Patent Application
20210164928
The present patent application relates to a device and a method for analysing a substance, taking particular, if not exclusive, consideration of detection methods that make use of a piezo-effect. The device described here and the method described here can be used, for example, for the analysis of animal or human tissue, bodily fluids and in one embodiment, for measuring glucose or blood sugar.
Known methods for analysing a substance, in particular for measuring blood sugar, are described, for example, in the following documents:
The object of the invention is to specify a device and a method which can be used to analyse a substance, in particular an animal or human tissue or a component or ingredient of the tissue, in a particularly simple and cost-effective manner. One aspect of the invention also involves the achievement of a small size of the device.
This object is achieved, inter alia, by a device having the features in accordance with claim 1. Embodiments of the device are specified in sub-claims. In addition, the invention relates to a method in accordance with the independent method claim with corresponding embodiments according to the sub-claim(s) dependent thereon.
Reference is made to the German patent specification DE 10 2014 108 424 B3, the content of which is specifically referred to here and on which the content of this application is based; the entire content of the German patent specification DE 10 2014 108 424 B3 is therefore to be regarded through this explicit reference as also being part of the disclosure content of this application (“incorporation by reference” for all details of the disclosure therein). In particular, this reference relates to all of the features mentioned in the granted patent claims. In addition, the reference also relates in particular to details of the excitation light beam mentioned there, for example to the numerical values of pulse frequencies and wavelengths (wavelength ranges) mentioned there, and also to the details of the measurement of glucose content in the interstitial fluid.
In addition to the subject matter of the claims and exemplary embodiments explicitly mentioned at the time of filing, this patent application also refers to other aspects listed at the end of the present description. These aspects can be combined individually or in groups, in each case with features of the claims cited at the time of filing. These aspects also constitute independent inventions, whether taken in isolation or combined with one another or with the claimed subject matter of this application. The applicant reserves the right to make these inventions the subject of claims at a later date. This may occur as part of this application or within the context of subsequent sub-applications, continuation applications (U.S.), continuation-in-part applications (U.S.), or follow-up applications that claim priority of this application.
In connection with the following statements the terms “light” or “laser light” mean electromagnetic waves or electromagnetic radiation in the visible range, the near, medium and far infrared range, and in the UV range.
One possible aspect of the method presented here is the focusing of the measurement of the response signal on selected depth ranges below the (spacing intervals of the) material surface. The parameter d has the greatest influence on the depth range measured using the method. It is defined as d=√(D/(π*f)), where D is the thermal diffusivity of the sample (e.g. here, skin) and f is the modulation frequency of the excitation beam. Literature on the thermal diffusivity of skin:
In order to eliminate response signals from the topmost layers of the substance for the purpose of improving the quality of the measurement, in one embodiment changes in the measurement values compared to previous measurements can be used if the measurements in the topmost layers change to a lesser extent or more slowly compared to other, deeper layers. This can be the case in an embodiment in measurements on human skin, where the topmost layers of the skin are in practice not subject to an exchange with the lower layers and therefore physiological parameters do not vary very much. The temporal derivative of measured values can also be used for response signals to exclude the signals from the topmost skin layers. In this way, the measurement or at least the evaluation can be limited to or focused on the interstitial fluid in the skin.
For this purpose, a measurement can include the acquisition of response signals for spectra that are acquired multiple times with different modulation frequencies of the excitation light source, combining the results for different modulation frequencies, for example by differentiating or forming the quotient of the measurement values of response signals for the same wavelengths and different modulation sequences. To perform such a measurement a device with an appropriate control device for the excitation beam and an evaluation device for the spectra of response signals should also be provided.
The following text first deals with the subject matter of the claims listed at the time of filing.
The object is achieved with the features of the invention according to patent claim 1 by a device for analysing a substance having:
In this case, the specified properties of the region can be, in particular, properties of the material of the region.
The preferred approach is to use such a device to analyse a substance in which the electrical property, which changes depending on the pressure or temperature,
wherein the device also comprises an electrical contact device which comprises the said electrodes, which are electrically conductively connected to the detection region of the measuring body for detecting the electrical resistance and/or the piezoelectric signals.
In the case of the detection of piezoelectric signals, the electrical property that varies as a function of the pressure or temperature can be referred to as “polarization”. Other electrical properties that vary as a function of pressure and/or temperature and can be exploited for the purposes of the invention are equally possible, such as the dielectric constant.
In this context, the excitation beam shall be understood to mean a light beam, a laser beam or even a multiplicity of substantially parallel laser beams which are emitted sequentially or simultaneously by the excitation beam source, in particular a laser device or individual laser elements of an excitation beam source, in particular a laser device, to the substance to be analysed. The coherence of the excitation beam is not required, so that even non-coherent or only partially coherent radiation can also be used. In this respect, in addition to laser devices other light sources, such as LEDs/semiconductor diodes or others, which allow the selection of wavelengths or wavelength ranges, can also be used as beam sources. When using a more broadband light source for the excitation beam, wavelength filters, such as tuneable filters, can also be used to selectively generate excitation beams for different wavelengths or wavelength ranges.
For different applications, it may be useful to select an excitation beam in the mid-infrared range. For example, it is also possible to select as the light source a laser which operates using the OPA (optical parametric amplification) or NOPA (non-collinear optical parametric amplification) or OPG (optical parametric generation) methods, and allows the generation of different wavelengths using such a method.
It is also possible to use a so-called optical parametric oscillator (OPO) in an optical resonator that has an optically nonlinear crystal, for example beta-barium borate. Due to the non-linear three-wave interaction, the crystal generates, inter alia, radiation of a transformed wavelength from the injected pump wave. In this way, as with the above-mentioned OPA/NOPA methods or arrangements, for example, from radiation in the near infrared wavelength range a radiation in the mid-infrared range can be obtained, which can be used for the spectroscopic procedures described in this application.
The detection region of the measuring body refers to a spatial region or section of the measuring body that exhibits the above properties by having a temperature- or pressure-dependent specific electrical resistance and/or by generating electrical, in particular piezoelectric, voltage signals under the application of pressure or temperature changes. This is achieved by the material selection and optionally also by further configuration, for example processing, of the material of which the detection region consists.
It may be the case that the regions of the measuring body adjacent to the detection region differ from the material of the detection region in this respect, in particular in terms of the material of which they consist. However, it may also be provided that the regions of the measuring body adjacent to the detection region, as well as the detection region itself, have a temperature- or pressure-dependent specific electrical resistance and/or generate electrical, in particular piezoelectric, voltage signals in the event of pressure or temperature changes. The detection region can be separated from other regions of the measuring body by electrodes and/or separation regions, wherein the separation regions can be made of a material that is considerably softer, more elastic or more flexible than the material of the detection region, so that the material of the separation regions conducts a pressure or temperature increase less well than the material of the detection region.
In particular, the measuring body may also be formed by a first part and a second part of the measuring body implemented as a sensor layer, wherein the sensor layer may have a different composition than the first part of the measuring body and, in particular, can be at least partially composed of a piezoelectric material. The sensor layer can be applied, in particular adhesively bonded, to the first part of the measuring body in the region of the measuring surface. The sensor layer can also be made of a material that has a greater dependence of the refractive index on pressure or temperature than the first part of the measuring body. The first part of the measuring body can be transparent to the excitation beam/excitation beams, and may consist of silicon, for example. If the sensor layer for the excitation beam(s) is not transparent or is less transparent than the first part of the measuring body, then the sensor layer can have a slot to allow the passage of the excitation beam(s). In the slot, for example, a lens may also be provided to focus the excitation beam(s) onto a point in the substance to be analysed.
An optical waveguide that ends in, on or in front of, the measuring surface may also be provided inside the measuring body to guide the excitation beam(s). The optical waveguide can be integrated into a substrate of the measuring body and manufactured in SOI technology. The optical waveguide can pass through the detection region or can also be guided past it. The optical waveguide can be composed of a material that has no or only a minimal dependence of the refractive index on a mechanical pressure, in order to minimize the influence of piezoelectric pressure generation on the excitation beam. The optical waveguide material can also be mechanically spaced apart from the piezoelectric material provided in the detection region or be mechanically decoupled from it by a flexible, in particular elastic material layer or a gas layer.
The object is alternatively achieved with the features of the invention according to patent claim 2 by a device for analysing a substance having:
The excitation source, in particular the laser device, sends an excitation beam into the substance to be analysed, which, for example, sweeps through certain wave numbers/wavelengths or emits a multiplicity of excitation beams with specific fixed wave numbers, sequentially or simultaneously, both in the case of the subject matter of claim 1 and in the case of the subject matter of claim 2. In this case, the wavelength selection can also be carried out later by means of filters in the light path behind the excitation beam source.
When using an array, the laser array may have simple fixed-wavelength lasers. At certain wavelengths, the beam is absorbed depending on of the material of the substance to be analysed, so that energy is released which is transported at least partly in the form of a thermal wave to the surface of the material, and then into the measuring body and there also to the detection region. The excitation beam is advantageously intensity-modulated, wherein the use of different, even a plurality of, modulation sequences is possible. It is also possible to form laser pulses that contain a multiplicity of modulation frequencies in the Fourier-transform domain. The pulsed heating of the material in the detection region causes a change in resistance and/or an electrical voltage signal to be generated and/or other parameter changes, such as a change in the refractive index. By means of the electrodes of the contact device and their supply cables the first two electrical phenomena mentioned can be connected to a measuring device that measures voltages and/or electrical resistances and which evaluates these changes and assigns them a temperature increase and/or an absorption intensity of the excitation beam in the substance. The absorption intensity can thus be measured as an absorption spectrum as a function of the wave numbers/frequencies of the excitation beam that are traversed.
