WO2008046464A1

WO2008046464A1 - Method and device for measuring the concentration of at least one substance from a group of n substances contained in a sample material and influencing the dispersion of the sample material

Info

Publication number: WO2008046464A1
Application number: PCT/EP2007/007364
Authority: WO
Inventors: Daniel Bublitz; Michel Stutz; Martin KÜHNER
Original assignee: Carl Zeiss Ag
Priority date: 2006-10-16
Filing date: 2007-08-21
Publication date: 2008-04-24
Also published as: DE102006048849B4; DE102006048849A1

Abstract

The invention relates to a method for measuring the concentration of at least one substance from a group of n substances contained in a sample material and influencing the dispersion of the sample material. According to said method, a bundle of rays containing electromagnetic radiation with a discreet wavelength spectrum is split into a measuring bundle and a reference bundle, the bundle of rays having n+1 different wavelengths. The measuring bundle is guided through the sample material and the reference bundle which is not guided through the sample material is positioned above the measuring bundle in order to generate interference radiation. The intensity of the interference radiation is measured simultaneously and selectively for each of the n+1 wavelengths, n pairs of wavelengths from the n+1 wavelengths being formed in such a way that the wavelength difference of each pair is different from all wavelength differences of the other pairs. A differential value between the refractive index of the sample material for one wavelength of the pair and the refractive index of the sample material for the other wavelength of the pair is determined respectively from the measured intensities for each of the n pairs. A relative dispersion is prepared for each of the n substances, which only describes the influence of the individual substance on the dispersion of the sample material as a function of the wavelength difference and the concentration of the corresponding substance. A complete dispersion comprising the determined refractive index differences as functional values is prepared by linear superposition of the n relative dispersions with the concentration of the individual substances as a parameter, thereby enabling the concentration of the at least one substance to be determined.

Description

Method and device for measuring the concentration of at least one substance from a group of n located in a sample material and the dispersion of the

Sample materials affecting substances

The present invention relates to a method and a device for measuring the concentration of at least one substance from a group of n substances in a sample material and influencing the dispersion of the sample material, in particular for measuring the glucose concentration in the aqueous humor of the eye.

Such non-invasive measurement of glucose content is preferred because of non-invasive performance. Thus, the conventional standard blood sugar measurement based on the glucose oxidation repeatedly encounter difficulties, since this method requires a blood sample from the body and thus is an invasive procedure.

However, previously known non-invasive methods often have the disadvantage that they require a complex optical design, often long measurement times are necessary and the evaluation of the measurement results is mathematically extremely complex and complex.

Proceeding from this, it is an object of the invention to provide a method for measuring the concentration of at least one substance from a group of n in a sample material and the dispersion of the sample material influencing substances, with the simple, fast and accurate concentration can be measured , Furthermore, a device is to be provided with which the method for measuring the concentration can be carried out.

According to the invention, the object is achieved by a method for measuring the concentration of at least one substance from a group of n substances located in a sample material and influencing the dispersion of the sample material, in which a) a beam having electromagnetic radiation with a discrete wavelength spectrum is divided into a measuring and a reference beam, wherein the beam n + 1 has different wavelengths, b) guided the measuring beam through the sample material and then with the not by the sample material c) the intensity of the interference radiation is measured simultaneously and selectively for each of the n + 1 wavelengths, d) n pairs of wavelengths from the n + 1 wavelengths are formed so that the wavelength difference of each pair is different for all the wavelength differences of the other pairs, e) from the measured intensities for each of the n pairs a difference between the refractive index of the sample material for the one wavelength of the pair and the refractive index of the sample material for the other wavelength of the pair is determined each of the a relative dispersion is provided which describes only the influence of the individual substance on the dispersion of the sample material as a function of the wavelength difference and the concentration of the corresponding substance, g) an overall dispersion which has the determined refractive index differences as functional values by linear superposition of the n relative dispersions with the concentration of the individual substances as parameters and thus the concentration of the at least one substance is determined.

With this method, it is possible to calculate the concentration of the at least one substance analytically. In the method according to the invention, no Fourier transformation is to be carried out. Furthermore, an extremely short measurement time is sufficient. Overall, the calculation time in the method according to the invention compared to conventional methods by several orders of magnitude (for example, by a factor of 1,000) be shorter.

It is essential that the measurement of the intensity of the interference radiation is carried out simultaneously for all wavelengths. Thus, an extremely high accuracy can be achieved because time-varying parameters that would lead to a change in the phase are not measured.

By determining the wavelength difference, the advantage is achieved that such parameters of the sample material and / or the measuring arrangement for the measuring and the reference beam, although change the phase, but not dependent on the wavelength, need not be known because these parameters cancel each other in the difference formation.

The sample material may in particular be transparent or partially transparent tissue or aqueous solutions, such as. B. the aqueous humor of the human eye act.

When the concentration of a substance in the aqueous humor is measured, the measuring beam is preferably reflected at the interface between the aqueous humor and the front of the crystalline lens. In particular, the measuring beam can be focused on this interface. Furthermore, it is preferable to confocally detect the radiation reflected at this interface.

Furthermore, a measurement can be carried out with a at a further interface between the back of the cornea of the eye and the aqueous humor to the influence of the cornea (ie the influence on the phase shift in measuring the reflected Meßbündels at the interface between aqueous humor and eye lens) to take into account the measurement of the concentration of a substance in the aqueous humor.

Of course it is also possible to measure the concentration of a substance in the cornea. For this purpose, the measuring beam which is reflected at the further boundary surface (which may in particular be focused on the further boundary surface) is preferably used.

The measuring beam can be reflected back into itself so that it is passed twice through the sample material. In particular, an interface adjacent to the sample material can serve as a mirror. If the sample material is the aqueous humor of an eye, the interface may be the contiguous side of the eye lens.

In the method, in step a, the n + 1 wavelengths and the intensities of the n + 1 wavelengths in the beam can be measured (preferably simultaneously with the measurement of the intensity of the interference radiation) and in steps d and e the measured wavelengths and the intensities of the n + 1 wavelengths are used in the beam.

By measuring the intensities and wavelengths of the n + 1 wavelengths, it is possible to use inexpensive laser diodes. Although such laser diodes have a certain temporal variation in terms of intensity and wavelength of the emitted laser radiation. However, since the currently available wavelengths and intensities in the beam are measured, these values are known with sufficient accuracy to perform the measurement of the concentration of the at least one substance with the method according to the invention.

In particular, in step d, one of the n + 1 wavelengths can be selected as the reference wavelength, which is one of the two wavelengths in each of the n pairs. Thus all wavelength differences are related to the same reference wavelength, which simplifies the calculation of the concentrations.

