WO2020070222A1

WO2020070222A1 - Method and device for the non-invasive optical measurement of characteristics of living tissue

Info

Publication number: WO2020070222A1
Application number: PCT/EP2019/076769
Authority: WO
Inventors: Vera Herrmann
Original assignee: Nirlus Engineering Ag
Priority date: 2018-10-04
Filing date: 2019-10-02
Publication date: 2020-04-09
Also published as: DE102018124537A1

Abstract

The invention relates to a method for the non-invasive optical measurement of characteristics of living tissue inside a body, wherein said body is exposed to light of at least one light wavelength by means of at least one light source, and the backscattered light from the body is sensed by at least one detector positioned, at a pre-defined distance a from the incident light, in a direction x running parallel to the surface of the body. The method is characterised in that the incident light in the form of a light bundle on the surface of the body has an extent d of more than 1 mm in the direction x.

Description

Method and device for non-invasive optical measurement of

Properties of living tissue

Description:

The invention relates to a method for the non-invasive optical measurement (or in vivo measurement) of properties of living tissue (including flowing blood) inside a (human) body, the body being illuminated with light by means of at least one light source with at least one light wavelength and wherein the light scattered back from the body is detected with at least one detector (for example placed on the body), which along a direction oriented parallel to the surface of the body (towards the body) at a predetermined (mean) distance from the light (in the body) is arranged.

The body is therefore preferably a human body. Non-invasive measurement means e.g. B. the non-invasive measurement of the concentration of blood components in blood vessels, e.g. B. the measurement of hemoglobin concentration, oxygen saturation, blood sugar or the like. The invention also includes measurement in tissue outside a bloodstream, e.g. B. in the course of in vivo tissue classification. Light, e.g. B. a laser light source is radiated into the body and by measuring and evaluating the backscattered scattered light, the parameters sought are determined in a variety of ways. For this purpose, electromagnetic radiation (e.g. laser light radiation) from the visible range and / or the infrared range is usually used, e.g. B. between about 550 nm and 2,000 nm. Often used to optimize the measurement methods

the backscattered light is measured under the influence of ultrasound radiation in order, for. B. to mark the location of the measurement with the ultrasound radiation.

A method for the optical measurement of properties of flowing blood by means of ultrasound localization is e.g. B. known from EP 1 601 285 B1. The ultrasound radiation is focused on the interior of a central blood vessel and a light source and an adjacent detection unit for detecting the backscattered light on the skin surface are positioned above the blood vessel in such a way that the distance between the light source and the majority of the light receptors of the detection unit with the Depth of the examining blood tissue corresponds. The target tissue is illuminated with at least two discrete light wavelengths and the backscattered light is measured. The interaction with blood and tissue causes changes in the optical properties, in particular the reflectivity and scattering power, of the ultrasonic wave field. This leads to a modulation of the backscattered light with the frequency of the ultrasound radiation, so that the modulated portion can be extracted in the course of the evaluation. In connection with the determination of the blood glucose concentration, DE 10 2006 036 920 B3 describes a method for the spectrometric determination of the blood glucose concentration in the pulsating flowing blood. Implementation of this method for the non-invasive in vivo determination of the glucose concentration additionally requires a non-invasive determination of the temperature of the blood. Such a method for non-invasive, optical determination of the temperature of a medium within a body is, for. B. is known from DE 10 2008 006 245 A1. Even with this optical temperature measurement, the location of the measurement inside a body, e.g. B. a bloodstream, are marked by means of pulsed ultrasound radiation.

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A modification of the described methods, which are based on ultrasound localization, is known from WO 2015/177156 A1. Here too, the body is irradiated with ultrasound radiation to mark a blood vessel with ultrasound radiation, the body being illuminated by the blood vessel with light having at least one light wavelength and the backscattered light being detected by a detector, the part of the light reflected from the body outside the blood vessel also being included a frequency is modulated which corresponds to the ultrasound frequency. The backscattered portion of light inside the blood vessel is modulated due to the Doppler effect in the flowing blood with a frequency shifted by the Doppler shift relative to the frequency of the ultrasound radiation. With an evaluation unit, the signal component modulated with the shifted frequency can be extracted from the detector signal measured at the detector. This method ensures that only those light components of the backscattered light that actually are backscattered from the blood flow into the evaluation, since only these are modulated with a different modulation frequency than the light components backscattered from the adjacent tissue due to the Doppler effect. This makes it possible to mark the bloodstream precisely, regardless of whether or not focused ultrasound radiation is used. In contrast to the method known from EP 1 601 285 B1, in the method known from WO 2015/177156 A1 the ultrasound radiation is not used to find the blood vessel, but the use of the Doppler effect also flows directly into the evaluation of the optical measurement.