The detection region is advantageously located adjacent to the measuring surface, i.e. it is arranged either directly adjacent to it or at a distance from the measuring surface, wherein this distance should be small (for example, less than 10 microns or less than 100 microns, in each case measured at the smallest distance between the detection region and the measuring surface). For example, the detection device may also comprise a plate or a body that is joined together with another part of the measuring body as part of the measuring body, or else a coating of a part of the measuring body in the region of the measuring surface.
In particular in the case of a pressure change being detected, for example when using a piezo-sensitive material/piezo-sensor, the detection device can also be used to detect a response signal in the form of a sound wave, which is generated by the absorption of the excitation beam in the substance to be analysed and travels to the measuring surface and to the detection region at a known speed (in human tissue, approx. 1500 m/s). By means of an evaluation device connected to a modulation device for the excitation beam, due to the good temporal resolution of the measurement of the response signals, a phase shift between the modulation of the excitation beam and the response signal can be measured, thereby determining the depth in the tissue in which the absorption took place. Since the signals are often a superposition of different response signals from different tissue layers, different measurements can be carried out at different modulation frequencies and the response signals at different modulation frequencies can be correlated to cancel out and eliminate, in particular, signals from upper tissue layers, as these are particularly susceptible to errors due to contamination by dirt and dead skin cells.
It should be noted that in the present disclosure, the same term “response signal” is used in several ways. On the one hand, it can describe the physical response to the excitation by the excitation beam, i.e. such as a sound wave, a temperature increase or the like. On the other hand, it can also refer to a (typically electrical) signal that represents this physical response, i.e. such as a voltage or a current flow measured by the electrodes. For the sake of simplicity and coherence of the presentation, the same term “response signal” is used throughout, it being clear from the context without further explanation whether it refers to the physical response (for example, a pressure wave), a physical consequence of that physical response (for example, a compression of a piezoelectric material), or the associated measurement signal (for example, the voltage generated by the piezoelectric material).
Instead of different modulation frequencies, signals with a steep rise (ideally so-called Dirac pulses) can also be formed, which represent a mixture of many modulation frequencies and allow an analysis of different modulation frequencies by means of a Fourier analysis.
An implementation of the device may provide that at least two electrodes, in particular along a surface normal of the measuring surface, are located one behind another at different distances from the measuring surface, or are spaced apart from each other on different sides of the detection region in a direction perpendicular to the surface normal.
The measuring surface can be flat or curved. In the curved case, the surface normal is understood to mean a normal to the measuring surface at a point, in particular at a location where the excitation beam passes through the measuring surface.
At least two electrodes should be arranged such that they completely or partially surround the detection region, or that the detection region is located completely or partially between the two electrodes. The electrodes can be distributed in different geometric locations on different sides of the detection region, in particular distributed around the detection region.
A further implementation of the device can provide for the excitation beam to pass through the measuring body, in particular through the detection region, wherein an optical waveguide is arranged in or on the measuring body, in particular to guide the excitation beam, and also in particular, the optical waveguide is integrated into the measuring body.
The excitation beam thus travels through the measuring body, for example directly through the material of the measuring body or through an optical waveguide arranged therein, and through the detection region or past the detection region to the point of the substance to be analysed, which absorbs the excitation radiation and emits the heat radiation.
An optical waveguide integrated into the material of the measuring body and/or into the material of the detection region can be used as an optical waveguide for guiding the excitation beam. Such optical waveguides can be applied, for example, by an epitaxial method or by selective doping of wafer material in or onto a wafer. However, a fibre-optic cable can be inserted into the measuring body or else at least partially applied to this on the outside.
It may also be provided that the excitation beam passes through the measuring surface in a region which is directly adjacent to and/or adjoins the detection region.
A further implementation of the device may provide for a modulation device to modulate the intensity of the excitation beam. In this case, different types of modulation are possible, using a mechanical chopper as well as using a controllable shutter or deflection mirror device, or a body/layer the transmission of which is controllable. In addition, modulation can also be achieved directly by the activation of the excitation light source/laser light source. A measurement may then include the acquisition of spectra at one or more modulation frequencies, wherein measurements at different modulation frequencies can be correlated with each other to obtain depth information and/or eliminate measurement data from specific depth ranges of the sample/substance to be analysed. In particular, measurement data originating from the surface of the substance can therefore be eliminated. These are measurement data and thermal waves that result from the absorption of the excitation light beam at the surface of the substance and which may be caused by impurities or anomalies on the surface of the substance to be analysed. One example of this, in the analysis of the skin of a patient, are the uppermost layers which consist partly of dead cells, which have an uninformative composition and/or provide false information. This is particularly the case if biologically active substances, active metabolism or metabolic products or similar are to be detected in the skin.
In the following, various geometric electrode configurations are presented and their advantages are discussed.
To this end it can be provided, for example, that at least two, in particular at least three or four, more particularly at least 6, more particularly at least 8 electrodes are arranged one behind another at different distances from the measuring surface, or spaced apart from each other in a direction perpendicular to a surface normal of the measuring surface.
At least one or more of the electrodes is/are arranged on each side of the detection region. This means that different pairs of electrodes are available that can be used to measure an electrical resistance or voltage.
An electronic device is provided for this purpose, which is connected to a plurality of or all electrodes via supply cables. The electronic device has a control device and, in particular, an evaluation device that causes/cause the acquisition and evaluation of electrical resistances or voltages between different selectable electrodes sequentially or simultaneously.
To this end, different pairs or all pairs of electrodes can be tentatively selected. The selected electrodes of a pair of electrodes for a tentative measurement should each have at least part of the detection region between them. Measurements from individual electrode pairs can be compared with each other and evaluated. Evaluation parameters can be, for example, the signal strength or the magnitude of the signal changes, or a signal-to-noise ratio or other parameter. In addition to the integration of the electrodes into the measuring body, another case that should also be comprised is that in which a plurality of electrodes are applied in a staggered pattern over the surface of the measuring body/measuring surface by adhesion, or have been incorporated or evaporated thereon.
It may also be provided that at least two, in particular at least three or four, in particular at least 6, in particular at least 8 electrodes are arranged in the direction of a surface normal of the measuring surface, or perpendicular to it, or in a direction between 0 and 90 degrees to the surface normal, one behind another at different distances from the detection region, in particular at different distances from the centre of the detection region. The detection region in this case can be defined, for example, by a spatial region of the measuring body consisting of a particular material. The detection region can also be defined by the overall arrangement as a region of the measuring body located above the entry point of the excitation beam into the material to be analysed.
In addition, the detection region can also be defined by the sum of the spatial points at which an electrical signal is potentially detectable by the available electrodes.
A further implementation can provide that at least two, in particular at least three or four, more particularly at least 6, more particularly at least 8 electrodes are arranged in an annular or spherical shell-shaped region around the detection region and at least partially opposite one another on different sides of the detection region, wherein different electrodes have essentially the same distance from the centre of the detection region or different distances from the centre of the detection region. This is intended to also include the case of electrodes distributed over the surface of the measuring body.
By means of the above electrode distribution and, for example, measuring at multiple pairs of electrodes, the electrode pair(s) that is or are most suitable for measurement can be selected and used.
As a suitable measure of the measurement quality when selecting the electrode pairs, either a signal strength or a signal dynamic range or a noise level or a signal/noise ratio can be used, for example.
It may also be provided that one or more or all of the electrodes of the contact device are designed to be disc-shaped or plate-shaped, annular, annular disc-shaped, in the form of a rectangular or polygonal frame with an opening, cap-shaped or rod-shaped.
An implementation of the device can provide that one or more or all of the electrodes of the contact device are arranged on one surface of the measuring body or the detector device and, in particular, are attached by means of a joining method, in particular by adhesive bonding or welding. They can also be applied by vapour deposition or coating. The measuring body can be made of a single homogeneous material, or in the detection region it may consist of a special material that differs from the material of the other regions of the measuring body.
The electrodes are usually made of metal for all embodiments, in any event from a material with good electrical conductivity. They can also be made of an electrically conductive plastic or a conductively filled material.
A further implementation of the device can provide that one or more or all of the electrodes of the contact device are arranged on the inner side or the outer side of the measuring body in one or more slots, such as bored holes, recesses or grooves of the measuring body, in particular being inserted, cast into, incorporated by injection moulding or by an additive manufacturing method (3D printing). These variants allow the insertion of electrodes into a measuring body in a technically simple way.
Electrodes can also be created in the measuring body by making regions of the material of the measuring body electrically conductive by irradiation or by bombardment with particles. This is possible, for example, in plastics in which high-energy radiation partially destroys carbon molecules and forms carbon accumulations that are conductive.
In addition, it can be provided that the measuring body is formed as a flat body, in particular as a plane-parallel body in the form of a plate, wherein in particular the thickness perpendicular to the measuring surface is less than 50% of the smallest extension of the measuring body in a direction extending in the measuring surface, in particular, less than 25%, more particularly less than 10%.
This design variant of the measuring body can be used for different detection methods of the thermal response signals and is not limited in principle to the detection method based on a piezo-effect. It can also be used in the measuring method with a measurement beam reflected at the measuring surface and a detector for detecting its deflection, and allows a significant reduction in the dimensions of the measuring body in the direction perpendicular to the measuring surface. Regardless of the measurement method, for example by using the piezo-effect or by measuring the deflection of a reflected beam, the measuring body formed as a flat body can have a layer in the region of the measuring surface, which layer in the case of the piezo-measurement method can consist of a piezoelectric material and in the case of detection by measuring the deflection of a reflected measurement beam, of a material in which the refractive index changes more strongly as a function of temperature than in the material of the other regions of the measuring body.