The measuring beam and the reference beam can be coupled into two arms of a Michelson interferometer arrangement, the sample material being arranged in the arm into which the measuring beam is coupled. This makes it easy to generate the required interference radiation.

The measuring beam is detected in particular confocal. As a result, unwanted interference radiation is effectively suppressed, resulting in a higher measurement accuracy.

The relative dispersions are preferably provided in each case based on one of the n + 1 wavelengths. In particular, one of the n + 1 wavelengths may be the reference wavelength, thereby further simplifying the calculation of the concentration of the at least one substance.

The sample material may comprise a major medium, and to provide the relative dispersion, for each substance, the phase change for different wavelengths at a predetermined concentration of only one substance in the main medium may be measured. In particular, an interferometer arrangement according to Michelson can be used for this measurement.

Before step g, the length of the distance that the measuring beam passes through the sample material can be determined. The length is then taken into account in step g.

The determination of the route length can be carried out, for example, with an external device. For example, if the sugar concentration in the aqueous humor of a person's eye is to be determined, known devices for measuring the length of the anterior chamber can be used. The measured value is then preferably stored in an evaluation unit of a device with which the method according to the invention can be carried out. Further, it is possible to select one of the n pairs of wavelengths from step d. This is then compared with a known water dispersion function which describes the phase shift when passing through a water section of predetermined length as a function of the wavelength difference and the water path. From this, it is then possible to deduce the actually passed length in the anterior chamber.

Furthermore, with the method according to the invention, for example, the measuring beam can be focused, the measuring focus being shifted from the back of the comonomer to the front of the lens, and this displacement can be measured directly.

Of course, more than n + 1 wavelengths can be contained in the beam and also detected wavelength-selective. By using p wavelengths, where p> n + 1, one usually comes to an overdetermined system of equations, which can be solved by minimizing the sum of the error deviations.

If p wavelengths are used, p pairs of wavelengths are also formed in step d, and a difference value is determined for each of the p pairs in step e. In step f, of course, n dispersions are still provided, which are used in step g for the linear superposition.

In the method, the sample material may comprise a main medium for which in step f a relative dispersion is provided which describes only the influence of the main medium on the dispersion of the sample material as a function of the wavelength difference and the span to be traversed by the measuring beam, and in step g, in addition to the n relative dispersions of the n substances with the concentration of the individual substances as a parameter, the relative dispersion of the main medium with the route to be traversed is taken into account as a parameter for determining the concentration of the at least one substance.

In particular, for example, when measuring the concentration of a substance in the aqueous humor of the eye, n + 2 wavelengths in the beam may be used, with the additional (n + 2nd) wavelength being used to determine the length of the anterior chamber.

In particular, the individual wavelengths of the beam have a bandwidth such that their coherence length is greater than 0.1 mm. In addition, if their coherence length is even smaller than 5 mm, that is in the range of 0.1 to 5 mm, the additional advantage can be achieved when determining the concentration of a substance in the aqueous humor of the eye, that when focusing the Meßbündels on the Lens front side unwanted reflections on the cornea lead to no (or a very small) contribution to the interference radiation due to the specified coherence length.

Furthermore, the reference beam in step b can be guided through a dispersion reference unit which compensates at least part of the dispersion of the sample material. This is understood here to mean that the dispersion reference unit imparts a similar phase shift to the reference beam as the phase shift that impresses the sample material to the measuring beam. The dispersion of the dispersion reference unit is of course known and is taken into account in the concentration determination.

The dispersion reference unit is particularly advantageous if the sample material has a main medium (in the determination of the concentration of a substance in the aqueous humor of a person's eye, the main medium is the water in the aqueous humor), which imparts a relatively large phase change to the measuring beam. In this case, this phase change, which is relatively large compared to the phase change caused by the individual substances in the aqueous humor, can be largely compensated by the dispersion reference unit.

The dispersion reference unit may comprise a dispersion reference body which may be formed as a transparent solid or liquid of known dispersion (e.g., of known thickness and temperature). In a Michelson interference setup for step b), the beam splitter can be designed as a dispersion reference body.

The dispersion reference unit can also be designed such that the reference beam is divided into different reference sub-beams as a function of wavelength, the dispersion of which is compensated in each case as a function of wavelength and then superimposed to form a dispersion-compensated reference beam, which is combined with the test beam in FIG

Step b) is superimposed. This can be used, for example, in a Michelson construction to provide different reference arms of different lengths, so that excellent dispersion compensation can be performed.

In the method, the measuring beam can be reflected back into itself and thereby pass through the sample material twice. This is easily achieved, especially in a construction according to Michelson.

In particular, the measuring beam is focused in the plane in which it is reflected. When determining the concentration of a substance in the aqueous humor of the eye, this is for example the interface between the aqueous humor and the front of the Eye lens. The focus position can be determined by changing the focus length. On the other hand, the distance between the sample material to be examined and the plane in which the measuring beam is focused, can be changed.

Furthermore, the interference radiation may be substantially opposite to the beam. In this case, the method can be realized with an extremely compact measuring device.

Furthermore, the object is achieved by a device for measuring the concentration of at least one substance from a group of n substances located in a sample material and influencing the dispersion of the sample material, with an interferometer module having a measuring arm and a reference arm, wherein the sample material in the Measuring arm is arranged, a the interferometer module downstream detection module, a beam generating module which generates a beam having electromagnetic radiation with a discrete wavelength spectrum with n + 1 different wavelengths and which is divided by the interferometer into a Meßbündel for the measuring arm and a reference beam for the reference wherein the interferometer module passes the measuring beam through the sample material and then superimposed with the not guided by the sample material reference bundle from the reference arm for generating interference radiation and the detection module, which measures the intensity of the interference radiation simultaneously and selectively for each of the n + 1 wavelengths, an evaluation module that forms n pairs of wavelengths from the n + 1 wavelengths such that the wavelength difference of each pair is different from all the wavelength differences of the other pairs, measured intensities for each of the n pairs each determined a difference value between the refractive index of the sample material for the one wavelength of the pair and the refractive index of the sample material for the other wavelength of the pair, for each of the n substances provides a relative dispersion, which only the influence of the individual Substance on the dispersion of the sample material as a function of the wavelength difference and the concentration of the corresponding substance, and a total dispersion having the determined refractive index differences as functional values, by linear superposition of the n relative dispersions with the concentration of the individual Substances are determined as parameters and thus the concentration of the at least one substance.

