DE8126894U1 - Device for the quantitative in vivo determination of blood components by laser light scattering - Google Patents

Description

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Dr. Arno Mueller
Garden dump 22
Ulm-Mähringen

Device for the quantitative in vivo determination of blood components by laser light scattering

The invention relates to a highly sensitive device for the injury-free transcutaneous quantitative determination of blood components, in particular of Glucose, in vivo on living organisms.

The invention is based on the physical principle of light scattering. It is known that by interaction For example, a monochromatic light beam with a molecule depends on the type and structure of the molecule Light scattering occurs. In a multi-component system, e.g. a biological system such as the human blood, however, contains very many different molecules of different sizes, so that of a selective determination of only one component, eg glucose, by light scattering does not appear to be possible from the outset.

709-X2145 G-SF-CH

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t) 1 II »

The invention is based on the object of a highly sensitive device for quantitative transcutaneous in vivo determination of blood components such as proteins, hemoglobin, blood cells and in particular of glucose indicate in vivo on living organisms, with a selective and quantitative determination of one or more certain components should also be possible in the presence of other dissolved or disperse substances.

The problem is solved according to the claims.

The device according to the invention represents a laser diffractometer or a laser light scattering photometer and essentially comprises a light source, a sample space, one or more light detectors to measure the intensity of the central beam or the scattered light, a device for processing the measured values of the intensity of the central beam and the scattered radiation, if necessary one or more mirrors and, if applicable, a device for output, display, registration, Signaling and / or forwarding of the measurement results.

The device according to the invention for the quantitative determination of dissolved low molecular weight and certain of high molecular weight substances in single and multi-component systems, whereby the individual components are in linear dimensions sufficiently distinguish the molecules, their structure and / or composition and / or molecular weight, is characterized by - a basically U-shaped support with a joint with a spring provided in its bottom area, which presses the two side parts of the carrier against each other under spring pressure, and such Distance of the two side parts from each other that in the space between the two side parts

Ill «

I t (

t

a human earlobe can be inserted into the wearer and held in it like an ear clip,

- one provided on or in a side part of the carrier, laser diode arranged in a cooling block, - a deflecting mirror attached above the laser diode, which deflects the light emitted by the laser diode by about 90 ° in an approximately horizontal direction,

- An optical receiving part provided opposite the deflecting mirror on the other side part of the carrier, the the central ray and the scattered radiation of the earlobe passing through the inserted into the wearer or scattered light of the laser diode detected in at least one predetermined angular range and over at least a light detector supplies corresponding electrical signals,

- an electronic signal processing device with amplifiers and devices for correcting the measurement signals,

- A signal display device and / or a signal output device

as well as |.

- a power supply, wherein the electronic signal processing device, the signal display device and / or the signal output device and the power supply each with the Carriers are integrated or provided independently of him.

Advantageous developments of the invention are shown in | '

specified in the subclaims. i

f

The device according to the invention is particularly suitable for transcutaneous measurements on skin folds and especially on the earlobe. It is according to the invention accordingly preferably designed in miniaturized form and represents an ear clip-like arrangement with the

• «O *.» * · ItY * ^ J

- ft -

for example the blood glucose concentration without injury can be measured transcutaneously in vivo.

The invention is based on the surprising finding that, contrary to professional expectation, solved low-molecular and macromolecular components such as proteins and hemoglobin as well as larger particles, like blood cells or blood cells by laser | Light scattering can be determined quantitatively and selectively can.

The principle of the invention is explained by way of example below with reference to the determination of glucose. I.

The size of the glucose molecule is between the

+ + 2+
The size of ions such as K, Na, Ca and the like and the size of macromolecules such as lipids, proteins and the like as well as the blood cells. While the wide-angle scattering is predominantly characteristic of the above ions, the small-angle scattering is primarily characteristic of the macromolecules. For molecules that are in between in terms of size, such as glucose, a range of scatter is decisive that lies between the wide-angle scattering and the small-angle scattering.

The method of measuring light scattering on small particles is theoretical for both gases and solutions thoroughly investigated (see H.C. van de Hülst, Light Scattering by Small Particles, John Wiley and Sons, New York 1957, Ch. Tanford, Physical Chemistry of Macromolecules, John Wiley and Sons, New York 1961; W. Holzmüller, K. Altenburg, Physics of Plastics, Akademie-Verlag, Berlin 1961 and E.P. Geiduschek and Holtzer, Advances in Biol. And Med. Phys. 6 ^ (1958) 431); due to the existing theoretical foundations must be checked whether

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the respective requirements for the angular range in question are valid.

The ratio of the scattered light intensity I to the intensity I of the incident light

2 1t ² η ² (dn / dc) ² Mc

γ = ² -4 '2 (1 + cos Θ ²⁾ (1);

ο N · \ · r

in this equation mean:

M I = intensity of the incident light

s I = intensity of the scattered light

η = refractive index of the solvent c = molar concentration

dn / dc = change in the refractive index of the solution with the

concentration

M = molecular weight of the solute N = Avogadro's number (Loschmidt's number / molar volume J. r = distance from the scattering center

λ = wavelength of the incident light θ = angle in the forward direction, measured to the primary beam .

