferably with a magnification of 2:1 to 0.8:1, particularly preferably with a magnification of 1.1:1 to 0.9:1 and ideally 1: 1.

Embodiment 15: the device according to one of the above-described embodiments, wherein the device is designed to characterize, in particular to evaluate, the wetting of the test element with the body fluid, wherein the device is designed to carry out the characterization by comparing a plurality of pixels in at least one dimension, preferably by comparing adjacent pixels of a pixel row oriented parallel to the analysis region.

Embodiment 16: the device according to one of the above-described embodiments, wherein the device is designed to recognize a null value, wherein the null value is an optical property of the image area and/or of the evaluation image area without wetting the test element with a body fluid, wherein the device is designed to determine the null value according to a method selected from the group consisting of:

-recording a temporal image sequence, wherein an analysis region is determined, wherein at least one pixel arranged within the analysis region is identified, and a starting value of the pixel is determined from the temporal image sequence and used as a null value;

-storing start values of pixels of the image area, determining an analysis area from the temporal image sequence of pixels, discarding pixels outside the analysis area, and using at least one start value of pixels within the analysis area as a null value;

-determining an analysis area, using at least one pixel outside the analysis area as a null value.

Embodiment 17: method for identifying an analysis region of a test element for detecting at least one analyte in a body fluid, in particular using a device according to one of the above-described embodiments, wherein at least one lancet element having at least one capillary is used, wherein the body fluid received in the capillary is transported onto the test element, wherein at least a part of the test element is imaged onto an image region by means of at least one spatially resolved optical detector, wherein at least a part of the analysis region of the test element is imaged onto an analysis image region, wherein the analysis region is automatically identified according to a method selected from the group consisting of:

-a pattern recognition method, wherein a lancet element (114) and/or a capillary (116) is recognized in the pattern recognition method, wherein an extrapolation of the lancet element (114) and/or the capillary (116) onto the test element (120) is identified as an analysis region (136); and

-a signal change method, wherein a region of the test element (120) is identified as an analysis region (136), within which region an optically identifiable change occurs by the delivery of a body fluid onto the test element (120).

Drawings

Further details and features of the invention emerge from the following description of preferred embodiments, in particular in conjunction with the dependent claims. In this case, the respective features can be realized individually or in combination with one another. The invention is not limited to the embodiments described. These embodiments are schematically shown in the figures. The same reference numbers in the individual figures denote identical or functionally identical elements or elements which correspond to one another in terms of their function.

In detail:

FIG. 1 shows an embodiment of the apparatus of the present invention;

FIGS. 2A and 3A show a comparison of conventional imaging of an analysis region (FIG. 2A) with imaging of the invention (FIG. 3A);

FIGS. 2B and 3B show a comparison of a conventional apparatus (FIG. 2B) and an apparatus of the present invention (FIG. 3B) in perspective view;

figures 4 to 7 show the measurement error in different dimensions when using a conventional detector (figures 4 and 6) compared to the detector of the invention (figures 5 and 7); and

fig. 8A to 8C show a comparison of the specified specimen transport (fig. 8A) and the different transport errors (fig. 8B and 8C).

Detailed Description

Fig. 1 shows a highly schematic exploded view of an inventive device 110 for detecting at least one analyte in a body fluid. Device 110, in the illustrated embodiment, includes a microsampler 112 having a lancet element 114 and a capillary tube 116. For example, a metal lancet, into which a capillary tube 116 is inserted as a capillary gap. The lancet element 114 can be driven into a puncturing movement, for example, by a drive device 118, for example, one or more actuators (e.g., spring-driven actuators), wherein in a forward movement, for example, a puncture is made into the skin of a user, and in a rearward movement, a body fluid is collected in the capillary 116.

Furthermore, the device 110 comprises in the embodiment shown at least one test element 120. The test element 120 can comprise, in particular, at least one test field 122, for example a test strip and/or a test strip with a plurality of test fields 122 and/or a test field 122 of a test strip with a plurality of test fields 122. In principle, other embodiments are also possible. For example, a plurality of microsamplers may be provided, each assigned at least one test field 122. For example, the micro-sampler 112 and the at least one test field 122 may be housed separately in a chamber and collectively form a test. Other embodiments are also possible.