In addition, it is generally known that the location of the backscattered light depends on the depth of the scattering center within the tissue from a statistical point of view. The backscattered light therefore occurs all the more

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farther away from the tissue, the deeper it is scattered in the tissue. When examining a body or tissue, scattered light with a particularly high intensity is consequently determined at a certain distance from the point of incidence. It is generally known to take advantage of this fact. For example, DE 10 2007 020 078 A1 proposes a device for collecting scattered light scattered back on or in a specimen, light from at least one light source being irradiated at an irradiation point in the specimen and a plurality of collecting light guides being provided whose entry ends in the Area of the sample body are arranged on at least one substantially circular measuring surface with a predetermined radius, the irradiation point being arranged essentially in the center of the circle of the circular measuring surface. This device consequently collects the scattered light relevant for the desired examination by means of a large number of optical waveguides which are arranged in a ring around the point of incidence. On the one hand, this results in a particularly efficient measurement, because the decisive scattered light is optimally used. On the other hand, this arrangement allows detection, so to speak, so that stray light from other depths is suppressed.

In addition, US 2006/0173255 A1 describes the monitoring of biological parameters with the aid of a compact analyzer based on a spectrometer, such an IR spectrometer in particular containing a grating and a detector array.

On the basis of the considerations described, the invention is based on the technical problem of creating a method for the non-invasive optical measurement of properties of living tissue in the interior of a body which is versatile and yet can be used efficiently.

4th

To achieve this object, the invention teaches in a generic method of the type described at the outset that the irradiated light is not collimated or punctiformly irradiated into the body, but as a (widened) light beam which is applied to the surface of the body along the direction x which is the direction along which the detector is arranged at a distance from the point of incidence of the light source - has an extension d of more than 1 mm. The incident light particularly preferably has an extent of more than 1.5 mm, preferably at least 2 mm, along the defined direction x.

The invention is based first of all on the fundamentally known finding that there is a statistical relationship between the depth of the scattering center or the tissue section from which the backscattered photon comes and the distance of the exit point from the tissue from the entry point of the incident light. This is because the photon paths on their way from the entry point into the tissue to the exit point or to the detector form a typical curved path, which is also referred to as a “banana shape” or “light banana”. The photons that are irradiated into the tissue from a point-shaped laser light source or enter the tissue at a point-like entry point are also partially backscattered after multiple scattering events. From a statistical point of view, the starting point or the exit point from the tissue is related to the depth of the photon on its way through the tissue in such a way that the distance a of the exit point from the entry point (approximately) the depth T of the photon reached in the tissue corresponds.

Based on these considerations, the invention deliberately suggests a larger lighting area and consequently an irradiation of the light than

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expanded light beam with a relatively large expansion. With a fixed arrangement of the detector and consequently a fixed predetermined distance of the detector along the direction x relative to the incident light or the light source, it is achieved that the detector statistically seen photons that are scattered at different depths. In contrast to the considerations from the prior art, the invention therefore dispenses with a statistical assignment of the backscattered light to a specific depth of the scattering center, by deliberately registering photons from different scattering depths with a fixed detector, even then, if the detector itself has a very small detector area in relation to the direction x. Despite the fixed geometric arrangement between the detector and the light source or incident light, tissue areas can be analyzed at different depths within certain limits. This is e.g. B. interesting if the properties of blood are to be determined based on a measurement in a bloodstream and if the depth of the bloodstream (or other tissue to be examined) varies within certain narrow limits. In particular, a variable adaptation of the detector can be dispensed with.