With this device, it is possible to measure the concentration of the at least one substance with high accuracy, wherein the structure of the device has a low overall complexity and the measurement time can be very low. In the apparatus, the beam generating module can simultaneously measure the n + 1 wavelengths and the intensities of the n + 1 wavelengths in the beam for intensity measurement of the interference radiation, and the evaluation module can use the measured wavelengths and intensities of the n + 1 wavelengths in the beam to determine the refractive index difference. Thus, it is possible to use inexpensive laser diodes, since the temporal variations in intensity and wavelength of such low-cost laser diodes are detected by the measurement by means of the beam generation module and therefore can be considered.

The evaluation module can select one of the n + 1 wavelengths as the reference wavelength, which is one of the two wavelengths in each of the n pairs. This simplifies the calculations of the substance concentration.

The sample material may be the aqueous humor of an eye, in which case the Mefibündel is reflected at the interface between aqueous humor and eye lens. This makes it very easy to measure the sugar concentration in the aqueous humor of the eye. If the dependence of the glucose concentration in the aqueous humor on the glucose concentration in the blood is known, the glucose concentration in the blood can thus be determined by measuring the glucose concentration in the aqueous humor of the eye.

In particular, the detection module confocally detects the measuring beam. This increases the accuracy of measurement.

The interferometer module has in particular a structure according to Michelson. With this structure, the required measurement accuracy can be easily achieved.

The evaluation module may provide each of the n relative dispersions, each related to an n + 1 wavelength. In particular, the evaluation module provides the n relative dispersion with respect to the reference wavelength.

The sample material may comprise a main medium, wherein to provide the relative dispersion for each substance, the phase change for different wavelengths at a predetermined concentration of only one substance in the main medium is measured. For this measurement, a conventional interferometer can be used. However, it is also possible to use the device according to the invention for this purpose. In this case, both the reference arm and the measuring arm can be completed by an end mirror. In the reference and Meßarm the main medium of a certain thickness is introduced in each case, wherein in the measuring arm or in the reference arm the main medium of a substance is supplied with the predetermined concentration. Then, for different wavelengths, the relative dispersion can be measured.

The device according to the invention can also determine the length of the distance that the measuring beam passes through the sample material, and the evaluation module can take into account the length in determining the refractive index differences.

The beam generation module may comprise a measuring unit which continuously measures the individual wavelengths. This makes it possible to use relatively inexpensive laser diodes whose actual wavelength is always measured.

For measuring the wavelength, for example, at two positions in the beam path of the beam for each of the wavelengths a portion of the radiation can be coupled, wherein the decoupled at both positions radiation is superimposed so that interference radiation is generated. The intensity of this interference radiation is measured as a function of wavelength. From the exact knowledge of the distance of the two positions, the exact wavelength can be calculated. In particular, two plane-parallel interfaces can be arranged at the two positions. This can be realized in a particularly simple manner by means of a cavity resonator which has two spaced-apart and parallel aligned interfaces in the propagation direction of the radiation beam. These can be realized for example by wedge-shaped plates, wherein the mutually facing sides of the wedge-shaped plates are aligned parallel to each other. The wedge-shaped plates are preferably welded with a plane-parallel spacer layer around the beam cross-section of the same material, so that an airtight interior closed, in which gas or air can be located or in which there is a vacuum. The wedge-shaped plates and the spacer layer are dimensioned and formed from such a material that the distance between the facing sides, for example, by not more than 10 ^"6 changed.

Furthermore, in the reference arm of the interferometer module, a dispersion reference unit can be introduced, which compensates a part of the dispersion in the measuring arm (as the reference beam imprinted a similar phase shift as the sample material to the measuring beam). This is particularly advantageous in the measurement of the concentration of a component in the aqueous humor of a person's eye, since the dispersion reference body in this case is preferably designed so that it can change the phase by passing through the aqueous chamber alone (ie the aqueous humor without the other components ) as well as completely compensated. The dispersion reference body may include, for example be transparent solid or a liquid each having a known thickness, temperature and dispersion. In a Michelson setup, the dispersion reference body may be the beam splitter for splitting the beam into measurement and reference beams.

However, it is also possible to arrange a dispersive element in the reference arm, which splits the reference beam as a function of wavelength and thus couples the reference beam into a plurality of reference lower arms. The length of each reference lower arm can be adjusted individually (for example via the position of the end mirror), whereby an excellent dispersion compensation can be achieved. Of course, in at least one subarm again a dispersion reference body can be arranged. In this case, the length of the corresponding partial arm can not (but need not) be adjustable.

The number of reference lower arms preferably corresponds to the number of wavelengths. For splitting, the dispersive element may be e.g. be designed as a prism, dichroic mirror or as a grid.

In general, the merging or splitting of the individual radiations can take place here via dichroic dividers, via a grating or via a prism.

The beam generation module can have, for example, n + 1 beam sources. For each of the radiation sources, the actual wavelength can be continuously measured. The measurement can be carried out for example with the above-described Hohlraumresonatoreinheit, said ^"should guarantee. ^6, the length of the interior of the Hohlraumresonatoreinheit so should not vary with time and not more than ^10" a measurement accuracy of the wavelengths of 10 change. ⁶

Alternatively, it is possible that at least one of the radiation sources is wavelength stabilized, e.g. a wavelength stabilized laser. In this case, the length of the interior of the Hohlraumresonatoreinheit could change over time, since this length can be normalized by the wavelength-stabilized laser and thus the wavelengths of the remaining radiation sources can be determined very accurately.

In particular, the device also has a focusing module with which the focus position of the measuring beam can be changed in the direction of propagation. In particular, the focusing module is designed so that the measuring beam can be focused at least on the back of the cornea and on the front of the eye lens. This is preferably realized by moving the entire interferometer module relative to the sample material. Alternatively, the sample material may also be moved relative to the interferometer module. In determining the concentration of a constituent of the aqueous humor of an individual's eye, the measured concentration of the constituent may be compared with, for example, the concentration of that constituent in the person's blood. The concentration in the blood will usually be invasive to determine. If, for example, the sugar content in the blood is to be determined, the sugar content in the aqueous humor of the eye can be determined. With the invasive blood sugar determination carried out at the same time, a correction factor or a correction function is then obtained, which makes it possible to convert the blood sugar concentration or the blood sugar level based on the measured sugar concentration in the aqueous humor. The correction factor or the correction function can be stored in particular in the evaluation module of the measuring device.

The device may also be designed so that the interference radiation extends substantially in the opposite direction to the beam in the beam generating module, so that the same optical elements for guiding the beam and for guiding the interference radiation can be used. This leads to a saving of optical components, whereby the device is smaller, lighter and cheaper overall.

Of course, in the described device, more than n + 1 wavelengths can be used in the same way as described above in connection with the measuring method.

The device according to the invention may in particular be designed so that the method according to the invention and the developments of the method according to the invention can be carried out with it.