The test field 122 may comprise, for example, an identification layer 124 with at least one test chemical which, in the presence of at least one analyte to be identified, carries out an optically identifiable and preferably analyte-specific reaction and/or undergoes an identifiable change. For example, reference can be made to the above-mentioned prior art with respect to common test chemicals. Furthermore, the test field 122 may comprise additional layers, such as one or more separation layers 126, which separate undesired constituents of the body fluid sample (e.g. interfering red blood cells for optical identification) before the sample reaches the identification layer 124. Furthermore, the separation layer 126 may have reflective properties, for example in such a way that it comprises one or more reflective substances, for example white pigments.

The test element 120 has a sample application side 128, on which at least a portion of the body fluid sample received in the capillary 116 within a sample application region 130 is transported to the test field 122. For this purpose, the device 110 may comprise a proximity device 132 which is set up to bring the capillary 116 into proximity with the sample application region 130 of the test field 122 after sampling of the capillary 116. The proximity device 132 may have, for example, one or more actuators which actively bring the lancet element 114 into proximity with the test field 122, for example, press it against it. Alternatively or additionally, however, the approach device 132 can also interact with the drive device 118, for example by bringing the capillary 116 close to the test field 122 by correspondingly guiding the lancet element 114 during the retraction of the lancet element 114 after the sampling movement. It is particularly preferred, however, that the proximity device 132 has at least one actuator, for example a plunger, which presses the lancet element 114 against the test field 122, so that a defined sample application region 130 is formed, which is wetted with the sample in a defined manner.

A probing side 134 is provided on the opposite side of the test element 120 from the sample application side 128. After the sample is transported from the capillary 116 to the sample application region 130 of the sample application side 128, an analysis region 136 is formed on the detection side 134. For example, the analysis region 136 may be a projection of the sample application region 130 as the body fluid is transported from the capillary 116 to the sample application side 128 as specified. The analysis region 136 can thus be characterized in particular by a region of the detection side 134 in which an optically detectable change occurs after the defined transport of the sample from the capillary 116 to the test field 122.

Furthermore, the device 110 comprises in the illustrated embodiment at least one detector 138, which in the illustrated embodiment is composed of a plurality of components, which may, however, also be combined to a common component, for example a detector assembly. The detector 138 for example comprises at least one light source 140 for illuminating the detection side 134, which light source may for example comprise a light emitting diode. Furthermore, the detector 138 comprises an optical arrangement 142, which is shown in fig. 1 in a strongly simplified manner and may have one or more lenses, for example. Furthermore, the detector 138 comprises in the embodiment shown an optical sensor 144, such as a CCD chip and/or a CMOS chip, comprising a plurality of pixels 146 arranged in a matrix. The pixels 146 are preferably rectangular in design and are aligned with their longitudinal sides in the x direction parallel to the longitudinal extent of the capillary 116 or the analysis region 136 and with their narrower, lateral sides in the y direction perpendicular to this longitudinal extent. The optical device 142 is designed to image a part of the test element 120, in particular a part of the detection side 134 of the test element 120, onto the optical sensor 144. Other portions of the device 110 may also be imaged. So that a portion of the micro-sampler 112, preferably together with a portion of the capillary 116, can be imaged by the detector 138 or by the optical device 142, for example from the edge of the test field 122, onto the optical sensor 144, so that a portion of the capillary 116 can preferably be viewed directly. In this way, a plurality of regions preferably occur on the optical sensor 144. Thereby forming an image area 148 shown in fig. 1 in a dotted manner, wherein the test element 120 and/or a part of the test element 120, for example a part of the detection side 134 of the test field 122, is imaged onto said image area 148. Within this image region 148, the evaluation region 136 is imaged onto an evaluation image region 150, which is shown shaded in fig. 1. In addition, a region in which the component of the test element 120 is not imaged is optionally formed on the optical sensor 144. In this region, for example, an image 152 of the lancet element 114, an image 154 of the capillary 116 recorded past the edge of the test field 120, can be made. The evaluation image region 150 is thus essentially an extension of this imaging 154 of the capillary 116, as is symbolically shown in fig. 1.