This is also possible without enlarging the active detector area, i. H. In a preferred development, it is possible to work with a detector with a very small detector area or a small width c along the direction x, this detector area preferably being less than 1 mm, particularly preferably less than 0.5 mm, e.g. B. is less than 0.1 mm. This consideration is based on the knowledge that the use of a detector with a small detector area can be advantageous for various reasons, in particular when working with a high temporal resolution and consequently a detector is used which works correspondingly quickly. This

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is z. B. useful when working with an ultrasound marker and the backscattered light is modulated with the frequency of the ultrasound radiation. Even if no runtime measurements or runtime evaluations are carried out, it is expedient because of the ultrasound radiation used to work with a detector with a high temporal resolution and consequently a small detector area. It can e.g. B. a diode detector with a width or a diameter of about 10 square meters to 100 square meters can be used. The solution according to the invention with an enlarged irradiation area for utilizing a larger scattering depth or an enlarged depth range is particularly advantageous if either an exact localization of the depth is not required or the localization or marking is achieved by other technical means, e.g. B. by an ultrasound marking known from the prior art. The method according to the invention is consequently used particularly preferably in combination with a fundamentally known ultrasound marking. The invention consequently preferably relates to a method for the non-invasive optical measurement of properties of flowing blood in the interior of a living body, the blood path to be examined being marked by means of ultrasound radiation and wherein such signal components are extracted from the signals measured by the detector with a modulation frequency dependent on the ultrasound radiation will. The invention can preferably be used in such processes that, for. B. in EP 1 601 285 B1 or WO 2015/177156 A1 or EP 3 170 446 A1.

It is Z. B. possible to irradiate the tissue to be examined with focused ultrasound radiation and to focus the ultrasound radiation on the bloodstream, so that exclusively or at least predominantly that

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flowing blood is modulated with the ultrasound radiation and consequently exclusively or predominantly the light scattered back from the bloodstream is modulated with the ultrasound frequency. When using focused ultrasound radiation, the modulated portion of the light that is scattered back outside the bloodstream is consequently low, so that it is possible to work with an enlarged illumination area in the manner according to the invention, and consequently statistically also those photons that do not reach the detector are scattered back into the bloodstream because they are not modulated with the frequency of the focused ultrasound radiation and are therefore “eliminated” during the evaluation.

However, the method according to the invention with the enlarged illumination area can also be implemented with unfocused ultrasound radiation or with ultrasound radiation with a relatively large focus, specifically when - as described in WO 2015/177156 A1 - the principle of the “echo blood optode” is used . In order to mark the tissue to be examined (or a blood vessel), the body is irradiated with ultrasound radiation at an ultrasound frequency, the body being illuminated with light with at least one wavelength of light and the backscattered light is detected with the detector. The proportion of light scattered back from the body outside the blood vessel is modulated with a frequency that corresponds to the frequency of the ultrasound radiation. In contrast, the back-scattered light component within the blood vessel is modulated with flowing blood at a frequency shifted by the Doppler shift due to the Doppler effect. With an evaluation unit, the signal components modulated with the shifted frequency can then be extracted from the detector signal measured at the detector. The corresponding property of the blood, for. B. the concentration of blood components or the temperature of the

8th

Blood determined. With this method variant, the success therefore does not depend on the focusing of the ultrasound radiation, since the light component modulated with the “shifted” ultrasound frequency is evaluated in a very targeted manner. In this variant too, light with a relatively large area or a light bundle with a relatively large area can consequently be irradiated, so that, statistically speaking, the detector reaches photons from a certain depth range. However, since the localization is supported with the aid of ultrasound radiation, backscattering from a relatively large depth range, which may also affect areas outside the bloodstream, can be accepted.

The light source to be used according to the invention, e.g. B. a laser, preferably generates a (widened) light beam with a along the direction x over the extent d homogeneous intensity distribution. This means that the light bundle has an essentially identical intensity along the direction x over the entire extent d. However, it may be expedient to radiate the light into the body with an inhomogeneously distributed entry intensity. For this purpose, the light when entering the body can have an inhomogeneously distributed entry intensity over the extension along the direction x, this intensity decreasing with a reduced distance from the detector, preferably decreasing exponentially. The invention in turn is based on the knowledge that the intensity of the backscattered light at the location of the detector depends on the depth in the tissue. Regardless of the fact that, statistically speaking, the exit location or the distance of the exit location from the point of incidence depends on the scattering depth, the backscattered intensity also decreases with increasing depth of the scattering center, since the light covers a longer path through the tissue. That means being more homogeneous across the entire area

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Irradiation of light into the body at the detector for different scattering depths different intensities can be measured.