A further implementation of the device may provide that the measuring body has a mirror device for reflecting the excitation beam irradiated by the excitation beam source, in particular the laser device, or carries such a mirror device.
In the case of a very flat measuring body, the excitation beam can be irradiated from the flat side of the measuring body. The excitation beam then propagates from the excitation beam source, initially essentially parallel to the measuring surface within the measuring body or parallel to the boundary surfaces of the measuring body, and is then deflected towards the measuring surface.
Instead of reflecting the excitation beam, it can also be diffracted towards the measuring surface by means of suitable material design of the measuring body. The flat body can also have optical focussing elements for the excitation beam or be connected to such elements, for example, one or more lenses.
It can also be provided that the excitation beam is irradiated into the measuring body parallel to the measuring surface or at an angle of less than 30 degrees, in particular less than 20 degrees, more particularly less than 10 degrees or less than 5 degrees to the measuring surface, and that the excitation beam is diverted or deflected towards the measuring surface and passes through it.
Integrated into or directly connected to the measuring body, especially when a flat body is used, a focussing device can be provided, e.g. in the form of a diffracting element/lens, which focusses the excitation beam onto the measuring surface and the substance surface of the substance to be analysed.
It may also be provided that the excitation beam passes through the material of the measuring body.
It may also be provided that the measuring body has at least one slot, in particular a bored hole, which is penetrated by the excitation beam, wherein the slot and/or bored hole extends, in particular, from the measuring surface into the measuring body, or wherein the recess or slot and/or bored hole passes through the entire measuring body from a boundary surface opposite the measuring surface of the measuring body to reach the measuring surface. The recess can extend as a channel or bored hole with its longitudinal axis also at least partially in the direction of the excitation beam parallel to the measuring surface. If a sensor layer is provided, the slot, recess and/or bored hole can extend into the measuring body from the boundary surface of the sensor layer opposite the measuring surface, so that the sensor layer itself is not penetrated by the slot.
In this case, the measuring body can have a hollow channel/bored hole/recess for the excitation beam, so that the excitation beam does not penetrate the material of the measuring body, even though the excitation beam passes through the measuring body and the measuring surface to the substance to be analysed.
It may also be provided that the measuring body has a first part that has a continuous channel for the excitation beam, and that the measuring body on its underside on the first part has a sensor layer, which is either continuous without a recess or with a continuation of the recess of the first part. If the sensor layer is thinner than 200 microns, in particular thinner than 100 microns, the excitation beam can pass through it—even if it is an infrared beam—without too much absorption, and a recess, bored hole or channel in the sensor layer is not necessary. The sensor layer of the measuring body can consist of a material that has piezoelectric properties and forms a detection region according to the invention. The sensor layer can also consist of a material in which a change in temperature and/or pressure causes a change in the refractive index, so that this change can also be detected as a response signal, for example by detecting the angle of reflection of a detection beam that is reflected in the sensor layer. For example, the first part of the measuring body can then consist of a material such as quartz or sapphire, which is transmissive in the visible range and for a detection beam, but is less transmissive or opaque in the infrared spectral range.
A further implementation of the device can provide that in or on the measuring body, in particular in the detection device, or directly adjacent to and in thermal contact with it, at least one heat sink is arranged in the form of a body, the specific thermal capacity and/or specific thermal conductivity of which is greater than the specific thermal capacity and/or specific thermal conductivity of the material from which the measuring body is composed, or which is designed as a Peltier element.
Instead of a heat sink in the form of a body, the specific thermal capacity and/or thermal conductivity of which is greater than the specific thermal capacity and/or specific thermal conductivity of the material from which the measuring body is made, an active or passive cooling element, in particular a Peltier cooling element for adjusting a temperature gradient, may also be provided. The temperature gradient or the absolute temperature can also be controlled by means of the Peltier element using a closed-loop control device.
With heat sinks of this kind, for example in the form of metal or crystal bodies or actively operated Peltier elements, the appropriate thermal properties of the measuring body with regard to the thermal diffusivity can be achieved, which are necessary to ensure that both the temperature change builds up sufficiently in the detection region with the modulation frequency, and that the heat is transported away sufficiently quickly. Of course, this depends primarily on the material of the measuring body/detection device, but it can be influenced by the appropriate addition of one or more heat sinks. For example, these can be at least partially arranged around the detection region or else be provided on one side of the detection region.
A further implementation of the device can provide that in or on the measuring body, in particular in the detection device or directly adjacent thereto and in thermal contact therewith, at least one thermal barrier is arranged in the form of a body, the specific thermal capacity and/or specific thermal conductivity of which is less than the specific thermal capacity and/or specific thermal conductivity of the material from which the measuring body is made.
With thermal barriers of this kind, alone or also in combination with heat sinks, the appropriate thermal properties of the measuring body with regard to the thermal diffusivity can be achieved, which are necessary to ensure that both the temperature change is built up sufficiently in the detection region with the modulation frequency, and that the heat is also transported away corresponding to the modulation frequency sufficiently quickly. This can be influenced by suitable addition of one or more thermal barriers. For example, these can be at least partially arranged around the detection region or else be provided on one side of the detection region. Thermal barriers can be implemented, for example, by thermally insulating plastic elements. For example, one or more heat sinks can be provided on the first side of the detection region and one or more thermal barriers on a second side of the detection region opposite the first, to generate a temperature gradient and to control the direction of the heat transport.
It may be provided that the detection device and/or the measuring body consists at least partially of a piezoelectric material, in particular a piezoelectric ceramic, in particular a PZT ceramic, more particularly a sintered ceramic, or a single-crystalline piezoelectric material, in particular quartz, tourmaline, lithium niobate, gallium orthophosphate, berlinite, Seignette salt, ferroelectrics such as barium titanate (BTO) or lead zirconate titanate, gallium phosphate or a lead-magnesium niobate, or zinc oxide (ZnO) or aluminium nitride as a thin-layer deposit or polarized polyvinyl fluoride.
The respective material should be as transparent as possible in the infrared frequency range, advantageously in the mid-infrared frequency range.
The above-mentioned piezoelectric materials can be provided as a thin layer on a measuring body and form the measuring surface. The layer thickness should then be less than 0.5 mm, in particular less than 300 microns, and/or have a recess or slot, such as a bored hole or a channel for the excitation beam. The remaining part of the measuring body may then not be piezoelectric and transparent to the excitation beam and/or have a recess for the excitation beam. This remaining part of the measuring body can act as a heat sink for the coating with a piezoelectric material, which means it can have a greater specific thermal capacity and/or thermal conductivity than the piezoelectric layer.
A further implementation of the device can provide that a piezoelectric element or a piezoelectric region of the measuring body can be connected as an actuator to a voltage source and depending on a controllable input voltage, forms a blockage for an excitation beam.
In this way, the material of the measuring body can also be used as an optical chopper for the excitation beam by changing the dielectric constant.
A method for operating a device according to the invention can provide that a modulated excitation beam is directed, in particular through the measuring body, onto the substance to be analysed and that signals from different electrode pairs of the contact device are acquired and evaluated simultaneously or sequentially, that it is firstly determined based on criteria which one or more of the pairs of electrodes delivers/deliver signals suitable for further processing, and that the signals from one or more selected electrode pairs are then used for measurement and evaluated, and that, in particular, a subsequent measurement is performed in which the signals of the selected electrode pair or pairs are acquired and evaluated.
Suitable signals can be selected, for example, based on the strength of the signals, the signal/noise ratio or the steepness with which the signals follow the modulation of the excitation beam. With the selection of the suitable electrodes, it is possible if applicable to detect and correct any misalignment of the substance to be analysed with respect to the measuring device, if e.g. the thermal wave does not reach the centre of the measuring region. In this case, differently distributed electrodes are selected for the current measurement.
During the measurement, the excitation beam is modified continuously or in steps with respect to the wave number/wavelength/frequency, or characteristic wavelength ranges are scanned. When using an array, an excitation beam can also be emitted simultaneously or sequentially through different elements of an array at different wavelengths or in different wavelength ranges.
In one implementation of the method it can also be provided that, after an initial test measurement, depending on the signals detected a misalignment of the device relative to the substance to be analysed is determined and indicated and, in particular, the user is requested to perform a re-alignment.
This method can even be used in parallel with another detection method, for example with a reflected detection beam, to detect and signal only misalignments of a finger on which a measurement is to be performed.
Misalignments can be detected, for example, by determining the signal strengths of different pairs of electrodes in an initial measurement in the form of a profile/vector and comparing this profile/vector with corresponding values from previous measurements or specified reference values. The specific profile can also be normalized to a signal strength. If the difference relative to a reference profile exceeds certain thresholds for certain elements of the profile or with regard to asymmetry, then a misalignment can be inferred.
In a further implementation of a method, it can also be provided that
also shown are
The device comprises an excitation transmission device 3 in the form of an excitation beam source, in particular a laser device for emitting one or more electromagnetic excitation beams, preferably in the form of excitation light beams with one or more excitation wavelengths, into a volume 5a that is located in the substance 5 underneath a first region of the surface of the substance. The excitation transmission device 3 is also briefly referred to hereafter as a laser device. The laser device can be a laser that is tuneable with respect to wavelength, in particular a tuneable quantum cascade laser; it is preferable, as explained further below, to use a light source strip or a light source array with at least two single emitters in the form of lasers, in particular semiconductor lasers with fixed wavelengths, or light-emitting semiconductor diodes, each of which emits a specified individual wavelength or light within a defined narrow wavelength range, including the possibility of using light sources combined simultaneously or sequentially with suitable filters and connected in series to isolate specific wavelengths or wavelength ranges.