The invention will be explained in more detail with reference to the drawings by way of example. Show it:

Fig. 1 is a schematic view of a first embodiment of the invention

Contraption;

Fig. 2 is an enlarged fragmentary view of the eye A of Fig. 1; FIG. 3 is an enlarged view of the cavity resonator unit 25 of FIG. 1; FIG. Fig. 4 is a schematic side view of a part of the beam generation module 1 of Fig. 1; Fig. 5 is a graph showing relative dispersions of individual aqueous humor components; Fig. 6 is a schematic view of a second embodiment of the device according to the invention, and FIG. 7 is a schematic side view of a portion of the beam generating and measuring module of FIG. 6. FIG.

In the embodiment shown in Fig. 1, the inventive device for measuring the concentration of at least one substance from a group of several in a sample material and the dispersion of the sample material influencing substances is designed so that with it the glucose concentration in the aqueous humor of an eye A of Person can be measured.

In this measurement, the fact is exploited that changes with changing glucose or sugar concentration in the aqueous humor, the refractive index of the aqueous humor. However, other ingredients are still present in the aqueous humor, e.g. NaCl, albumin, lactate, alcohol and urea, whose concentrations also vary, which also leads to a change in the refractive index of the aqueous humor. However, the influence of the further components of the aqueous humor on the refractive index can be taken into account with the device according to the invention such that the desired sugar concentration can be measured.

For this purpose, according to the invention with the device, as will be described in more detail below, at the same time a phase shift caused by the aqueous humor is measured interferometrically for different wavelengths. In order to determine the portion of the phase shift caused by the sugar and hence the sugar concentration, it is assumed that the known influence, the sugar and each of the further components alone, as a function of its concentration on the refractive index of the aqueous humor. Calculated can then be determined from the known influence of the individual substances and the measured phase shift, the concentration of each of the substances and thus also the sugar concentration. The proportion of aqueous humor in the phase shift is also taken into account, since this is usually due to a slight change in the length of the anterior chamber, e.g. due to temperature changes or because of the pulse beat of the person, is not constant.

For this purpose, the device has a beam generation module 1, an interferometer module 2, a detection module 3 and an evaluation module 4.

In the embodiment described here, the beam generation module 1 comprises eight laser diodes 5 to 12, each of which emits a laser beam with a different wavelength. The laser diodes 5 to 12 used laser beams with the wavelengths 405 nm, 445 nm,

475 nm, 532 nm, 632 nm, 780 nm, 980 nm and 1300 nm. These eight laser beams with the eight different wavelengths are collimated by means not shown lenses and superimposed on dichroic divider 13 to 19 to a beam 20.

The beam 20 is directed via the elements 21 to 26 and 56, which will be explained in more detail below, to a beam splitter 27 of the interferometer module 2. The beam splitter 27 splits the beam 20 into a measuring beam 28, which is directed to the eye A located in the measuring arm 30 of the interferometer module 2, and into a reference beam 29, which is directed into a reference arm 31 of the interferometer module 2. The reference arm 31 has an end mirror 32 which reflects the reference beam 29 back to the beam splitter 27.

In the measuring arm 30, the measuring beam 28, as shown in particular the enlarged detail view of the eye A in Fig. 2, through the cornea 33, the aqueous humor 34 in the anterior chamber of the eye A and is at the interface between aqueous humor 34 and eye lens 35 in reflected back, so that the measuring beam 28 runs to the beam splitter 27 and is superimposed co-linear there with the reference beam 29 reflected back from the end mirror 32.

In the described embodiment, the beam 20 or Meßbündel 28 is focused on the front as an eye lens 35. The two mirrors 23, 24 and the pinhole diaphragm 56 cause confocal filtering of the beam 20 to ensure the colinearity of the laser beams in the beam 20.

The optical lengths of the measuring and reference arm 30, 31 are chosen so that the superimposed by means of the beam splitter 27 Meßbündel 28 and reference beams 29 interfere with each other, so that interference radiation 36 is generated (Fig. 1). The intensity of the interference radiation 36 is measured in the detection module 3 selectively for each of the eight wavelengths.

For this purpose, the interference radiation 36 is guided via a concave mirror 37 through a diaphragm 38. The concave mirror 37 and the diaphragm 38 are used for confocal suppression of unwanted interference radiation, that is to say interference radiation which has not been generated by the reference beam 28 reflected at the eye lens 35 and the reference beam 29 reflected at the end mirror 32. The interference radiation 36 thus detected confocally is reflected at a further concave mirror 39, which directs the interference radiation 36 as a parallel beam onto a prism 40, which deflects the different wavelengths in the interference beam due to its dispersion to different degrees.

The interference radiation 36 emerging from the prism 40 and fanned as a function of the wavelength strikes a concave focusing mirror 41 which detects the Interference radiation directly or via the polygon mirror 42 to eight separate detectors 43, 44, 45, ... 50 directs. To simplify the illustration, only the respective beam axis for each of the eight wavelengths is drawn from the focusing mirror 41 to the detectors 43-50. The intensity values thus measured are a measure of the phase shift between the measuring beam 28 and the reference beam 29 and thus also a measure of the sugar level in the aqueous humor and are supplied to the evaluation module 4.

In addition, the intensities and precise wavelengths of the laser beams of the eight laser diodes 5-12 are supplied to the evaluation module 4 (ie, the laser radiation coupled into the interferometer module 2), which are measured as follows.

The laser radiation generated by the laser diodes 5-12 is linearly polarized and is passed through a polarizer 21 (here a Rochon prism or a Wollaston prism), from which the beam emerges linearly polarized and then through an achromatic λ / 4 element 22 (here eg a Fresnel rhombus or a K prism), which converts the polarization into circular polarization. The radiation beam 20 with circular polarization is directed via the two concave deflection mirrors 23 and 24 onto a cavity resonator unit 25.

As can be seen in the enlarged cross-sectional view in Fig. 3, a cavity between a front and rear glass element 51, 52 is formed by

Spacers 53 and 54, which are also made of glass, sealed to the outside. The elements 52 to 54 are all made of a special glass which has a very low expansion with temperature changes. The facing sides of the front and rear glass elements 51 and 52 are aligned parallel to each other and have a reflectivity of about 4%.

As indicated in Fig. 3, therefore, a certain part of the beam 20 is reflected back on both sides in each case. The reflected portions interfere with each other and are guided via the mirrors 24 and 23 to the λ / 4 unit 22, which converts the circular polarization of this radiation into linear polarization, the polarization direction being 90 ° to the polarization direction of the polarizer 21 to the λ / 4 unit 22 coming beam 20 is rotated. Due to this rotated linear polarization, the polarizer 21 deflects the reflected-back light downwards, as shown diagrammatically in the side view of FIG. The back-reflected light therefore does not strike the laser diode 5 but the detector 55 arranged below the laser diode 5, which measures the intensity of the back-reflected radiation. In the embodiment of Fig. 1, a detector 55 is disposed below each laser diode 5 to 12 so that, due to the diochroic splitters 13 to 19, the intensity of the back-reflected radiation can be selectively measured for each wavelength. From the measured intensity, the wavelength of the laser radiation in the beam 20, which is coupled into the interferometer module 2, can be calculated for each laser diode 5-12. For this purpose, of course, the measured values of the detectors 55 are supplied to the evaluation module 4 via lines not shown.