Furthermore, the device 110, in particular the detector 138, may comprise at least one analysis device 156, which is symbolically shown in fig. 1. The analysis device may also be fully or partially integrated in the detector 138, for example in a detector assembly. The analysis device 156 may, for example, as indicated above, comprise at least one data processing device (e.g., at least one microcontroller) and/or other electronics such as logic devices and/or memory devices. The evaluation device can be designed, for example, to carry out the method of the invention together with the other components of the device 110. The analysis device 156 may, for example, perform image analysis.

As indicated above, an important idea of the invention is to use as the detector 138 a detector with macro-pixels 146, i.e. pixels that are large compared to common CMOS camera sensors. This is illustrated in fig. 2A and 2B, which exemplarily show an image on such an optical sensor 144. Here, fig. 2A shows a conventional CMOS chip, while fig. 3A shows an optical sensor 144 with "macro-pixels" 146, which are particularly preferred within the scope of the present invention. While the histogram analysis is carried out in the conventional manner in the case of the CMOS sensor 144 according to fig. 2A, as described, for example, in EP1843148a1, an almost classical analysis can be carried out in the case of the detector 138 with macro-pixels 146 of the device 110 according to the invention, in which, for example, the signal of each individual pixel 146 is stored and/or analyzed, for example, by means of the analysis device 156.

Table 1: using histogram analysis and 3: the characteristics of the conventional camera detection with 1 imaging (middle column) are compared to the macro-pixel detection with 1:1 imaging (right column).

The conventional method ("camera" column) is compared in Table 1 with the analysis method under the conditions of using the inventive device 110 with macro-pixels, here an optical arrangement with a magnification of 3:1 is used in the case of the conventional method, as is typically required for imaging with CMOS chips.the number of pixels is about 65000, of which about 2500 pixels actually carry information about the analyte (referred to herein as glucose information), i.e. the pixels within the analysis image area 150. the pixel size is typically 20 × 20 μm²And is a square pixel. In this method, a preliminary evaluation of the data on the sensor chip itself is typically required, since otherwise a high level cannot be guaranteedImage recording rate at every 10ms to 100ms of image recording, a data volume of 256 × 2 bytes per cycle is generally obtained.

Whereas in the case of the device 110 according to the invention using macropixels 146, imaging is carried out at a scale of 1:1 in the test series shown by means of the optical means 142. The volume of the optical means and the optoelectronic means, i.e. the volume of the entire detector assembly, is about 2.57cm in the case of conventional devices³Whereas the volume of the optical means and optoelectronic electronic means can be reduced to 1.77cm in the case of the device 110 according to the invention³The number of pixels is a maximum of 256 pixels, of which about 10 carry glucose information, the macropixel 146 has in the embodiment shown a value of 30 × 70 μm²Pixel size and rectangular shape. Pre-analysis, e.g. pre-processing, of the data on the sensor chip itself is not required, but in principle can be performed if this is desired. The storage requirements per cycle are in principle unchanged without preprocessing the data. In such cases where the amount of data is small due to a small number of macropixels, a special simplified algorithm may be used to determine the concentration of the analyte in the body fluid. For example, the algorithm may involve analysis of all pixels 146 disposed within the analysis image area 150, or analysis of only the center pixel.