If a plurality of individual emitters is combined, the individual excitation light beams can be injected into a light path jointly by means of a multiplexer, for example into a fibre-optic cable or an isolated channel or other light path in the optical medium. A collimator can also be provided to align the light beams emitted by different emitters as closely as possible parallel to each other and to combine them as much as possible into a single beam, both in the case of multiple beams of light emitted simultaneously and in the case of multiple beams of light emitted sequentially.
On the path of the excitation light, an optical element for focussing the excitation light can also be provided. This can be provided, for example, between the laser device and the measuring body, or on the measuring body itself where the excitation beam enters it, or also on the measuring body in the region where the excitation beam leaves the measuring body, for example in the region of the measuring surface, on the measuring surface, flush with the measuring surface or between the measuring surface and the detection device.
For example, the optical element can be machined from the material of the measuring body as a convex lens, or it can also consist of a different material from the material of the measuring body.
In addition, a device 9 is provided for the intensity modulation of the excitation beam(s)/excitation light beam(s), which is preferably formed by a modulation device for the excitation beam source, in particular laser device, in particular for its activation, and/or at least one controlled mirror arranged in the beam path and/or a layer, controllable with regard to its transparency and arranged in the beam path.
A thermal wave emitted after absorption of the excitation beam in the region 5a of the substance enters the measuring body where it can be detected in a detection region 4 by a detection device. This is carried out by detecting a local temperature increase or temperature change that follows the absorption very rapidly in time. Also, the reversal of the temperature change (decrease in temperature) after the end of an absorption phase (when the intensity of the excitation beam decreases as part of the modulation of the excitation beam) follows the intensity curve of the absorption intensity very quickly with a certain phase offset, which depends on the depth at which the excitation beam is absorbed in the substance.
Herein, the amplitude of the response signal depends on the wavelength of the excitation beam, the absorption properties of the sample, as well as the thermal properties, in particular the thermal diffusivity and thermal conductivity of the sample and of the measuring body/optical medium 1. In addition, the coupling of the thermal signal from the sample into the measuring body also plays a role.
In the exemplary embodiment shown, the detection device 4, 6 is formed as a region 4 of the measuring body 1, which at least partially or in some sections consists of a piezoelectric material, wherein the detection device 4, 6 also has electrodes 6a, 6b, 6c and 6d, which are arranged on respectively opposite sides of detection region 4. The electrodes 6a to 6d make an electrical contact with the material of the detection region 4 and are referred to jointly hereafter as “contact device” 6. In this way, a temperature or temperature change can be detected, depending on the material selection of the piezoelectric material, by a piezo-voltage generated between the electrodes, or by an electrical resistance or a change in resistance.
In the example of
An evaluation device 16 for analysing the substance, which is designed as an electronic device, in particular a digital processing device, for example as a microcontroller or processor or as a computer, is in electrical contact with the electrodes 6a, 6b, 6c and 6d of the contact device 6 via electrical cables 17, 18, evaluates the detected response signals and generates a glucose or blood sugar level indication (BSI) in one embodiment.
The evaluation device 16 is also electrically connected to the modulation device 9, so that the information about the frequency/wavelength of the excitation beam and in particular the frequency and/or phase of the modulation, is available in the evaluation unit 16 and can be taken into account in the evaluation. In this way, for example, the phase shift of the response signals relative to the modulation function of the excitation beam can be evaluated to obtain information about the depth in the substance, i.e. also the distance from the measuring surface 2 or the detection region 4, at which the response signal was generated. This allows information to be obtained about a depth profiling of the distribution of a detected substance, such as glucose, in the substance 5.
The information about the modulation of the excitation beam can be sent from the modulation device 9 to the evaluation device 16, but it may also be provided that the control device 16 directly controls the modulation. The evaluation device 16 can also have a lock-in amplifier for the evaluation, which evaluates the signals specifically at the modulation frequency.
The arrangement of electrode pairs 6a/6b, 6c/6d shown is only an example. A single pair of electrodes may also be sufficient, but it is important that at least a portion of the detection region 4 must be located between the two electrodes. In addition, for optimum function, the substance to be analysed, such as a finger of a test subject, must be placed at the designated point on the measuring surface 2. Any lateral displacement of the finger/substance may cause the heat pulse not to exert its effect accurately between the electrodes and the measurement readings to be suboptimal or incorrect.
The electrodes 6a, 6b, 6c, 6d can be inserted into or attached to the measuring body 1 by an additive method (3D-printing), by moulding, evaporation, doping, targeted alteration of the raw material of the measuring body (e.g. conversion of hydrocarbons into electrically conducting carbon by means of particle radiation or gamma radiation or laser radiation), glueing or inserting into previously introduced recesses or slots.
The operation of the device in accordance with
One or more excitation beams 8, preferably infrared beams, are generated sequentially or simultaneously with the laser light source 3. The wavelength of the infrared beam or beams is preferably in a range between 3 μm to 20 μm, particularly preferably in a range from 8 μm to 11 μm.
The excitation beams 8 are intensity- or amplitude-modulated by the intensity modulation device 9. In one embodiment, the intensity modulation device 9 generates short light pulses, preferably with a pulse frequency between 1 kHz and 1 MHz, or pulse packets (double or multiple modulation), preferably with an envelope frequency of between 1 kHz and 10 kHz.
The modulated excitation beams 8 are coupled into the optical medium/measuring body 1, in particular directly into the material of the measuring body, and, after passing through the measuring surface 2, they enter the volume 5a within the tissue 5.
It is possible for the function of the invention, but not necessary, that the excitation because passes through the measuring body 1 or enters the material of which the measuring body is made, provided it is ensured that the excitation beam 8 enters the substance 5 to be analysed on the underside of the measuring surface 2. This is illustrated by the fact that a recess/slot 13 is represented in
The wavelength of the excitation beams 8—with a view to the example of a blood sugar measurement described here—is preferably chosen in such a way that the excitation beams 8 are significantly absorbed by glucose or blood sugar. The following glucose-relevant infrared wavelengths (vacuum wavelengths) are particularly suitable for measuring glucose or blood sugar and can be set individually or in groups simultaneously or in succession as fixed wavelengths for measuring the response signals: 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 937 μm. In addition, glucose-tolerant wavelengths that are not absorbed by glucose can be used to identify other substances present and exclude their influence on the measurement.
For a measurement, a spectral region can be continuously scanned by scanning the excitation source, in particular a laser device 3, or the spectrum can be covered discontinuously at support points by suitable specific fixed wavelengths.
If substances other than glucose are to be detected, the corresponding wavelengths are to be selected for the excitation beams, which are characteristic of absorption wavelengths for these substances.
The absorption of the excitation beams 8 in the tissue 5 causes a local temperature increase in the region of volume 5a, which triggers a heat transfer and hence associated pressure waves and thermal pulses towards the surface of the tissue 5 and the measuring surface 2 in contact therewith. Due to the temperature and pressure fluctuations that occur at the measuring surface 2 and adjacent to this in the measuring body 1, the density, refractive index or the deformation, microstructure and the reflection behaviour in the detection region 4 near to the measuring surface 2 are modulated and, as a result, in the case of a piezo-material an electrical resistance is influenced or a piezo-voltage is generated or changed/modulated as a response signal.
The magnitude/amplitude of the intensity modulation of the measured values/response signal depends on the wavelength of the excitation beams (due to the necessary absorption in the tissue) and on the pulse frequency/modulation frequency of the excitation beams (due to the heat transfer and the pressure waves from the interior of the tissue towards the measuring surface 2) and on the thermal properties of the sample and the measuring body 1.
The measurement can be performed for a plurality of different modulation frequencies and the measurement results, for example in the form of spectra, can be correlated with one another. The individual spectra represent the response signal, for example a piezo-voltage or the amplitude of a variable piezo-voltage as a function of the wavelength of the excitation beam. Different spectra can be correlated in such a way that measured values from the surface of the sample (of the substance 5) can be cancelled out/eliminated or that specific information can be obtained from a specific depth range.
Each of the spectra at a given modulation frequency arises from the superposition of response signals from the substance 5 to be analysed from different depths, since the excitation beam 8 is partially absorbed in different depth layers as it passes into the sample.
The response signal thus represents a mixture of signals from different depths.
The mixture ratio of the signals from different depths depends on the frequency of the modulation of the excitation beam 8.
By correlating different spectra at different modulation frequencies, for example, calculating differences between spectra at higher modulation frequencies and spectra at lower modulation frequencies or dividing the spectra at higher modulation frequencies by spectra at lower modulation frequencies, in each case with different weighting of the individual spectra, effects of upper layers of the substance can be eliminated or at least reduced.
On the basis of comparisons with calibration or comparison measurements carried out previously, or with reference data sets, which in one embodiment are stored in the form of comparison tables or comparison curves in a memory of the evaluation device 16, the device can provide information about the current concentration of glucose or blood sugar within the tissue or within the volume 5a and generate a corresponding glucose or blood sugar level indication. For example, the comparison tables or comparison curves may have been created based on glucose or blood sugar values obtained from blood samples analysed outside the patient's body.