Since the distance of the mutually facing sides of the glass elements 51 and 52 is known, the actual wavelength of the respective laser radiation can be calculated from the measured intensity. The accuracy of the measurement of the actual wavelength depends on the accuracy with which the distance of the two mutually facing sides of the glass elements 51 and 52 is known. Since the glass elements have an extremely low thermal expansion and the cavity resonator unit 25 can still preferably be kept at a constant temperature in order to avoid temperature changes in the enclosed cavity, the distance between the two sides is known with an accuracy of 1.times.10.sup.- ⁶ be measured with this accuracy, so that even rapid time fluctuations of the wavelengths can be measured synchronously to the measurement of the interference signals in the detector module 3.

The opposite sides of the front and rear glass element 51, 52 are inclined relative to the sides facing each other so that the radiation reflected on the opposite sides of the radiation does not enter the detector 55 (it is for the most part already held by the aperture 56), so that this radiation does not affect the measurement of the intensity of the radiation reflected at the mutually facing sides of the glass elements 51, 52.

With the device described, it is thus possible to measure the intensity and wavelength of the individual laser beams of the laser diodes 5-12 extremely accurately and also to simultaneously measure the intensity of the interference radiation 36 for the different wavelengths.

With these measured values and the knowledge of the length L of the anterior chamber, which is traversed by the measuring beam 28, one can calculate refractive index difference values Δn (λ) = n (λ) -n (λo) from the following formula:

_{An (λ) (1)}

where l (λ) is the measured intensity of the interference radiation, l _o (λ) is the intensity of the corresponding wavelength in the incident beam 20 and n (λ) is the wavelength-dependent refractive index of the chamber water. Δn (λ) can be referred to as a relative dispersion of the aqueous humor with respect to a reference wavelength X ₀ . Due to the fact that only the refractive index difference values are determined here, the parameters which change the phase but do not depend on the wavelength need not be known, since these parameters cancel each other out during the subtraction. Since the measurement is carried out simultaneously for all wavelengths, even temporal fluctuations of individual parameters, which are caused, for example, by the pulse beat and hardly to be avoided eye movements, have no influence on the measurement accuracy. This simplifies the measurement significantly.

Furthermore, for various substances contained in the aqueous humor, whose concentration can vary and which change the refractive index of the aqueous humor, the relative dispersion Δn _stO ff (K λ) = n _stOff (k, λ) -n _Sto ff (k, λ ₀ ) as a function of the substance concentration k and relative to the reference wavelength λ ₀ . In Fig. 5, the relative dispersion for five aqueous humor components for each of the indicated concentration is shown. It is plotted along the x-axis and along the y-axis in rad the

Wavelength difference

2πL 'relative dispersion times (hereinafter also referred to as the relative dispersion phase). L 'λ is a known length to be considered for obtaining the relative dispersion shown, due to the measurement described below. As can be seen in FIG. 5, all the curves meet at point P1, which corresponds to the relative dispersion for λ = A ₀ , where here A ₀ = 405 nm. The maximum wavelength difference is 895 nm (point P2).

The measured values were obtained by arranging in each case a water-filled cuvette with a thickness L 'of 5 mm in a Michelson interferometer arrangement in both arms. For example, one of the two cuvettes was added with NaCl until a concentration of 6.5 g / l was reached. Then the phase changes were measured for the specified wavelength differences. After the relative dispersion phase is directly proportional to the concentration in the relevant concentration range, the relative dispersion phase for NaCl as a function of the substance concentration and the wavelength λ in relation to the reference wavelength λ ₀ is therefore known after measurement for a concentration. The same determination of relative dispersion is made individually for each of the remaining materials, the relative dispersion for alcohol not being shown here for ease of illustration since it is qualitatively similar to the relative dispersion of NaCl but has significantly greater absolute values for the dispersion phase , Preferably, the Determination of the relative dispersion with the same wavelengths used in the device according to the invention.

As can be seen from FIG. 5, a relative dispersion for pure water (H ₂ O), that is to say water without any of the components of the aqueous humor, is also shown. This relative dispersion is not dependent on a concentration, but on the length of the passing waterway. FIG. 5 shows the relative dispersion phase for water for a length of 40 μm. This relative reference dispersion phase was determined by arranging in each case a water-filled cuvette in a Michelson interferometer arrangement, with a first cuvette being 5 mm thick (= L ') and the second cuvette being 40 μm thicker than the first cuvette cuvette. This makes it possible to consider the influence of the anterior chamber length, since the relative dispersion of water is directly proportional to the water length. As far as the concentration of a substance is mentioned here, the water to be traversed is always meant for water.

In order to determine the sugar concentration, the evaluation module 4 carries out a linear superposition with the known relative dispersions of six individual substances (FIG. 5) with the concentration of the individual substances as parameters and the relative dispersion of water with the water length as parameters in such a way that they come from them resulting relative total dispersion having the values of relative dispersion (according to formula 1) determined as functional values. The resulting parameters then correspond to the concentrations of the substances in the aqueous humor (or, in the case of water, the parameter value of the water segment corresponds to).

In other words, a linear equation system with m equations and m unknowns is set up, which can be solved analytically. It is thus possible, e.g. To accurately determine the glucose concentration in the aqueous humor by a single, rapid measurement. At the same time, if the sugar concentration in the person's blood is determined by a known invasive method, it can be deduced from it for the person e.g. determine the conversion factor to convert from the glucose concentration in the aqueous humor to the glucose concentration in the blood. This conversion factor can e.g. be stored in the evaluation module 4 and can be used in the future to non-invasively determine the blood glucose concentration for this person with the described method and / or the device described.

In the above formula 1 for the relative dispersion of the aqueous humor, the knowledge of the length L of the anterior chamber of the eye A was assumed. However, since, as described above, the relative dispersion phase of water in the computational Determining the sugar concentration is taken into account, an approximate knowledge (eg ± 10%) of the length L. The error of eg ± 10% is compensated in the computational determination by taking into account the relative dispersion phase of water. This is advantageous in that therefore the length L at the time of measurement can be determined extremely accurately. If one did not consider the relative dispersion of water, one would have to know the length L with extremely high accuracy at the time of measurement. However, since even by the pulse of the person during the measurement to be taken into account a change in the length L, one would have to measure extremely accurately at the measurement time, the length L with another device, which is hardly possible, and if so, then only with very large Effort. Therefore, the described path is preferably chosen here, in which one determines the length L of the anterior chamber with an accuracy of, for example, ± 10% and, during the mathematical determination as a substance, takes into account the relative dispersion of water.