The so-called scatter vector s, which is defined by, is usually introduced in the literature

IN _ 2 sin θ

IS ι - - ^ ■

Λ.

30 In the case of laser light scattering, the exponential approximation is useful for the central line:

(s) = (q _o V _Q ) e ^% ' ^S d' (2),

35 where mean

- 10 -

oV = number of scattering particles

'O O

R = scattering radius

{see W. Koechner, Solid-state Laser Engineering, Springer-Verlag New York (1976), R. Beck, W. English, K. Cürs; Table of Laser Lines in Gases and Vapors, Springer, Berlin (1976) and H. Kressel, Editor, Topics in Applied
Physics, Vol. 39, Semiconductor Devices for Optical Communication, Berlin, - Heidelberg, New York (1980)).
10

The scattering mass radius of the central line is here in its physical meaning a characteristic for the laser line and the pure solvent (e.g. water). From the ratio of the intensities at s = 0 and for example s = 0.4, the scattering mass radius

determine. For glucose, a ratio of 47.5: 1 results at a wavelength of 0.829 μm; it follows from this a scattering mass radius R of 0.233 μΐη.

To capture all of the scattered radiation, you have to
the occurring interferences are taken into account by an additional term. Using the same approximation that was used in equation (2), the following relationship results for the interference function:

I ¹ (S) =

2 π

1Ö - e TO

the constants R have the following meaning:
30th

R ₁ = inner radius of the scattering centers

R "= outer radius of the scattering centers, where the

Scatter zones have different densities.

The total intensity is a good approximation

- 11 -

additively from the partial intensities. However, since the amplitude always decreases with increasing interference, I '(s) must have a negative sign. This results in the solution for the entire scattering intensity the relationship

Ks) = I ⁰ (s) - I ¹ (s) (4).

In principle, the sizes R. and R ₂ depend on the concentration of the respective solution. However, since this dependency can be very different for each component of a multicomponent solution because of the different interactions, and interactions between molecules of different types must also be taken into account, this dependency is very difficult to determine.

Ks is therefore useful, the influence of concentration of the dissolved substance, for example of glucose, through a formalistic product approach of the form

Ks) = 1 ° (s) - F (c) I ¹ (S) (5)

to be taken into account, whereby the following power approach appears reasonable for F (c):

F (c) = Ac ^B ,

where A and B represent constants to be determined empirically.

First of all, two cases with different spreading behavior should be distinguished for explanation: 1. one-component solutions and 2. multi-component solutions, eg biological systems.

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1. One-component solutions, e.g. solutions of glucose in water:

Formula (1) results in the proportionality of the intensity of the scattered radiation to the concentration of the scattering substance; this proportionality is to be expected experimentally, at least for low concentrations, since at high concentrations the interactions of the dissolved molecules with one another can lead to interference phenomena (see S. Flügge, (editor) Handbuch der Physik, Volume XXXII (structural research), Prof. Dr. WW Beeman , Size of Particles and Lattice Defects, Berlin, Heidelberg, Göttingen, 1957).
15th

For hemoglobin solutions in water there was a decrease only in the concentration range of 10% and more Expcrimcntell the intensity of the scattered radiation at a scattering angle of about 1 ° with increasing concentration established.

For the person skilled in the art, there was therefore no expectation that low molecular weight substances such as For example, glucose can be determined quantitatively in aqueous solutions even at low concentrations by light scattering permit.

It is completely surprising in the context of the invention that even at concentrations of glucose around 1% in Water when using a He-Ne laser (power approx. 8 mW) as a light source in an angle range of 0.5 to 1.5 ° results in a decrease in the intensity of the scattered radiation with the concentration, the maximum of the change in intensity being around 1.5 °.

- 13 -

Such surprising measurement results are shown in FIG., Where the change in intensity with the glucose concentration is plotted on the ordinate and the scattering angle is plotted on the abscissa.
5

Equation (5) gives the relationship for the change in intensity with the glucose concentration

ims) = C. IMs) (6)

3) d -A F. • (C) c ^B " ¹ dc d C. with C = B

15th

This function is with the parameters R ₁ = 3.0 μηι,

2
R ₂ = 3.12 μπι and 0 (9.V ₁ Zo ₀ V ₀ ) = 0.6 shown in Fig. 1 for a 1% solution of glucose in water as a dashed line. The measurement results are as

drawn curve entered. Fig. 1 shows accordingly that the theoretical approach of equation (6) one at least qualitatively with the measurement with regard to the angular position of the maximum of the change in intensity provides good match.