The excitation beam source, which in the exemplary embodiment shown is formed by a laser device 3 for emitting the excitation light beam or beams 8, can be implemented as an array. The array has at least 5, advantageously at least 10, more advantageously at least 15 or at least 50 or 100 individually controllable emitters 100a for monochromatic light of different, fixed wavelengths in the absorption spectrum of a substance to be analysed. The individual emitters can be laser emitters, but they can also be other types of emitters, such as suitable light-emitting diodes or other semiconductor components, which selectively emit radiation in a specific wavelength range.
The array preferably produces beams of monochrome light at one or more, particularly preferably at all of the following wavelengths (vacuum wavelengths): 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 9.7 μm and, if desired, additionally glucose-tolerant wavelengths.
It may be provided that the excitation transmission device/excitation light source 3 is permanently mechanically connected to the optical medium/measuring body 1 either directly or by means of an adjustment device. The adjustment device preferably allows an adjustment of the distance of the excitation light source 3 from the measuring body 1 or an adjustment in the longitudinal direction of the beam and/or an adjustment in the plane perpendicular thereto.
It may also be provided that the excitation transmission device 3 and the measuring body 1 with the detection device 4, 6 are attached directly to each other or to a common carrier (not shown). The carrier may be formed by a plastic part, a printed circuit board, or a metal sheet mounted in a housing.
The carrier can also be formed by the housing itself or a part of the housing.
It may also be provided that the device for analysing a substance, with a housing (not shown) in which it is arranged, can be attached to the body, for example to the torso of a person, wherein the excitation transmission device 3 for emitting one or more excitation light beams 8 and the detection device 4, 6 for detecting the time-dependent response signal are arranged and configured in such a manner that the side suitable for the measurement and the measuring surface 2 of the device are located on the side of the device opposite the body/torso, so that the substance to be analysed can be measured on the side of the housing facing away from the body/torso, for example by the patient placing a finger on the measuring surface 2. For this purpose, for example, the housing is attached to a person's body by means of a strap that forms part of the body, in an embodiment in the form of a wristband, to a wrist. On the opposite side to the wrist, the housing then has a window that is permeable for the excitation light beam 8, or the measuring body 1, with its outward-facing measuring surface 2, is fitted directly into the side of the housing facing outwards away from the body and forms some sections of the surface of the housing itself, for example, together with the measuring surface 2.
In this design, a finger pad can then be placed on the measuring body 1 and monitored.
The measuring body 1 can be mounted inside the housing, in the same way as the carrier, or directly on the housing. The measuring body 1 can also be connected directly to the carrier, wherein an adjustment device should be provided for the positioning of the carrier relative to the optical medium/measuring body 1.
It is also possible to mount the excitation light source 3 directly on the measuring body.
Through the optical window in the housing and/or through the measuring body 1, other parameters of the substance surface or the applied finger pad can also be monitored, such as a fingerprint in one embodiment. For this purpose, an optical detector in the form of a camera can also be attached to the carrier, for example, which digitally acquires an image of the surface of the substance 5 through the measuring body or past it next to the measuring body. This image as well as the measurement information from the detection device 4, 6 is processed within a processing device wherein the processing device can be directly connected to the detection device 4, 6 and also to the excitation transmission device 3. The processing device can also perform control tasks for the measurement. It can also be at least partially separated and remote from the other parts of the device and communicate with them via a radio link.
The image data from the camera can thus be further processed inside the housing or also via a radio connection outside the housing and compared with a personal identification database in order to retrieve calibration data of the identified person and use this data as a basis for the measurement.
Such calibration data can also be stored for retrieval remotely in a database, in one embodiment a cloud. The measurement data of the detection device can also be further processed both inside and outside the housing.
If data are processed outside the housing, the result data should preferably be transmitted by radio back to the device inside the housing in order to be displayed there.
In any case, a display (not shown) can be provided on the housing, which can advantageously be read off through the optical window, in one embodiment also partly through the measuring body or on the measuring body 1. The display can also project an indicator light onto a display surface through the optical window and, for this purpose, comprise a projection device. In one embodiment the display allows a measurement or analysis result, in particular a glucose concentration, to be displayed. The output can be implemented in one embodiment using a character or colour code. In one embodiment, a suggestion for an insulin dose depending on other patient parameters (e.g. insulin correction factor), or an automatic signal transmission to a dosing device in the form of an insulin pump, can be output via the display or a signal device that is parallel to this.
Alternatively, a recommendation can be made for the consumption of certain foods in a particular quantity. This can be linked, for example, to a proposal for preparation, which can be retrieved from a database and, in particular, transmitted in electronic form. This preparation instruction can also be sent to an automatic food preparation device.
The connection of the device to and from an external data processing device can be implemented using all common standards, such as optical fibres, cables, radio (e.g. Bluetooth, WiFi), or even ultrasound or infrared signals.
In addition, a pair of flat, plate-shaped electrodes 6l, 6m, for example, can be provided on the outside behind the electrodes 6i, 6j, 6k.
The annular design of the electrodes, together with the size that increases outwards, can result in the outer electrodes being less shielded by the internal electrodes and different electrode pairs being able to be used independently of each other.
On each side of the detection region, laterally outside the electrodes, a heat sink 14, 14a is shown, which can be incorporated into the measuring body or attached to the outside thereof. For example, these heat sinks may consist of a metal or another material, the thermal capacity and/or thermal conductivity of which is greater than that of the material(s) making up the measuring body 1.
A single body, such as an annular body, may also be provided as a heat sink, which surrounds detection region 4 or the entire measuring body 1. A heat sink can also be implemented by a Peltier element. The heat sink ensures that the temperature increase caused by the arrival of a thermal wave/heat pulse in the detection region can be compensated as quickly as possible by cooling, so that the material of the measuring body 1 in the detection region 4 can react as quickly as possible to a subsequent heat pulse.
The heat pulses follow one another with the modulation frequency of the excitation beam. Above the detection region, a plate-shaped thermal barrier 15 is provided, which has an opening for the passage of an excitation beam 8. This ensures that if the thermal conductivity of the material of the measuring body 1 is too high, the heat pulse is not dissipated too quickly when it arrives in the detection region, so that a temperature increase can briefly build up in the detection region 4 before the heat is dissipated, e.g. via heat sinks.
One or more heat sinks and/or one or more thermal barriers may be integrated into or mounted on the outside of a measuring body to direct the heat transfer appropriately. This can be particularly practical for flat measuring bodies or for measuring bodies that have a thin coating of a piezo-material and are otherwise composed of a material that does not have a piezo-effect.
In this context, it should be noted that the detection region 4 is identified in the figures as a region of the measuring body that corresponds to the required material selection, so that it displays a piezo-effect and that at the same time is located in a region of the measuring body 1 in which a response signal from the substance 5 to be analysed arrives in the form of a heat pulse. A possible detection region 4 also depends on the electrodes 6 selected for the measurement and is usually located between the electrodes 6 selected for the measurement when the measuring body 1 in this region 4 consists of the required material or displays a piezo-effect. The detection region 4 is therefore not necessarily specified in the measuring body, but in fact is obtained as the region in which the response signals from the substance to be analysed can be detected by the selected contact electrodes 6 by means of the physical effect used when the substance 5 is suitably positioned under the measuring surface 2.
The electrodes 6s, 6t, 6u shown in
The electrodes can be selected for a measurement as already described above.
For example, it can be provided that the layer 1′ of the measuring body 1 consists of a piezoelectric material, while the rest of the measuring body 1 consists of a different material, either also piezoelectrically sensitive or non-piezoelectric.
The flat body can also consist entirely of a piezoelectric material or have a piezoelectric layer in the region of the measuring surface.
Alternatively, it may also be provided that the laser device 3 is positioned slightly above the flat body 11, so that the excitation beam 8 is radiated parallel to the flat body to a mirror device 12 arranged on top of the flat body 11 and reflected there into the flat body 11 perpendicular to the measuring surface 2. In both cases, the extension of the device in the direction of the surface normal 7 is drastically reduced compared to the embodiment shown in
Electrodes 22, 23 can be provided inside, below or at the side of the flat body 11, which are used for the measurements on the detection region 4. In this design, any of the arrangements of two or more electrodes described above can also be used.
Also, such a measuring body formed as a flat body 11 can be formed from a first part and a sensor layer, e.g. a piezoelectric layer, joined/glued to these parts, wherein the piezoelectric layer then forms the measuring surface and is equipped with electrodes. In this case also, a recess can be provided for the excitation beam in the first part of the measuring body 11, which can then optionally consist of a material impermeable or not very permeable to infrared radiation, such as quartz or sapphire.
In the lower part of
In the event that a flat body described above is used with a laser device which is positioned at the side of it and aligned in such a way that it emits an intensity-modulated excitation beam which varies in wavelength, substantially parallel to the measuring surface in or above the flat body, wherein the excitation beam is diverted to the measuring surface, a measurement beam produced separately by a beam source, which is injected into the measuring body and reflected in the region of the measuring surface, can be used for detection, the deflection (deflection angle) of which in the measuring body in the region of the measuring surface is influenced by the response signals from the substance to be analysed. The deflection angle can be measured and used to determine the intensity of the response signals, which corresponds to the absorption intensity of the excitation beam in the substance 5 and the density/concentration of an absorbing substance/substance to be detected in the substance.
Even for such an application, the flat body may be constructed homogeneously from a material, the refractive index of which depends on the temperature, or it may have a layer in the region of the measuring surface made of a material, the refractive index of which depends on the temperature.