For this purpose, for example, an evaluation image region 150 within the image region 148 can first be identified, for example by means of one of the methods described above. Thus, for example, discoloration and/or grey value changes of the macropixels 146 can be recognized, thereby defining the analysis image region 150. One or more macropixels 146, preferably centrally located within analysis image area 150, may then be used to read image information therefrom. The identification of the analysis image area 150 may be performed, for example, based on a change in gray scale values and/or identification of the capillary-based imaging 154, which continues and/or extrapolates into the image area 148 to illustrate the analysis image area 150. For example, the pixels 146 may be arranged parallel to the x-direction in the pixel rows 158 and thus parallel to the capillaries 116 and in the y-direction in the pixel columns 160. The pixel row 158 which is located furthest in the center of the analysis image area 150 can be used for analysis, for example. Alternatively, multiple pixel rows 158 and/or portions thereof may be employed.

In fig. 2B and 3B, the detector assembly 162 of the conventional apparatus (fig. 2B) and the detector assembly 162 of the apparatus of the present invention (fig. 3B) are compared with each other. Here again, reference numeral 120 denotes a test element, for example a test field. The test element 120 may, for example, be movably arranged relative to the detector assembly 162, for example, as part of an analysis strip. In the exemplary embodiment shown, a light source 140, which is not resolved in more detail in the drawing, and optionally a deflection device 164, which deflects the reflected light toward the optical sensor 144, in the case of fig. 2B toward a CMOS chip with typically more than 10000 pixels, and in the case of the present invention fig. 3B toward the optical sensor 144 with macropixels 146, preferably with a maximum of 256 macropixels, are arranged below the test element 120. Furthermore, an optical device 142 is arranged in the beam path, and in the exemplary embodiment according to fig. 2B is an optical device with a magnification of 3:1 and thus a larger installation space, whereas in the case of fig. 3B according to the invention it is an optical device with a preferred magnification of 1: 1. As is apparent from fig. 2B and 3B, the installation space requirement of the embodiment of the invention in fig. 3B is significantly smaller than the installation space requirement according to fig. 2B.

In fig. 4 to 7, a comparison test is carried out between a conventional CMOS chip according to fig. 2A and an optical sensor 144 with macropixels 146, for example, according to fig. 3A. The total error of the glucose concentration determination, which is indicated by F, is plotted in percent on the vertical axis, respectively. The number of pixels of the optical sensor 144 is plotted on the horizontal axis. Here, N is_yIndicates the number of pixels perpendicular to the capillary tube 116 or its image (fig. 4 and 5), i.e., the number of pixel rows 158 on the optical sensor 144, and N_xRepresenting the number of pixels 146 parallel to or imaged by the capillary 116 (fig. 6 and 7), i.e., the number of pixel columns 160 per optical sensor 144. FIGS. 4 and 6 herein show experiments with conventional CMOS sensor chips, where filled circles represent the case where the entire pair isThe filled squares represent measurement points where the region to be analyzed (region of interest, ROI) is first selected in advance, i.e. before data analysis, and then analyzed within said region to be analyzed, the latter requiring a great demand for time, computing power and thus resources in the analysis device 156, while the measurement points (filled triangles) for the inventive device 110 with macro-pixels 146 are shown in Figs. 5 and 7, these experiments are performed on capillaries 116 with a width of 120 μm, 20 × 20 μm is used in the case of conventional CMOS chips²And a macro-pixel 146 of the present invention having a pixel size of 30 × 70 μm²(i.e., 30 μm in the y-direction and 70 μm in the x-direction) with its longer side oriented parallel to the capillary 116 as shown in fig. 3A.

As can be seen from a comparison of substantially identical fig. 6 and 7, conventional sensor chips have reliable results only starting from approximately 200 to 250 pixels in the x-direction and y-direction with conventional analysis methods. In the case of the device 110 of the invention with macropixels 146 in contrast, (note the different scales of the vertical axes in fig. 7 and 6) already obtain a characteristic minimum starting from about 5 pixel columns, and even in the case of less than 5 pixel columns small errors are already noted in fig. 7, which can be compared with the errors that occur starting from about 250 pixels in fig. 6. For example, 3 pixel columns 160 also having high accuracy can also be used. In the y direction, too, even in the case of a very small number of pixels or of pixel rows 158, very small errors can already be recorded, which can likewise be compared with the errors which occur in fig. 4 only starting from 200 or 250 pixels. So that for example an optical sensor 144 with 30 macropixels 146 or 30 pixel rows 158 in the y-direction can be employed prominently, as can be gathered from fig. 5. Detailed analysis shows in particular that an optical sensor 144 with 32 pixel rows 158 and 7 pixel columns 160, i.e. with a pixel size of 30 μm × 120 μm, is already sufficient to enable good analysis.