The length L can be measured in advance, for example, with known measuring devices. As a rule, a single determination suffices for an eye and a person, since the length L of the anterior chamber can be determined with the desired accuracy of e.g. ± 10% is considered to be a substantially constant value for a person. The anterior chamber length is usually in the range of 1, 5 to 6 mm.

Furthermore, the length L can also be derived directly from the determined refractive index difference values. It is assumed that only the length of the anterior chamber (and thus the length of the aqueous humor passed through the laser radiation) determines the measured relative dispersion values or the measured phase. Thus, the influence of the substances on the phase is neglected, which is possible here because the absolute influence of the substances on the phase is about 10% and the sugar concentration should also be determined with an accuracy of 10%. To calculate the length of the anterior chamber, one starts from the relative dispersion phase of water as a function of the passing length in the water. The evaluation module 4 can determine the relative total dispersion by varying the length L (in formula 1), in which the determined values of the relative dispersion phase are contained as function values.

Further, in addition to the measurement described above, it is possible to measure at the interface between aqueous humor 34 and the crystalline lens 35 at the interface between the posterior surface of the cornea 33 and the aqueous humor 34. This is possible, for example, with an active calibrated focus shift. Thus, on the one hand directly the length L can be measured. On the other hand, by subtraction (the measured values in reflection at the front of the eye lens 35 on the one hand and on the back of the cornea 34 on the other hand) of Influence of the dispersion of the cornea on the dispersion measurement in reflection at the front of the eye lens 35 are calculated out.

In the previous description, it was always assumed that the absolute maximum intensity (zero order) is measured. However, it is also possible that higher interference orders are measured. This can be determined, for example, by measuring over a certain period of time. Since already due to the normal eye movements and thickness variations of the anterior chamber (eg due to the pulse beat) during the measurement, a variation of the length of the measuring arm 30 of the Interferometermodυls 2 occurs, which leads to a passage of several interference maxima, is preferably continuously measured by means of the detection module 3, so that the variations in intensity are also detected. It can therefore be determined, for example, by simply counting the maximum intensity which interference order has just been measured.

It has also been found that the linear superposition of the known relative dispersion of the individual substances with the concentration of the individual substances as parameters must be carried out successively only for the interference orders in question. A wrongly assumed interference order then leads to a relative total dispersion, the course of which already qualitatively clearly differs from the expected relative total dispersion. It is thus easy to find out the correct order of interference by testing the relevant interference orders.

With the described method, the relative dispersion can be determined at a first time. If in the consequence only changes of the concentration of the

If aqueous humor components are to be determined in relation to the concentration at the first time, the relative dispersion determined at the first time can be subtracted in the case of a new measurement. Thus, the change can be measured very accurately relative to the first time, without having to measure the dispersion of the cornea, if this dispersion should not be included in the dispersion signal of the aqueous humor.

In the dispersion measurement and the described focusing of the measuring beam 28 on the front of the eye lens 35, a passive migration of the focus can preferably be exploited, which occurs, for example, solely due to the pulse beat of the person whose aqueous humor concentration is to be measured. Further, the focusing can be effected by manually moving the eye A to and from the beam splitter 27. During the movement of the focus, the intensity of the interference radiation is continuously measured as a function of wavelength, so that the phase can also be determined continuously. To For example, the maximum and minimum of the measured intensity for each wavelength may be determined by interpolating an envelope, as the amplitude changes due to confocality and coherence. Each measured value of the detectors 43 to 50 is then related to the local amplitude and from this the phase is determined.

This described passive migration of focus can of course also be carried out in the above-described reference measurement at the interface between cornea and aqueous humor.

The embodiments and developments described above and described below can be combined with one another as desired.

So it is e.g. Furthermore, it is possible to introduce a dispersion compensation body into the reference arm. This may be, for example, a solid of known thickness and dispersion, tempered water of known thickness and / or water of known thickness with temperature measurement. Furthermore, it is possible to carry out a selective dispersion compensation for each wavelength, for example dispersive elements in the form of a grating, a prism and / or a dichroic can be used. Thus, e.g. a splitting of the beam paths for each wavelength is generated by the dispersive element, so that the reference arm is divided into n lower arms. Each forearm has an end mirror that allows the length of each forearm to be adjusted independently of the lengths of the remaining forearms. Thus, excellent dispersion compensation for each wavelength can be achieved, which facilitates concentration determination. The resulting compensation of the dispersion is taken into account in the subsequent computational determination of the sugar concentration. The dispersion compensation is advantageous here, since the relatively large proportion of the phase shift produced, which is caused by the aqueous humor and does not provide any information about the sugar concentration, can be almost completely compensated, whereby the measurement accuracy can be increased.

In the embodiment previously described in connection with FIG. 1, a plurality of (here 8) separate laser light sources are precisely measured or referenced via the cavity unit 25, the λ / 4 unit 22, the polarizer 21 and the detectors 55. This has the advantage, among other things, that this solution is extremely cost-effective. Of course, stabilized lasers can also be used. In this case, no separate measurement of wavelength and intensity is necessary. However, the cost of such a device is significantly higher due to the stabilized lasers compared to the solution shown in FIG. Instead of the individual laser light sources 5 to 12 which have been described in connection with FIG. 1, it is also possible, for example, to use one or more broadband light sources to generate the desired laser radiation which emits or emits laser radiation in one or more bands. From this band or bands then the desired wavelengths can be extracted (for example by filters, grids or prisms). The extracted wavelengths may in turn be either stabilized or referenced (as described in connection with FIG. 1).

For measuring or referencing the wavelengths, the elements 21, 22 and 25 are essentially used in FIG. However, one can omit the elements 21 and 22, if the facing sides of the glass elements 51, 52 are no longer aligned perpendicular to the incident beam 20, but at an angle of unequal

90 °. With such a tilting of the cavity unit 25, the desired

Beam separation achieved so that the reflected radiation is no longer colinear to the incident beam 20.