In
On the opposite side of the measuring body or the substrate 120 to the measuring surface 118, a lens 116, 116′, 116″ is integrated into the substrate 120, in particular formed by the material of the substrate 120 and extracted from the material of the substrate, for example by means of abrasive methods, in particular by etching or sputtering.
Three examples of possible lens shapes are shown in
The first lens 116 corresponds to a normally refracting, refractive convex convergent lens, the second lens 116′ corresponds to a (refractive) convergent lens ground to the Fresnel form (Kinoform lens), and the third lens 116″ corresponds to a diffraction lens, which focusses the excitation beam 10 by diffraction at a concentric lattice structure. The optical axes of the lenses 116-116″ can each be positioned vertically on the measuring surface 118, so that an excitation light source can pass straight through the substrate 120 directly. However, the optical axes can also be inclined with respect to the perpendicular to the measuring surface 118 in order to allow a potentially space-saving positioning of the excitation light source at an angle to the substrate.
Corresponding recesses or grooves 128, 129 can be provided on all electrodes shown in this text in the various measuring bodies and may be cast with a non-piezoelectric material, such as a polymer.
The material recesses 128, 129 can be provided, for example, during the production of the measuring body 1 or introduced later by etching or sputtering, or by sawing or laser cutting.
However, as can be seen from
Due to the low penetration depth into the substance to be analysed, the region of the substance in which the excitation beam 8 interacts with it lies directly below the detection device and electrodes 123, 124, despite an oblique irradiation direction. For example, the curved optical waveguides 133, 134 can be provided at least in sections as fibre-optic cables in a bored hole or similar recess of the measuring body 1, where they are glued or cast in place.
As can be seen from
The detail shown in
The present patent application relates (as already mentioned at the outset) to the following aspects in addition to the subject matter of the claims and exemplary embodiments described above. These aspects, or individual features thereof, can be combined with features of the claims, either individually or in groups. The aspects also constitute independent inventions, whether taken in isolation or combined with one another or with the subject matter of the claims. The applicant reserves the right to make these inventions the subject of claims at a later date. This may take place within the scope of this application or in the context of subsequent part applications or subsequent applications, claiming the priority of this application.
1) Method for analysing a substance in a body, comprising:
The detector may be formed, for example, by an optical medium/measuring body with a detection region, which is in particular adjacent to or directly adjacent to the measuring surface (=boundary surface of the measuring body in contact with the substance to be analysed), and which has a pressure- or temperature-dependent specific electrical resistance and/or generates electrical, particularly piezoelectric, voltage signals in the event of pressure or temperature changes, and with an electrical contact device which has electrodes that are electrically conductively connected to the detection region of the optical medium/measuring body for detecting the electrical resistance and/or the electrical signals, wherein a detection device is formed with the contact device and the detection region.
For example, the detector/detection device can comprise a piezoelectric material or a temperature-dependent resistance with a positive or negative temperature coefficient (thermistor) or a thermocouple.
The modulation can be carried out in one embodiment by interference or by manipulating the phase or polarization of the radiation of the excitation transmission device, in particular if this comprises a laser light device. The modulation can also be performed by controlling an actively operated piezoelement, which is a part/element of the measuring body and the transmission or reflection property/reflectivity of which can be controlled by a voltage controller on the piezoelement. The response signals can be, for example, intensities or deflection angles of a reflected measurement beam or voltage signals of a detector operating with a piezoelectric effect.
2) Method according to aspect 1, characterized in that the excitation light beam/excitation beam is generated by a plurality of emitters or multi-emitters, in particular in the form of a laser array, which emit light at different wavelengths simultaneously or sequentially or in pulse patterns, or also alternately.
3) Method according to aspect 1 or 2, characterized in that an acoustic response signal is detected by an acoustic sensor at the first region of the surface of the body.
4) Method according to any one of aspects 1 to 3, characterized in that at the first region of the surface of the body, a response signal is detected by an infrared radiation sensor, in particular a thermocouple, a bolometer or a semiconductor detector, such as a quantum cascade detector, or a piezo-detector. The piezo-detector can be formed, for example, in or on a measuring body/optical medium.
5) Method according to any one of aspects 1 to 4, comprising the steps:
6) Method according to aspect 5, characterized by
This method can also be used, for example, with a flat measuring body and lateral irradiation of the excitation beam (substantially parallel to the measuring surface), and with the excitation beam being reflected to the measuring surface and to the substance to be analysed.
7) Method according to any one of aspects 5 or 6, characterized in that the measuring light beam is generated by the same light source that generates the excitation light beam.
8) Method according to any one of aspects 5, 6 or 7, characterized in that the measurement beam is reflected one or more times within the optical medium, outside the optical medium, or partly inside and partly outside the optical medium after deflection and before detection.
9) Method according to aspect 1 or any of the others preceding or following, characterized in that the excitation light beam is an intensity-modulated, in particular pulsed excitation light beam, in particular in the infrared spectral range, wherein the modulation rate is in particular between 1 Hz and 10 kHz, preferably between 10 Hz and 3000 Hz.
10) Method according to aspect 1 or any of the others preceding or following, characterized in that the light of the excitation light beam(s) is generated simultaneously or sequentially or partially simultaneously and partially sequentially, by means of an integrated arrangement having a plurality of individual lasers, in particular a laser array.
11) Method according to aspect 1 or any of the others preceding or following, characterized in that an intensity distribution of the response signals is determined from the response signals obtained at different modulation frequencies of the excitation light beam as a function of the depth below the surface at which the response signals are generated.
12) Method according to aspect 1 or any of the others preceding or following, characterized in that an intensity distribution of the response signals is determined from the phase offset of the response signals in relation to a modulated excitation light beam at one or different modulation frequencies of the excitation light beam, as a function of the depth below the surface at which the response signals are generated.
13) Method according to aspect 11 or 12, characterized in that to determine the intensity distribution of the response signals as a function of the depth below the surface, the measurement results at different modulation frequencies are weighted and correlated with each other.
14) Method as claimed in aspect 11, 12 or 13, characterized in that a material density of a substance that absorbs the excitation light beam in specific wavelength ranges at a specific depth or in a depth range is determined from the intensity distribution over the depth below the surface of the body.
15) Method according to aspect 1 or any of the others preceding or following, characterized in that immediately before or after or during the detection of the response signal/signals, at least one biometric measurement is carried out on the body in the first region of the surface in which the substance analysis is performed or directly adjacent thereto, in particular a measurement of a fingerprint, and the body, in particular a person, is identified and that, in particular, associated reference values (calibration values) are assigned to the detection of the response signals by the identification of the person.
The biometric measurement can also include the measurement of a spectrum of response signals when scanning over a spectrum of the excitation light beam. By evaluation of the spectrum, a profile of substances present in the body and their quantity or density ratio can be determined, which can enable the identification of a person.
16) Device for analysing a substance,
17) Device according to aspect 16, having a device for determining response signals separately according to different intensity modulation frequencies and/or having a device for determining response signals as a function of the phase offset of the respective response signal relative to the phase of modulation of the excitation light beam, in particular as a function of the modulation frequency of the excitation light beam.
18) Device for analysing a substance as defined in 16 or 17, having an optical medium/measuring body for making the contact between the surface of the optical medium (for example, a so-called measuring surface) and a first region of the substance surface, and having
In this aspect and the following aspects relating to it, it may also be provided for the measuring body to have a first part that has a recess/slot in the form of a continuous channel for the excitation beam and that the measuring body on its underside has a sensor layer on the first part, which is either continuous without a recess/slot for the excitation beam or is provided with a continuation of the recess of the first part. If the sensor layer is thin enough, for example thinner than 200 microns, in particular thinner than 100 microns, then depending on the selected material of the layer the excitation beam, even if it is an infrared beam, can also pass through without too much absorption and a recess/slot in the sensor layer is not necessary. The sensor layer of the measuring body can be adhesively bonded to the first part/remainder of the measuring body or be joined to it by another joining technique, and can consist of a material that has piezoelectric properties and forms a detection region according to the invention. The sensor layer can also consist of a material in which a change in temperature and/or pressure causes a change in the refractive index, so that this change can also be detected as a response signal, for example by detecting the angle of reflection of a detection beam that is reflected in or on the sensor layer. For example, the first part/remainder of the measuring body can then consist of a material which is permeable in the visible range and for a detection beam, but is less permeable or impermeable in the infrared spectral range, such as quartz or sapphire or a plastic, for example a polymer.
19) Device according to aspect 18, characterized in that the excitation light source is directly permanently mechanically connected to the optical medium/measuring body.
20) Device according to aspect 18, characterized in that a device is provided for transmitting a measuring light beam into the region of the optical medium/measuring body that is in contact with the first region of the surface of the substance and that this device/or the detection device for detecting the measuring light beam is permanently directly mechanically connected to the optical medium/measuring body, integrated into it or coupled to it by means of an optical waveguide.
21) Device according to aspect 18, 19 or 20, characterized in that the optical medium/measuring body directly carries an imaging optics and/or that an imaging optics is integrated into the optical medium/measuring body.
22) Device according to aspect 18 or any of the others preceding or following, characterized in that the surface of the optical medium/measuring body has a plurality of partial faces inclined towards one another, at which the measuring light beam is reflected multiple times.
23) Device according to aspect 18 or any of the others preceding or following, characterized in that in or on the optical medium/measuring body, one or more mirror surfaces are provided for the reflection of the measuring light beam.