In this case, it can also be mentioned in particular that each pixel 146 typically requires a wiring with at least 3 transistors each, due to the high requirements for the measurement accuracy of photometry, for example in the case of the usual CMOS technology. Thus, on a conventional sensor 144, for example a CMOS chip, the ratio of the photo-sensitive area to the total area for each pixel (including electronics), the so-called fill factor, decreases as the size of the pixel 146 decreases. In the case of common CMOS chips, such as the one shown in fig. 2A, the fill factor is typically only between 10% and 30%. With the proposed macropixel 146, the fill factor rises again to more than 80% in an estimated manner, so that the signal gain is higher and thus the reliability, in particular the signal-to-noise ratio and/or the current requirement, is made more beneficial by the possibility of reducing the optical power of the light source 140 with the same signal quality.

As described above, the analysis region 136 may be automatically identified. In this case, the evaluation region 136 is determined both in the x direction and in the y direction or only in one of these directions. It is particularly advantageous to determine the analysis region 136 at least in the y direction within the image region 148, i.e. perpendicularly to the capillary 116 or the image thereof. The vertical position of the capillary 116 or the evaluation image area 150 can be recognized here in particular by simple algorithms. The algorithm may be formed based on, among other things, the time difference of each pixel 146. Once two or more pixels 144 that are horizontally adjacent, such as in fig. 3A, experience the same variation, i.e., the same variation (except for a predetermined tolerance range of, for example, 5% or less), then it may be inferred that these pixels 146 are disposed within the analysis image area 150. In the case of 32 pixel rows 158 and image segments of, for example, 1mm and 1:1 imaging (which is a preferred solution), the above-mentioned capillary width of 120 μm corresponds, for example, to exactly 4 pixel heights, so that within the analysis image region 150, i.e. the imaging of the capillary 116, there is always at least one or even practically at least two pixel rows 158, and so that discoloration which is independent of, for example, edge effects of the capillary 116 which can be pressed onto the test field 122 can be measured.

According to the invention, an early detection of the capillary 116 and/or the evaluation image region 150 can optionally also be carried out by a change in the detection side 134 that can be detected, for example by a color change and/or shading of the detection side 134. The evaluation image region 150 can therefore already be deduced from the initial discoloration before the complete conclusion of the identification reaction. More precise analysis has shown that when the detection geometry of the detector 138 is designed such that, as described above, not only the test field 122 or a portion of the test field with its capillary 116 located above it is measured, but additionally the strip which is narrower at the edges detects the actual capillary 116 without the test field 122, the capillary 116 can be identified very early, i.e. also optionally before the actual contact between the sample or capillary 116 and the test field 122. This has already been described above with reference to fig. 1. Such a region in which imaging 154 of the capillary 116 outside the test field 122 can be identified is shown in fig. 2A and 3A. The capillary 116 can be determined very simply and reliably in these images. If imaging 154 of the capillary 116 is detected, in this way, the region to be expected to change color, for example pixel row 158 and thus analysis image region 150, can be identified or determined by extrapolation to the right in fig. 3A. The advantage in this case is that the null values in the evaluation image region 150 can be measured before the immersion without intermediate storage of the data. Without this simple capillary detection, a complete empty image would generally first have to be stored in the middle, but in the case of macropixels, for example, only 32 × 7=224 pixels 146 or their information would still be included, so that the corresponding row from the empty image can be used for determining the empty value at a later time, i.e., precisely when identifying the capillary position.