For example, in the apparatus shown in Fig. 1, the determination of the sugar concentration may be performed as follows. The patient holds his eye A in front of the device in the position shown in Fig. 1. If the device is compact enough, the patient can also hold the device in front of his eye. The eye is illuminated with the illumination beam 20, with the focus actively or passively traveling through the aqueous humor / eye lens interface, measuring all the signals from the detectors 43 through 50 and 55. From the measured values, the evaluation module 4 determines the relative dispersion for seven wavelength differences. Knowing the length L of the anterior chamber, the known relative dispersions of the individual substances (Figure 5) are linearly combined with the concentration of the individual substances as parameters and the relative dispersion for water with the water length as parameters such that the resulting total relative dispersion covers the determined relative dispersion values (according to formula 1). The calculated coefficient for glucose is a measure of the glucose concentration in the aqueous humor.

In the procedure described, the dispersion of the cornea 33 influences the measured dispersion since the measuring bundle 28 also passes through the cornea 33. In order to eliminate this influence, the influence of the cornea can be measured by focusing the measuring beam 28 on the interface between the back of the cornea 33 and the aqueous humor 34. In this case, a passive migration of the focus of the measuring beam 28 through this interface can also be used in this case. The thus measured relative dispersion of the cornea 33 is subtracted from the measured dispersion when focusing on the interface between aqueous humor 34 and the front of the lens 35, so that a difference Dispersion is present. The linear superposition is then carried out so that the total dispersion has the measured values of the difference dispersion determined. Thus, a higher absolute accuracy of the measurement of sugar concentration is achieved.

In Fig. 6, a further embodiment of the measuring device according to the invention is shown, which is a modification of the measuring device of Fig. 1. Therefore, like elements are designated by like reference numerals, and to avoid unnecessary repetition, reference is made to the corresponding description above regarding these elements.

The measuring device of Fig. 6 differs from the measuring device of Fig. 1 substantially only in that the cavity unit 25 is disposed between the divider 19 and the polarizer 21 in the embodiment of Fig. 6 with respect to the beam generating module 1. Further, the cavity resonator 25 is arranged so that the facing sides of the glass elements 51 and 52 are no longer aligned perpendicular to the incident beam 20, as indicated in the enlarged side view of the cavity unit 25 in Fig. 7. In order to simplify the illustration, the dividers 13 to 19 are not shown in FIG. 7 in the same way as in FIG. 4, and the beam path is shown schematically only for one laser diode (here the diode 5) and thus only for one wavelength.

Due to the oblique position of the cavity resonator unit 25 schematically shown in FIG. 7, the portions of the radiation beam 20 reflected and mutually interfering on the facing sides of the front and rear glass elements 51 strike the detector 55 arranged below the diode 5. After each laser diode 5 In the same way as in the embodiment of FIG. 1, because of the dichroic splitters 13 to 19, for each wavelength, the intensity of the back-reflected radiation can be measured selectively. From this measured intensity, in turn, the wavelength of the laser radiation in the beam 20, which is coupled into the interferometer module, can be calculated.

The beam 20 or the predominant portion of the beam 20, for which the intensity of each wavelength is measured in the manner described, passes through the elements 21, 22, the mirrors 23, 24 and 26 and the diaphragm 56 to the beam splitter 27 of the interferometer module second The measuring arm and reference arm 30, 31 of the interferometer module 2 have the same structure as in the embodiment of Fig. 1. However, in the measuring arrangement of Fig. 6, the interference radiation is detected, which runs from the beam splitter 27 to the deflecting mirror 26, which thus by superimposing the at the beam splitter 27 to mirror 26 towards reflected Measuring beam 28 is generated with the beam splitter 27 transmitted reference beam 29. The propagation direction of the interference radiation is indicated by the arrow P3.

The interference radiation is circularly polarized, since the coupled into the interferometer module 2 beam is circularly polarized due to the polarizer 21 and the achromatic λ / 4 element 22 through which the beam 20 before coupling into the interferometer module 2 runs.

The interference radiation, which now runs in the opposite direction to the direction of the radiation beam 20 in the beam generation module 1, is deflected at the mirrors 26, 24, passes through the diaphragm 56 between the mirrors 24 and 23 and then impinges on the mirror 23 on the λ / 4. Element 22. After passing through the element 22, the circular polarization of the interference radiation is converted into a linear polarization, but the polarization direction is rotated by 90 ° with respect to the polarization direction of the radiation beam 20 coming from the polarizer 21 to the λ / 4 unit 22. As a result of this rotation of the linear polarization direction, a deflection downwards takes place in the polarizer 21 (FIG. 7), which is chosen here so that the interference radiation strikes the mutually facing sides of the glass elements 51 and 52 as perpendicularly as possible. The interference radiation thus passes through the cavity unit 25 and then encounters a detector 43 which is disposed below the detector 55. Since a respective detector 55 for measuring the intensity of the supplied laser radiation and a detector 43-50 for measuring the intensity of the interference radiation of the corresponding wavelength is arranged below each laser diode 5-12, the intensity in the radiation beam and the intensity can thus be determined for each of the eight wavelengths the interference radiation are measured.

The structure can, of course, be chosen so that only the laser radiation coming from the laser diodes 5-12 passes through the cavity unit 25 and that the interference radiation no longer passes through the cavity resonator 25.

In the embodiment shown in FIG. 6, the dichroic dividers 13 to 19 are thus used both for the generation of the laser radiation (ie for the beam generation module 1) and for the detection and thus for the detection module 3. Therefore, as compared with the embodiment of Fig. 1, a plurality of optical elements (here, for example, elements 37-42) can be saved, resulting in a less expensive, more compact and lighter measuring device. Furthermore, it has been found that the influence of unwanted spurious radiation in the construction of Fig. 6 is lower and that the adjustment is easier, since the laser diodes 5 - 12 and the detectors 55 and 43 - 50 are arranged locally very close to each other. With the described method, not only the sugar concentration in a measurement on the aqueous humor can be determined, but for example, the alcohol concentration, so that the measuring device described can be used for example as an alcohol tester.

Claims

claims

1. A method for measuring the concentration of at least one substance from a group of n in a sample material and the dispersion of the sample material influencing substances, wherein a) a beam having electromagnetic radiation with a discrete wavelength spectrum, in a measuring and a B) the measuring beam is passed through the sample material and then superimposed with the not guided by the sample material reference beam to produce interference radiation c) the intensity of the interference radiation simultaneously and selectively for each the n + 1

Wavelengths is measured, d) n pairs of wavelengths from the n + 1 wavelengths are formed such that the wavelength difference of each pair is different from all the wavelength differences of the other pairs, e) from the measured intensities for each of the n pairs each a difference value between the Refractive index of the sample material for which one wavelength of the pair and the refractive index of the sample material for the other wavelength of the pair is determined; f) for each of the n substances a relative dispersion is provided which only influences the influence of the individual substance on the dispersion of the sample material describes the wavelength difference and the concentration of the corresponding substance, g) a total dispersion which has the determined refractive index differences as functional values, by linear superposition of the n relative dispersions with the concentration of the individual substances as parameters and thus the concentration of the at least one substance is determined.