In a preferred further development, the invention counteracts this effect in that the light enters the body with an inhomogeneously distributed entry intensity. Technically, this works. B. in that from an (originally) homogeneous intensity distribution of the light beam an inhomogeneously distributed entry intensity with the help of an optical element, for. B. is generated with an appropriately designed intensity filter. The light generated by the light source and distributed homogeneously over a large area passes through a filter with an exponential filtering capacity or a radially exponentially decreasing filtering capacity before entering the tissue or the skin. This ensures that the intensities of the backscattered light are constant in the detector regardless of the depth to which the light is backscattered. The filter therefore compensates for the effects of Lambert-Beer’s law in relation to the scattering depth. Reference is also made to the description of the figures.

The invention also relates to a device for non-invasive optical measurement or in-vivo measurement of properties of living tissue, including blood, inside a (human) body by a method of the type described. The device has at least one light source, e.g. . B. a laser radiation source and at least one detector. The detector is arranged at a fixed predetermined distance a from the incident light. The geometry of the device with detector and radiation is consequently fixed and preferably not variably adjustable. According to the invention it is provided that the incident light has an extension d of more than 1 mm, for. B. more than 1.5 mm, preferably at least 2 mm. The light source and are particularly preferably

10th

the detector is a structural unit with a common housing, this structural unit or the housing being placed on the body. Within the housing or within the device, the light source and the detector are geometrically positioned in a fixed arrangement to one another. The light source can e.g. B. be designed as a laser that generates a collimated light beam. With the help of at least one first optical element, this light beam can be expanded into a light bundle which, when placed on the body, has an extension of more than 1 mm in the described direction x at the entry into the body. So the device can, for. B. have an outlet panel and the specified extent refers to the expansion of the light beam in the area of this outlet panel, the housing with the outlet panel being placed on the body. The optical element may e.g. B. act as an optical waveguide, ie the light is coupled from the laser via an optical waveguide into the area of the body, this optical waveguide being arranged with its exit end at a predetermined distance from the exit point from the housing or from the body to be irradiated, so that the light beam expands in the manner according to the invention until it hits the body. In addition or as an alternative, a lens can also be used to expand the light beam, in particular if there is no coupling by means of optical fibers. In any case, the first optical element can initially be used to expand the light beam homogeneously to form a homogeneous light beam with a homogeneous intensity distribution. Alternatively or in addition, the device can be an optical element, e.g. B. have a second optical element with which an inhomogeneously distributed entry intensity is generated on the surface of the body from a homogeneous intensity distribution of the light beam. It can be z. B. can be a suitable filter with the (exponential) characteristics already described.

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A laser light source is preferably used as the light source in the manner described. In practice, several (laser) light sources with different wavelengths can be used, e.g. For example, to determine different properties of the tissue or if several wavelengths are required to determine one property. It is always advisable to use light from the visible spectrum and / or the infrared spectrum, e.g. B. Light with a wavelength of 500 nm to 2,000 nm. Regarding the wavelength typically to be used in practice, the prior art, for. B. EP 3 170 446 A1, EP 1 601 285 B1, WO 2015/177156 A1 or EP 2 046 190 B1 and EP 2 235 485 B1.

In practice, e.g. B. diode lasers or laser diodes are used, which are characterized by a compact design. As a detector z. B. a semiconductor detector or diode detector can be used.

The invention is explained in more detail below on the basis of a drawing illustrating only one exemplary embodiment. Show it

1 a device known from the prior art in a highly simplified, schematic representation,

2 shows a device according to the invention in a highly simplified schematic representation,

Fig. 3 shows a modified embodiment of the device according to Fig. 2 and

12th

Fig. 4 is a schematic representation of the filter characteristic of one in the

Embodiment according to Fig. 3 used intensity filter.