In addition, the apparatus 110 may also be set up to characterize the transport of the sample from the microsampler 112 onto the test element 120 as described above. In particular, the characterization can be designed such that a correct sample transport is distinguished from transport errors or filling errors. This is shown in fig. 8A to 8C. Fig. 8A shows a correct filling of the capillary 116 followed by a correct transport to the analysis region 136, while fig. 8B shows a situation in which the capillary 116 is not completely filled and/or in which the sample is not completely transported from the capillary 116 onto the sample application region 130, i.e. the wetting is insufficient. While figure 8C shows a situation in which flooding, i.e. over-wetting or overflow, occurs.

This identification of errors can be carried out, for example, by means of a simple logical query in the context of the proposed device 110 with macro-pixels 146, which are easily implementable in terms of manufacturing technology. So that for example a logical query can be performed: whether all pixels 146 within a pixel row 158 have the same gray value or the same signal, for example, within a narrow error tolerance of less than 5%. In this way, an insufficient wetting can be identified from fig. 8B. Furthermore, to identify an overflow according to fig. 8C, it is possible to query: for, for example, 10 pixel rows 158 above the capillary 116 or its imaging on the optical sensor 144 and/or at other predetermined offsets in the imaging, whether different gray values or different signals are generated after wetting. This is not the case in the case shown in fig. 8C, for example. If no deviations are identified, an overflow according to fig. 8C can then be inferred therefrom. In principle, however, other algorithms for detecting wetting errors can also be used.

List of reference numerals

110 apparatus for identifying an analyte

112 micro sampler

114 lancet element

116 capillary tube

118 drive device

120 test element

122 test field

124 authentication layer

126 separating layers

128 sample application side

130 sample application area

132 proximity device

134 detection side

136 analysis area

138 probe

140 light source

142 optical device

144 optical sensor

146 pixels

148 image area

150 analysing an image area

152 imaging of lancet elements

154 capillary imaging

156 analytical equipment

158 pixel row

160 pixel column

162 probe assembly

164 deflection device

Claims (42)

1. A device (110) for identifying at least one analyte in a body fluid, comprising at least one test element (120) having at least one two-dimensional analysis region (136), and further comprising at least one spatially resolved optical detector (138) having a plurality of pixels (146), wherein the detector (138) is designed to image at least a part of the test element (120) onto an image region (148), wherein at least a part of the analysis region (136) is imaged onto an analysis image region (150), wherein the detector (138) is adapted to the test element (120) such that a predetermined minimum number of pixels (146) is provided for each dimension within the analysis image region (150), wherein the pixels (146) are arranged in a matrix arrangement, wherein the matrix arrangement has pixel rows (158) and at least one pixel column (160), wherein the pixel rows (158) are arranged substantially parallel to the longitudinal direction of at least one of the analysis region (136) and the analysis image region (150), wherein the device (110) comprises at least one lancet element (114) having at least one capillary (116), wherein the detector (138) has a longitudinal side and a lateral side, wherein the longitudinal side is oriented parallel to the capillary (116) of the device (110), and wherein the lateral side is arranged perpendicular to the capillary (116), wherein the detector (138) has at least 3 pixel rows (158) in the direction of the lateral side, wherein the detector (138) furthermore has at least 1 pixel column (160) in the direction of the longitudinal side.

2. The device (110) according to claim 1, wherein the analysis region (136) is part of a test element (120), wherein the device (110) is designed such that a body fluid is supplied to the test element (120) for the purpose of identifying the analyte.

3. Device (110) according to one of claims 1 to 2, wherein the device (110) is designed to receive a body fluid by means of a capillary (116), wherein the device (110) is furthermore designed to deliver the body fluid onto the test element (120) by bringing the capillary (116) close to the test element (120).

4. The device (110) according to claim 3, wherein the analysis region (136) is a region of the test element (120) in which an optically identifiable change occurs by the delivery of a body fluid onto the test element (120).

5. The apparatus (110) according to claim 3, wherein the capillary (116) has one or more of the following dimensions:

-a width of 50-200 μm;

-a length of at least 1 mm.

6. The device (110) according to one of claims 1 to 2, wherein the device (110) is set up to automatically recognize the analysis region (136).