2. The method of claim 1, wherein in step a) the n + 1 wavelengths and the intensities of the n + 1 wavelengths in the beam are measured and in steps d) and e) the measured wavelengths and the intensities of the n + 1 wavelengths be used in the beam.

3. The method according to any one of the preceding claims, wherein in step d) one of the n + 1 wavelengths is selected as the reference wavelength and the reference wavelength in each of the n pairs is one of the two wavelengths.

4. The method according to any one of the above claims, wherein the sample material is the aqueous humor of an eye and the measuring beam is reflected at the interface between aqueous humor and eye lens.

5. The method according to any one of the above claims, wherein the measuring beam is detected confocally.

A method according to any one of the preceding claims, wherein each of the n relative dispersions is provided in each case with respect to one of the n + 1 wavelengths.

A method according to any one of the preceding claims, wherein the sample material comprises a major medium and for providing the relative dispersions, for each substance, the phase change for different wavelengths at a predetermined concentration of only one substance in the main medium are measured.

8. The method according to any one of the above claims, wherein prior to step g) the length of the distance is determined, the measuring beam passes through the sample material, and the length in step g) is taken into account.

9. The method according to any one of the above claims, wherein in step b) the reference beam is passed through a dispersion reference unit which comprises at least a portion of the dispersion of the

Sample material compensated.

10. The method of claim 9, wherein the reference beam is passed through a dispersion reference body of the dispersion reference unit.

11. The method of claim 9, wherein the reference beam is wavelength-dependent divided into different reference sub-beams whose dispersion each is compensated wavelength dependent and are then superimposed to a dispersion-compensated reference beam, which is superimposed with the Meßbündel in step b).

12. The method according to any of the preceding claims, wherein in step a) the generated beam p has different wavelengths, where p> n + 1, in step d) p pairs of wavelengths are formed and in step e) for each of the p pairs in each case a difference value is determined.

13. The method of claim 12, wherein the sample material comprises a main medium for which in step f) a relative dispersion is provided which only the influence of the main medium on the dispersion of the sample material as a function of the wavelength difference and to be traversed by the Meßbündel in the main medium Describes route, and in which in step g) in addition to the n relative dispersions of the n substances with the concentration of the individual substances as a parameter nor the relative dispersion of the main medium is taken into account with the route to be traversed as a parameter for determining the concentration of at least one substance ,

14. The method according to any one of the above claims, wherein the Meßbündel is reflected back in itself, while the sample material passes twice.

15. The method according to any one of the above claims, wherein the interference radiation is substantially opposite to the beam.

16. The method according to any one of the above claims, wherein the at least one substance is alcohol, so that in step g) the alcohol concentration is determined.

17. An apparatus for measuring the concentration of at least one substance from a group of n located in a sample material and the dispersion of the sample material influencing substances, with an interferometer module (2) having a measuring and a reference arm (30, 31), wherein the sample material is arranged in the measurement arm (30), a detection module (3) downstream of the interferometer module (2), a beam generation module (1) which generates a radiation beam (27) comprising electromagnetic radiation having a discrete wavelength spectrum with n + 1 different wavelengths and divided by the interferometer module (3) into a measuring beam (28) for the measuring arm (30) and a reference beam (29) for the reference arm (31), wherein the interferometer module (2) guides the measuring beam (28) through the sample material and then superimposes it with the reference beam (29) not guided by the sample material out of the reference beam (31) to generate interference radiation (36) and feeds it to the detection module (3), which measures the intensity of the interference radiation (36) simultaneously and selectively for each of the n + 1 wavelengths, an evaluation module (4) which forms n pairs of wavelengths from the n + 1 wavelengths such that the wavelength difference of each pair is different from all the wavelength differences the other pairs, from the measured intensities for each of the n pairs, each determining a difference value between the refractive index of the sample material for the one wavelength of the pair and the refractive index of the sample material for the other wavelength of the pair, for each of the n substances providing a relative dispersion, only the influence of the individual substance on the dispersion of the sample Mate describes rials as a function of the wavelength difference and the concentration of the corresponding substance, and a total dispersion having the determined refractive index differences as functional values, determined by linear superposition of the n relative dispersions with the concentration of the individual substances as parameters and thus the concentration of the at least one substance.

18. The apparatus of claim 17, wherein the beam generation module (1) measures the n + 1 wavelengths and the intensities of the n + 1 wavelengths in the beam (20) simultaneously with the intensity measurement of the interference radiation and the evaluation module (4) the measured wavelengths and the Intensities of the n + 1 wavelengths in the beam (20) used to determine the refractive index differences.

19. The apparatus of claim 18, wherein the beam generating module for measuring the n + 1 wavelengths and intensities at two positions in the beam path of the beam (20) decouples a portion of the radiation for each of the wavelengths, the radiation coupled out at both positions superimposed so that Interference radiation is generated, and the intensity of the generated interference radiation wavelength-dependent measures.

20. Device according to one of claims 17 to 19, wherein the evaluation module (4) selects one of the n + 1 wavelengths as the reference wavelength, which is one of the two wavelengths in each of the n pairs.

21. Device according to one of claims 17 to 20, wherein the sample material is the aqueous humor (34) of an eye (A) and the measuring beam at the interface between aqueous humor (34) and eye lens (35) is reflected.

22. Device according to one of claims 17 to 21, wherein the detection module (3) detects the measuring beam (28) confocally.

23. Device according to one of claims 17 to 22, wherein the evaluation module (4) provides each of the n relative dispersions in each case based on one of the n + 1 wavelengths.

24. An apparatus according to any one of claims 17 to 23, wherein the sample material comprises a main medium and for providing the relative dispersions for each substance, the phase change for different wavelengths at a predetermined concentration of only one substance in the main medium is measured.

25. Device according to one of claims 17 to 24, wherein the device determines the length (L) of the distance that the measuring beam (28) passes through the sample material, and the evaluation module (4) the length (L) in determining the refractive index differences considered.

26. Device according to one of claims 17 to 25, wherein in the reference space (31) a dispersion reference unit is arranged, through which the reference beam passes and compensates at least part of the dispersion of the sample material.

27. The apparatus of claim 26, wherein the dispersion reference unit comprises a dispersion reference body.

28. The apparatus of claim 26, wherein the dispersion reference unit divides the reference arm (31) into a plurality of reference sub-arms and comprises a split unit which divides the reference beam wavelength-dependent into reference sub-beams and couples them into the individual reference sub-arms.

29. Device according to one of claims 17 to 28, wherein the evaluation module (4) determines the concentration of alcohol as the concentration of the at least one substance.