A device for non-invasive optical measurement of properties of living tissue, e.g. B. blood, shown inside a (human) body 1. The device has at least one light source 2, the z. B. is designed as a laser radiation source. Furthermore, the device has at least one detector 3. Light source 2 and detector 3 can be combined to form a compact structural unit with a housing (not shown), this structural unit being placed on body 1 or on skin 4 of body 1. With the device z. B. the properties of the blood inside the body 1 are examined, for. B. the blood flowing in a blood vessel, but this is not shown in the figures. The body or the tissue to be examined is illuminated with the light from the light source 2. The light backscattered from the body is detected by the detector, this detector 3 being arranged at a predetermined (average) distance a from the incident light 5 along the direction x oriented parallel to the surface of the body. The device can additionally z. B. be equipped with an ultrasound source, not shown, so that the tissue to be examined is marked with the ultrasound radiation, by extracting such signal components with a modulation frequency dependent on the ultrasound radiation from the signals measured with the detector. Such an ultrasound marking is known from the prior art.

There is a connection between the distance a of the exit point of the backscattered scattered light 6 from the irradiation point P on the one hand and the depth r of the scattering center at which the light is scattered back in the tissue. The backscattered scattered light 6 passes further from the point of incidence P.

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removed from the tissue the deeper it is scattered in the tissue. This means that for the examination of tissue at a very specific depth within the body, a fixed predetermined distance a between the point of incidence and the exit point is generally expedient. This is shown in Fig. 1 for a device according to the prior art. There is essentially spot lighting with a collimated laser beam. Because of the predetermined distance a, the detector only or essentially reaches those photons that were scattered at a certain depth r. The distance of the exit point from the point of incidence corresponds approximately to the depth of the scattering center. Photons that were scattered at a different or more inward depth reach the surface of the body at a greater distance, so that they do not hit the detector 3. In the prior art it has therefore been considered to make the distance a of the detector from the irradiation point P variable or adjustable in order to enable individual adaptation to the measurement at different depths.

According to the invention, it is now provided according to FIG. 2 that the incident light does not enter the body in a punctiform manner in a very small area, but rather as a widened light beam 5 ′ on the surface of the body along the direction x, a relatively large extension d of more than 1 mm has, preferably more than 1.5 mm, e.g. B. at least 2 mm. In contrast, the detector 3 has a very small detector area with a width c along the direction x of significantly less than 1 mm, z. B. less than 0.1 mm. The detector 3 on the one hand and the light source 2 or its light bundle 5 'are arranged fixed to one another in the embodiment according to the invention according to FIG. H. with a fixed, average distance between detector 3 on the one hand and light bundle 5 'on the other. The embodiment according to the invention means that the detector 3 is not only statistically considered

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mainly reach photons that are scattered from a single, local scattering depth, but photons that correspond to a specific depth range D, which corresponds to the extent d of the expanded light beam 5 '. This leads to the fact that with the configuration according to the invention with a fixed arrangement of detector 3 and light source 2, investigations of the tissue can be carried out not only at a single, local depth, but over a relatively large depth range D. This is e.g. B. useful if the depth of the bloodstream (not shown) varies over a certain depth range, since in this case a reliable measurement can be made without adjusting the geometry of the device.

The invention takes advantage of the fact that the photon paths have a curved path with the shape of a “banana” in the case of scattering in the tissue and that the distance r correlates with the depth d. Various photon paths are indicated by way of example in FIG. 1, and their illustration is omitted in FIG. 2.

It can be seen in FIG. 2 that the broad irradiation with a relatively wide light bundle 5 ″ photons from different depth ranges reach the detector 3 and that the individual irradiation points within the light bundle 5 ″ represent different scattering depths. The intensities of the backscattered light in the detector 3 are consequently statistically maximum for a corresponding depth. However, it can also be seen that the backscattered intensity decreases with increasing scattering depth, exponentially according to Lambert-Beer’s law:

Io q ^mG

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, with r = d, the radius r corresponding approximately to the depth of the backscattered light.

Based on this, a modified embodiment is shown in FIG. 3, in which a filter 7 is additionally inserted into the radiation path of the light source 2, so that this filter 7 is used to distribute the homogeneous intensity distribution of the light beam 5 'into an inhomogeneously distributed entrance intensity and consequently an inhomogeneously distributed one Intensity of the light at the entry surface F of the body 1 and consequently on the skin 4 is converted. The filter 7 has an exponential filter characteristic along the longitudinal direction x over the width d

I = Io b ^{+ mr} , where r is between dmin and dmax. The use of such a filter consequently means that the “illumination” of the detector 3 by the backscattered photons is independent of the depth of the respective scattering centers.