7. The device (110) according to claim 6, wherein the device (110) is set up to identify the analysis region (136) according to a method selected from the group consisting of:

-a pattern recognition method, wherein the device (110) comprises at least one element selected from the group consisting of at least one lancet element (114) and at least one capillary (116), wherein the element is recognized in the pattern recognition method, wherein an extrapolation of the element onto the test element (120) is identified as an analysis area (136); and

-a signal change method, wherein a region of the test element (120) in which an optically detectable change occurs by the delivery of a body fluid onto the test element (120) is identified as an analysis region (136).

8. The device (110) according to one of claims 1-2, wherein the detector (138) has a total number of maximum 1000 pixels (146).

9. The device (110) according to one of claims 1 to 2, wherein at least 3 pixels (146) are arranged in the analysis region (136).

10. The device (110) according to one of claims 1 to 2, wherein the analysis region (136) has a longitudinal side and a broadside, wherein the detector (138) is configured such that at least 3 pixel rows (158) are arranged in the direction of the broadside within the analysis region (136), and wherein the detector (138) is further configured such that at least 1 pixel column (160) is arranged in the direction of the longitudinal side.

11. The device (110) according to one of claims 1-2, wherein the pixels (146) have an elongated pixel geometry, wherein the analysis region (136) has a longitudinal side and a lateral side, wherein the pixels (146) have a length in the direction of the longitudinal direction, and wherein the pixels (146) have a width in the direction of the lateral side, wherein the length exceeds the width.

12. The device (110) according to one of claims 1 to 2, wherein the detector (138) has a spatially resolving optical arrangement (142), wherein the spatially resolving optical arrangement (142) is designed to image the evaluation region (136) onto the evaluation image region (150) with a magnification of 3:1 to 0.5: 1.

13. Device (110) according to one of claims 1 to 2, wherein the device (110) is designed to characterize the wetting of the test element (120) with the body fluid, wherein the device (110) is designed to carry out the characterization by comparing a plurality of pixels (146) in at least one dimension.

14. Device (110) according to one of claims 1 to 2, wherein the device (110) is set up to recognize a null value, wherein the null value is an optical property of at least one of the image area (148) and the analysis image area (150) without wetting the test element (120) with body fluid, wherein the device (110) is set up to determine the null value according to a method selected from the group consisting of:

-recording a temporal image sequence, wherein an analysis region (136) is determined, wherein at least one pixel (146) arranged within the analysis region (136) is identified, and a starting value of the pixel (146) is determined from the temporal image sequence and used as a null value;

-storing start values of pixels (146) of the image area (148), determining the analysis area (136) from a temporal image sequence of pixels (146), discarding pixels (146) outside the analysis area (136), and using at least one start value of a pixel (146) within the analysis area (136) as a null value; and

-determining an analysis region (136), using at least one pixel (146) outside the analysis region (136) as a null value.

15. The device (110) according to claim 5, wherein the capillary (116) has a width of 90-150 μm.

16. The device (110) according to claim 5, wherein the capillary (116) has a width of 120 μm.

17. The apparatus (110) according to claim 5, wherein the capillary tube (116) has a length of at least 2 mm.

18. The apparatus (110) according to claim 5, wherein the capillary tube (116) has a length of 2 to 4 mm.

19. The apparatus (110) according to claim 8, wherein the detector (138) has a total number of maximum 500 pixels (146).

20. The device (110) according to claim 8, wherein the detector (138) has a total number of maximum 256 pixels (146).

21. The device (110) according to claim 1, wherein the detector (138) has a maximum of 100 pixel rows (158) in the direction of the broadside.

22. The device (110) according to claim 1, wherein the detector (138) has 20 to 50 pixel rows (158) in the direction of the broadside.

23. The device (110) according to claim 1, wherein the detector (138) has 2 to 20 pixel columns (160) in the direction of the longitudinal sides.

24. The device (110) according to claim 1, wherein the detector (138) has 5 to 10 pixel columns (160) in the direction of the longitudinal sides.