24) Due to the multiple reflection of the measurement beam, the path of the beam is extended so that angular deviations can be better detected (see also
25) Device according to aspect 16 or 17, characterized in that the detection device for detecting a time-dependent response signal has an acoustic detector for detecting acoustic waves on the surface of the material, in particular with a resonator, more particularly with a Helmholtz resonator.
Independently of this, a quartz tuning fork with preferably the same resonance frequency as a designated resonator can be used as a detector. The resonator can be open or closed. The quartz fork is preferably located in or on the neck of the resonator (off-beam) or inside/outside the resonator (in-beam).
26) Device according to aspect 16, 17 or 18, characterized in that the detection device for detecting a time-dependent response signal has a heat radiation detector for detecting the heat radiation on the surface of the substance, in particular an infrared detector, more particularly a thermocouple, a bolometer, or a semiconductor detector or a piezoelement.
27) Device according to any one of aspects 16 to 25, characterized in that the excitation light source and the detection device are attached directly to each other or to a common carrier, which is formed in particular by a housing or housing part of the device.
28) Device according to any one of aspects 16 to 26, characterized in that the device has a portable housing which can be attached to a person's body, wherein the device for emitting one or more excitation light beams and the detection device for detecting a time-dependent response signal are arranged and configured in such a manner that in operation, if the device is worn on the body, the substance to be analysed is measured on the side of the housing facing away from the body, in particular that the measuring surface of the measuring body is located on the side facing away from the body.
29) Device according to any one of aspects 16 to 26, characterized in that the device has a portable housing that can be attached to the body of a person and that the housing of the device has a window that is permeable to the excitation beam on its side facing away from the body at the intended wearing position.
The window can be located directly in front of the measuring body or be formed by the measuring surface of the measuring body.
29a) Device for analysing a substance with an excitation emission device for generating at least one electromagnetic excitation beam, in particular excitation light beam, with at least one excitation wavelength, a detection device for detecting a response signal and a device for analysing the substance using the detected response signal.
30) Device according to any one of the preceding aspects 16 to 29a, characterized in that the detection device is configured to measure the deformation of a crystal or other material transparent in the visible region of the spectrum.
The deformation can be measured more effectively by selecting steeper (larger) angles of incidence of the measurement beam to the sample surface, analogously to the photothermic ‘bouncing method’, and the deflection of the measurement beam caused by the mirage effect can be minimized.
Literature:
M. Bertolotti, G. L. Liakhou, R. Li Voti, S. Paolino, and C. Sibilia. Analysis of the photothermal deflection technique in the surface refection theme: Theory and Experiment. Journal of Applied Physics 83, 966 (1998)
A cantilever can either be placed directly on the sample or on a sufficiently thin optical medium on which the sample is placed on one side and the cantilever is placed on the opposite side. The thermal expansion of the sample or optical element causes the cantilever to vibrate as a result of the thermal expansion caused by the absorption of the modulated pump beam/excitation beam. The measurement beam is reflected at a measuring surface of the cantilever and is deflected by the vibration as a function of the irradiated wavelength and the thermal properties of the sample, as well as the modulation frequency. This deflection is detected.
31) Device according to any one of the preceding aspects 16 to 30, characterized in that the excitation transmission device contains a probe laser or an LED, such as a NIR (near-infrared) LED.
32) Device according to any one of the preceding aspects 16 to 31, characterized in that the excitation transmission device has a probe laser that has a smaller diameter than an additional pump laser (=laser for generating the excitation beam).
33) Device according to any one of the preceding aspects 16 to 32, characterized in that to achieve a more favourable signal-to-noise ratio, a special coating is provided, in particular on the emitter, e.g. IRE, so that heat is better dissipated (e.g. “thermal conductive paste”).
The optical element can be coated on the contact surface in such a manner that an improved conduction of the thermal signal into the optical medium can take place. In addition, the coating can also be used as scratch protection, and by skilful material selection can also provide a reflective surface for the measurement beam. In this case it is mandatory to retain the transparency for the excitation light.
34) Device according to any one of the preceding aspects 16 to 33, characterized in that the device has a system for
35) Device according to any one of the preceding aspects 16 to 34, characterized in that the device is designed to be permanently wearable for a person on the body, in one embodiment by means of a retaining device connected to the housing, such as a belt, a strap or a chain or a clasp, and/or the detection device has a detection surface which also serves as a display surface for information such as measurements, times of day and/or textual information.
The detection surface can be identical to the measuring surface or form its extension/continuation.
36) Device according to the previous aspect 35, characterized in that the device has a peel-off film in the region of the detection surface/measuring surface, preferably next to the detection surface/measuring surface, for pre-treatment of the surface of the substance and ensuring a clean surface and/or in one embodiment in the case of glucose measurement, specifically for skin cleansing.
37) Device according to any one of the preceding aspects 16 to 36, characterized in that The detection device is configured for reading and recognizing fingerprints to retrieve specific values/calibrations of a person and/or that it has a device for detecting the position of a finger, preferably for detecting and determining an unwanted movement during the measurement.
38) Device according to any one of the preceding aspects 16 to 37, characterized in that the detection device has a result display, preferably implemented with colour coding, as an analogue display, in one embodiment including error indication (e.g.: “100 mg/dl plus/minus 5 mg/dl”), acoustically and/or with a result display of measurement values in larger steps than the measuring accuracy of the device allows (e.g. using a multi-coloured traffic light display). This means that the user is not informed of small fluctuations, which could cause uncertainty for them.
39) Device according to any one of the preceding aspects 16 to 38, characterized in that the device
40) Device according to any one of the preceding aspects 16 to 39, characterized in that the device is configured such that a proposal for an insulin dose or substances/foodstuffs to be given to the person and the quantity to be consumed can be determined by the device (e.g. insulin correction factor) and/or that the body weight, body fat can be measured and/or entered manually or transferred from other devices to the device at the same time.
41) Device according to any one of the preceding aspects 16 to 40, characterized in that to increase the measuring accuracy the device is configured to determine further parameters, in one embodiment by means of sensors for determining the skin temperature, diffusivity/conductivity/moisture level of the skin, for measuring the polarization of the light (excluding water/sweat on the finger surface).
Water and sweat on the surface of a person's skin, which can affect the glucose measurement, can be detected by a test excitation with an excitation radiation by means of the excitation transmission device with the water-specific bands at 1640 cm−1(6.1 μm) and 690 cm−1(15 μm). If the absorption exceeds a certain value, the measurement site/substance surface/skin surface is too wet for a reliable measurement. Alternatively, the conductivity of the substance can be measured near to or directly at the measuring site to determine the moisture level. An error message and a drying instruction can then be issued.
42) Device according to any one of the preceding aspects 16 to 41, characterized in that the device is provided with a cover in the beam path of the pump and/or measurement beam laser. This can ensure the obligatory eye safety of human beings.
43) Device according to any one of the preceding aspects 16 to 42, characterized in that the device has a replaceable detection surface/measuring surface.
44) Device according to any one of the preceding aspects 16 to 43, characterized in that the device as an optical medium/measuring body has a partially grooved or roughened crystal as a measuring body, which enables the sample (e.g. the finger) to be better calibrated. The measuring point on which the surface of the substance to be analysed is placed is preferably designed without grooves and smooth.
45) Device according to any one of the preceding aspects 16 to 44, characterized in that a cylindrical TEMpl TEM00 mode is used for the measurement beam, or other modes TEM01 (Doughnut), TEM02 or TEM03 instead of the cylindrical TEMpl TEM00 mode. The latter, in particular, have the advantage that their intensity can be matched to the sensitivity profile of the quadrant diode, which forms the detector for the deflected measurement beam. In addition, rectangular TEMmn modes, such as TEM30 or TEM03 or higher, can be used. This allows the use of scanning/measurement beams that are less sensitive to interference in the horizontal or vertical direction.
46) Device according to any one of the preceding aspects 16 to 45, characterized in that the device measures not only at one point, but in a grid. This can be carried out either by displacing the pump or probe laser or the detection unit relative to the skin surface of a subject. Instead of a displacement, it is also conceivable to use one or more arrays of pump or probe lasers, which are spatially distributed across the array.
In addition, the following aspects of the invention must also be cited:
47) Device (10) for analysing a substance, in particular also according to any one of claims 16 to 46, having
The time-dependent response signal can take the form of the temperature or pressure increase in the measuring body as well as of any measured variable that detects the same, for example in the deflection of a measurement beam or an electrical signal of a piezoelement located in or on the measuring body.
48) Device according to aspect 47, (reference signs refer to
The detection device is therefore suitable for detecting a time-dependent response signal as a function of the wavelength of the excitation light and/or the intensity modulation of the excitation light. For this purpose, the evaluation unit 109 is also connected to a modulation device 9 for the excitation beam. Furthermore, the device is suitable for analysing the substance based on the detected response signal, wherein using different modulation frequencies of the excitation transmission device, response signals, in particular temporal response signal waveforms for different wavelengths of the excitation beam, are successively determined and a plurality of response signal waveforms at different modulation frequencies are correlated by the evaluation device 109 and that from this, information specific to a depth range below the substance surface is obtained.