The filter characteristic is also shown schematically in simplified form in FIG. 4. The transmission with an exponential course decreasing in the radial direction is indicated, the detector 3 being arranged in the center of this exponential filter capacity running in the radial direction. The location of the irradiation and the expansion of the initially homogeneous light beam in the region of the entry into the tissue can also be seen, it being possible for an indicated diaphragm 8 to be arranged at this point.

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Claims

Claims:

1. A method for the non-invasive optical measurement of properties of living tissue in the interior of a body (1), the body (1) being illuminated with light by means of at least one light source (2) with at least one wavelength of light, and the body (1) backscattered light (6) is detected with at least one detector which is arranged along a direction (x) oriented parallel to the surface of the body at a predetermined distance (a) from the incident light, characterized in that the incident light as a light beam (5 ') on the surface of the body (1) along the direction (x) has an extent (d) of more than 1 mm.

2. The method according to claim 1, characterized in that the incident light beam (5 ') along the direction (x) an extent (d) of more than 1.5 mm, preferably at least 2 mm, z. B. 1, 5 to 3 mm.

3. The method according to claim 1 or 2, characterized in that the

Detector (3) has a detector area with a width (c) along the direction (x) of less than 1 mm, preferably less than 0.5 mm, particularly preferably less than 0.1 mm.

4. The method according to any one of claims 1 to 3, characterized in that the detector (3) at a fixed distance from the light source (2) on the surface of the body (1), for. B. is placed on the skin (4).

5. The method according to any one of claims 1 to 4, characterized in that the light source (2) is used to generate a light beam (5 ″) with an intensity distribution which is homogeneous along the direction (x) over the extent (d).

6. The method according to any one of claims 1 to 5, characterized in that the light (5 ') on entry into the body (1) over the extent (d) along the direction (x) has an inhomogeneously distributed entry intensity, the intensity decreases with a reduced distance from the detector (3), preferably decreases exponentially.

7. The method according to claim 6, characterized in that the inhomogeneously distributed entry intensity from the homogeneous intensity distribution of the light beam with an optical element, for. B. an intensity filter (7) is generated.

8. The method according to any one of claims 1 to 7, characterized in that the tissue to be examined is marked by means of ultrasound radiation and that such signal components are extracted from the signals measured with the detector (3) with a modulation frequency dependent on the ultrasound radiation.

9. The method according to claim 8, characterized in that the tissue to be examined is marked with focused ultrasound radiation.

10. The method according to claim 8, characterized in that for marking a blood vessel it is irradiated with ultrasound radiation, the light portion scattered back outside the blood vessel being modulated with the frequency of the ultrasound radiation and wherein the signal portion backscattered inside the blood vessel having a Doppler shift relative to the Ultrasound frequency shifted frequency is modulated, the signal portion modulated with the shifted frequency is extracted from the detector signal.

11. Device for the non-invasive optical measurement of properties of living tissue inside a body (1) according to a method according to one of claims 1 to 10, with at least one light source (2), for. B. a laser radiation source and at least one detector (3), the detector (3) being arranged at a fixed predetermined distance from the incident light (5, 5 '), characterized in that the incident light as a light beam (5') Has an extent of more than 1 mm, for. B. more than 1.5 mm, preferably at least 2 mm.

12. The apparatus according to claim 11, characterized in that the light source (2) and the detector (3) form a structural unit with a common housing, which can be placed on the body (1).

13. The apparatus according to claim 11 or 12, characterized in that the

Light source (2) is designed as a laser, the light beam with at least a first optical element, for. B. an optical waveguide and / or a lens to a light bundle (5 '), which has an extension d of more than 1 mm.

14. Device according to one of claims 1 to 13, characterized in that the device has an aperture (8) which can be placed on the body (1) and whose width along the direction (x) limits the extent (d) of the light beam.

15. Device according to one of claims 1 to 14, characterized in that the first optical element is formed and / or is positioned relative to the diaphragm (8) such that the diaphragm (8) is homogeneously illuminated.

16. The device according to one of claims 1 to 15, characterized in that the device is an optical element, for. B. has a second optical element, the z. B. is designed as an intensity filter (7) and with which an inhomogeneously distributed entrance intensity is generated on the surface of the body (1) from a homogeneous intensity distribution of the light beam (5 ').