25. The device (110) according to claim 1, wherein the detector (138) has 7 pixel columns (160) in the direction of the longitudinal sides.

26. The device (110) according to claim 9, wherein 5 to 30 pixels (146) are arranged in the analysis region (136).

27. The device (110) according to claim 9, wherein 10 pixels (146) are arranged in the analysis region (136).

28. The device (110) according to claim 10, wherein the detector (138) is set up such that 3 to 10 pixel rows (158) are arranged in the direction of the broadside within the analysis region (136).

29. The device (110) according to claim 10, wherein the detector (138) is set up such that at least 3 pixel columns (160) are arranged in the direction of the longitudinal sides.

30. The device (110) according to claim 10, wherein the detector (138) is set up such that 3 to 10 pixel columns (160) are arranged in the direction of the longitudinal sides.

31. The device (110) according to claim 10, wherein the detector (138) is set up such that 7 pixel columns (160) are arranged in the direction of the longitudinal sides.

32. The apparatus (110) of claim 11, wherein the length is at least 1.3 times the width.

33. The apparatus (110) of claim 11, wherein the length is at least 1.7 times the width.

34. The apparatus (110) of claim 11, wherein the length is at least 2 times the width.

35. The apparatus (110) of claim 11, wherein the length is at least 2.3 times the width.

36. The apparatus (110) according to claim 12, wherein the spatially resolving optical arrangement (142) is designed to image the evaluation region (136) onto the evaluation image region (150) with a magnification of 2:1 to 0.8: 1.

37. The apparatus (110) according to claim 12, wherein the spatially resolving optical arrangement (142) is designed to image the evaluation region (136) onto the evaluation image region (150) with a magnification of 1.1:1 to 0.9: 1.

38. The apparatus (110) according to claim 12, wherein the spatially resolving optical arrangement (142) is designed to image the evaluation region (136) onto the evaluation image region (150) with a magnification of 1: 1.

39. The device (110) according to claim 13, wherein the device (110) is designed to evaluate the wetting of the test element (120) with a body fluid.

40. The device (110) according to claim 13, wherein the device (110) is set up to carry out the characterization by comparing neighboring pixels (146) of a pixel row (158) oriented parallel to the analysis region (136).

41. A method for detecting an analysis region (136) of a test element (120) for detecting at least one analyte in a body fluid, wherein at least one lancet element (114) having at least one capillary (116) is used, wherein the body fluid received in the capillary (116) is transported onto the test element (120), wherein at least a part of the test element (120) is imaged onto an image region (148) by means of at least one spatially resolved optical detector (138), wherein the detector (138) has a longitudinal side and a lateral side, wherein the longitudinal side is oriented parallel to the capillary (116), and wherein the lateral side is arranged perpendicular to the capillary (116), wherein the detector (138) has at least 3 pixel rows (158) in the direction of the lateral side, wherein the detector (138) furthermore has at least 1 pixel column (160) in the direction of the longitudinal side, wherein at least a part of an analysis region (136) of the test element (120) is imaged onto an analysis image region (150), wherein the detector (138) is adapted to the test element (120) such that a predetermined minimum number of pixels (146) is provided for each dimension within the analysis image region (150), wherein the pixels (146) are arranged in a two-dimensional matrix arrangement, wherein the matrix arrangement has pixel rows (158) and pixel columns (160), wherein the pixel rows (158) are arranged substantially parallel to a longitudinal direction of at least one of the analysis region (136) and the analysis image region (150), wherein the analysis region (136) is automatically identified according to a method selected from the group consisting of:

-a pattern recognition method, wherein in the pattern recognition method at least one element selected from the group consisting of a lancet element (114) and a capillary (116) is recognized, wherein an extrapolation of the element onto the test element (120) is identified as an analysis area (136); and

-a signal change method, wherein a region of the test element (120) in which an optically detectable change occurs by the delivery of a body fluid onto the test element (120) is identified as an analysis region (136).

42. Method according to claim 41, wherein a device (110) according to one of claims 1-2 is used.