For the embodiments according to aspects 47 or 48 also, it is conceivable to design the measuring body as a flat body, with a thickness/dimension perpendicular to the measuring surface which can be less than 50%, in particular less than 20%, more particularly less than 10% of the smallest dimension of the measuring body parallel to the measuring surface. The excitation transmission device/laser device for generating the excitation beam can then be positioned and aligned to the side of the measuring body in such a way that it emits the excitation beam into the measuring body substantially parallel to the measuring surface (or with an angular deviation of less than 20 degrees from this direction). (This may require that the excitation beam be coupled out of the excitation transmission device into an optical waveguide and from there into the measuring body. However, a mirror device may also be provided between the excitation transmission device/laser device and the measuring body, so that the excitation beam emerging from the excitation transmission device is initially reflected by a first mirror in the direction of a lateral, imaginary extension of the measuring surface and then diverted in a direction parallel to the measuring surface). The excitation beam can then be redirected to the measuring surface and from there enter the substance to be analysed.
49) Device according to either of the aspects 47 or 48,
In the devices of the above-mentioned type, in particular in the devices in accordance with aspects 47, 48 or 49, it can also be provided that the measuring body is coated in the region of the measuring surface with a material which changes its refractive index more strongly as a function of temperature or pressure than the rest of the measuring body, the coating being advantageously thinner than 1 mm, more advantageously thinner than 0.5 mm, in particular thinner than 0.2 mm or thinner than 0.1 mm. The coating can also be formed as an adhesively bonded sensor layer or one which is attached to a remaining/first part of the measuring body.
In the remaining part of the measuring body, which is connected to the coating or sensor layer, a recess 13 (cf.
The material of the measuring body, which is connected to the coating/sensor layer 1′ (see also
In this case, the reflection angle of the measurement beam represents the response signal to be detected.
50) Device according to any one of the aspects 47, 48 or 49,
51) Device according to aspect 47 or any one of the following,
52) Device according to aspect 47 or any one of the following,
53) Device according to aspect 47 or any one of the following,
54) Device according to aspect 47 or any one of the following,
The individual transmitting elements can be QC lasers or solid-state lasers with a fixed wavelength, for example.
55) Device according to aspect 47 or any one of the following,
56) Device according to aspect 47 or any one of the following,
57) Device according to aspect 47 or any one of the following,
58) Device according to aspect 47 or any one of the following,
59) Device according to aspect 47 or any one of the following,
60) Device according to aspect 47 or any one of the following,
61) Device according to aspect 47 or any one of the following,
62) Device according to aspect 47 or any one of the following,
63) Device according to aspect 47 or any one of the following,
The measuring surface can be the outer surface of a sensor layer that forms part of the measuring body and is connected to the remainder of the measuring body, in particular by adhesive bonding.
64) Device according to aspect 47 or any one of the following,
65) Device according to aspect 47 or any one of the following,
66) Device according to aspect 47 or any one of the following,
67) Device according to aspect 47 or any one of the following,
68) Device according to aspect 47 or any one of the following,
69) Device according to aspect 47 or any one of the following,
70) Device according to aspect 47 or any one of the following,
71) Device according to aspect 47 or any one of the following,
72) Device according to aspect 47 or any one of the following,
73) Device according to aspect 47 or any one of the following,
74) Device according to any one of the previous aspects, characterized in that the measuring body or optical medium is formed as a flat body, in particular as a plane-parallel body in the form of a plate, wherein in particular the thickness perpendicular to the measuring surface (in other words, the boundary surface of the optical medium on which the substance to be analysed is placed) is less than 50% of the smallest expansion of the measuring body in a direction parallel to the measuring surface, in particular less than 25%, more particularly less than 10% or less than 5% or less than 1%.
An imaging optics may be mounted on a surface adjacent to or opposite to the measuring surface, or on the measuring surface itself, or an imaging optics may be integrated into this surface. The imaging optics can contain at least one lens.
75) Device according to any one of the previous aspects, characterized in that the measuring body/optical medium has or carries a mirror device to reflect the excitation beam emitted by the laser device to the measuring surface (or the interface of the optical medium on which the substance to be analysed is placed).
76) Device for analysing a substance according to claim 1 or any one of the following, characterized in that the excitation beam is irradiated into the measuring body parallel to the measuring surface (or the boundary surface of the optical medium on which the substance to be analysed is placed) or at an angle of less than 30 degrees, in particular less than 20 degrees, more particularly less than 10 degrees or less than 5 degrees to the measuring surface (or the boundary surface of the optical medium on which the substance to be analysed is placed) and that the excitation beam is diverted or deflected towards the measuring surface (or the interface of the optical medium on which the substance to be analysed is placed) and passes through it.
The measuring body can have a channel-like recess for the excitation beam, the longitudinal direction of which runs parallel to the measuring surface, so that the distance that the excitation beam travels in the material of the measuring body until it exits through the measuring surface is reduced, in particular, reduced to zero. If a sensor layer is integrated into the measuring body, the recess/slot in the measuring body can reach as far as this.
77) Method for analysing a substance, wherein in the method
78) Method according to aspect 77, characterized in that using different modulation frequencies of the excitation transmission device, response signals, in particular temporal response signal waveforms, are successively determined and that a plurality of response signal waveforms at different modulation frequencies are correlated with each other and that from this, information specific to a depth range below the surface of the substance is obtained.
79) Method according to aspect 78,
80) Method according to aspect 79,
In this way, a plurality of signals at different modulation frequencies can be analysed successively and the results of different modulation frequencies can be correlated with one another to obtain depth information about the signals, or to eliminate signals coming from the surface of the substance.
81) Method according to any one of the preceding aspects 77 to 80,
The reflected measurement beam can be measured, for example, by detecting its intensity with a spatially-resolving, light-sensitive semiconductor device, in particular a quadrant diode.
82) Method according to any one of the preceding aspects 77 to 81,
In addition to or in combination with such a recommendation, a quantity indication can also be given for the foodstuffs or foodstuff combinations. Foodstuff combinations is also intended to mean prepared food portions.
All features and measures of the excitation beam, its optical guidance and modulation which are mentioned in the aspects in connection with any given measuring method, in particular in connection with a measurement light beam and the detection of its deflection, as well as the features of the mechanical structure and the adjustability, the features of the housing and the communication with external devices, databases and connected devices can also be applied to the detection method as claimed in the patent claims of the present application, i.e. using a piezoelectric effect to detect the thermal wave emitted from the substance into a measuring body as a response signal.
Other detection methods for detecting a response signal after emission of an excitation beam can comprise:
In principle, values of a phase shift of the response signal determined for depth profiling in response to a periodic modulation of the excitation beam can be used. (Heating/cooling phases of the substance surface should be evaluated more precisely with regard to their characteristics).
The device described may include a supply of adhesive strips for the removal of dead skin layers in order to allow the best possible interference-free measurement on a human body, as well as patches with thermal conductive paste, which can be regularly applied to the optical medium. The optical medium may be interchangeable given appropriate mounting and calibration of the remaining parts.
The device can be designed and configured for measurement not only on a person's finger, but also on a lip or earlobe.
The measurement can be improved by combining a number of the measurement systems described and explained with a similar susceptibility to error in terms of accuracy and reliability.
DAQ and lock-in amplifiers in the evaluation can be combined in one device and the entire evaluation process can be digitized.
The measurement can also be carried out with the device on a substance surface that is moving relative to the device, so that in the course of a grid measurement: the excitation light source and/or the measurement light source move across the skin in a grid pattern, allowing skin irregularities to be compensated or averaged out.
The sensitivity of the detection device/deflection unit can be optimized by adjusting/varying the wavelength of the sample beam/measurement light source. For this purpose, the measuring light source can be variable with respect to wavelength, or contain a plurality of laser light sources of different wavelength for selection or combination.
An optimum transversal mode (TEM) can be selected for the deflection of the pump/probe laser.
The excitation transmission device, measurement light source and detector can be assembled as a common array and the beams can be deflected in the optical medium in a suitable way to concentrate the transmission and reception of all beams on to one place.
A lens on or in the crystal of the optical medium can be used to deflect the measurement light beam more strongly depending on the response signal.
In addition, the use of a gap-free photodiode is conceivable for the detection, in which case a lens could focus the measurement light beam after its emission, thus enabling a more accurate measurement.
An additional configuration of the invention according to the patent claims is presented in the following concept. In addition, this concept, whether taken in isolation, combined with the above aspects or with the subject matter of the claims, constitutes at least one invention in itself. The applicant reserves the right to make this invention or inventions the subject of claims at a later date. This may take place within the scope of this application or in the context of subsequent part applications or subsequent applications, claiming the priority of this application.
The following concept for non-invasive blood sugar measurement by determining the glucose in the skin by stimulation by quantum cascade lasers and measuring the thermal wave due to radiant heat shall also be included in the invention and can be combined with the objects of the claims or pursued independently in a divisional application:
A method is described that allows the concentration of glucose or any other substance in the interstitial fluid (ISF) in the skin to be determined. Glucose in the ISF is representative of blood glucose and follows it rapidly when changes occur. The method consists of at least individual steps or groups of the following steps or from the overall sequence:
The heat radiation (in this case, the response signal) is collected, for example, by means of an optical element, in one embodiment an infrared lens or mirror, in particular a concave parabolic mirror, and in one embodiment is directed onto the detector via a convex mirror. For this purpose, a collecting mirror used in one embodiment can have an opening through which the collected beam is directed. In addition, a filter can be provided in the beam path that transmits only infrared radiation of a specific wavelength range.
In another exemplary embodiment, the heat radiation is detected by means of a measuring body, as claimed in the patent claims, by means of a piezoelectric effect.
Although the invention has been illustrated and described in greater detail by means of preferred exemplary embodiments, the invention is not restricted by the examples disclosed and other variations can be derived therefrom by the person skilled in the art without departing from the scope of protection of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/081398 | Dec 2017 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2018/083509 | 12/4/2018 | WO | 00 |