25th

A better agreement of a theoretical approach with the measured values shown in FIG. 1 can be achieved by a more differentiated elaboration of the function F (c) and / or by examining the dependence of the radii R ₁ and R "on the concentration of the solution.

A possible physical interpretation of the surprising light scattering phenomena explained above in low-concentration solutions low-molecular

ι β

- 14 -

rer substances is that even at low concentrations associative interactions between the Glucose molecules take place, whereby these assemble to form associations and in this way to lead to scattered radiation that cannot be deduced from the dimensions of a single molecule.

The intensities measured at 1.5 ° result in the ratio formation from equations (2) and (3) the relationship

I ¹ (S ₁ ) (S ₁ V ₁ ) ² x 0.0144
⁼

it follows from this

ⁿ o

- = 0.5. ⁿ 1

This means that about half of all molecules contribute to this scattered radiation.

2. Light scattering on multi-component solutions, e.g. biological systems such as blood:

In multi-component systems and especially biological systems, the interaction of the molecules is with each other with certainty no longer · negligible. This does not result in a fundamental one different shape of the scatter curve, but an order of magnitude different ratio the intensities at different scattering angles. While with one-component solutions about the above illustrated example an intensity ratio of

• ι β t> ι

- 15-

0.003 is present at a scattering angle of about 1.5 °, intensities are to be expected in multi-component systems with the same scattering angle, the ratio of which is approximately equal to 1. Theoretically, the intensity of the central ray can be below the intensity of the scattered radiation at certain angles (cf. A. Guinier, X-Ray Diffraction, WH Freeman and Company, San Francisco, 1963). In this publication, the scattering intensities are ^{investigated and calculated as a function of the quantity v} m / ^v o, where V _{M is} the volume of the molecule under consideration and V _{0 is} its free volume, which is inversely proportional to the concentration.

S-interpret. For V / V ₀ = 0 there is the usual form of a | ^!

Scatter curve (bell curve shape), while for V / V ₀ > 0.25? the intensity of the central ray initially increases with increasing scattering angle and only then decreases.

If one now examines this quantity, e.g. for different blood components, one finds that it is

cose has the value of about 10 ~ ³ , with numerous |

other blood components show similarly low values, | while the erythrocytes with 0.4, proteins with 0.1 '■

and hemoglobin of 0.3 for these considerations have values in a relevant range.
25th

For Conc & therefore tion as intended in the blood are erythrocytes, proteins as well as hemoglobin, resulting in a newly \-like transcutaneous determination of the erythrocyte, the <Hb values resulting invention udgl while the quantitative determination of glucose in the blood in this way initially seemed impossible.

Based on the experience of scattered light measurements with low-concentration glucose solutions in water,

- 16 -

within the scope of the invention an attempt to determine the glucose in multi-component solutions (such as blood) undertaken, which, contrary to expectations, was successful.

The invention is based on the completely surprising finding that low molecular weight substances, such as glucose, in multi-component systems such as blood, can be determined quantitatively by laser light scattering.

This finding can theoretically be explained as follows;

If the concentration of a low molecular weight component, such as glucose, changes in the blood, then the free volumes of the other components and thus the V / V ratios also change. (i = 1, 2, 3 ...), whereby the components indicated with i have values in the theoretically relevant range (0.1 - Mi - 0.5); thus changes

^V oi
the shape of the scatter curve.

However, for reliable identification of the low molecular weight component to be analyzed, eg glucose, additional information can be used or certain requirements are met. this means above all that the concentrations of the relevant components must remain constant. The constancy of the Blood cell concentration is known (Scientific Tables Geigy, Sub-Volume Hematology and Human Genetics, CIBA-GEIGY AG, Basel, 8th edition, 1979). An influencing of the free volume of the blood cells by different However, glucose concentrations are anyway because of the different by about seven orders of magnitude Molecular or particle volume unlikely. The protein concentration, on the other hand, varies in humans between an age of about 20 to about 70 years

β β a β · β * «β * ■ * * si 'f

- 17 -

ren only by about 2%, as also from scientific. Tables Geigy, Volume Hematology and Human Genetics, CIBA-GEIGY AG, Basel, 8th edition 1979. These The fluctuation is accordingly extremely small. However pathological changes are known that are monitored or taken into account if necessary have to; in normal cases, however, for example also in diabetics, the protein concentration can be assumed to be constant can be assumed.

₁₍₎

The hemoglobin concentration is also kept largely constant by regulatory mechanisms.

All other blood components can also either because of their low concentration or because of Their small volume in connection with their low concentration are not taken into account.

The small ions Na, K udgl, which are still potential interfering substances, are also kept at a constant concentration by very sensitive biological control mechanisms.

According to the invention, the determination of the concentration of only one component in multicomponent Solutions, for example of glucose in the blood, under the above-mentioned conditions by laser light scattering and analysis of the shape of the scatter curve or by means of corresponding intensity measurements, where the change in the free volume of the relevant components is presumably responsible for the measurability is; however, this theoretical justification has not yet been established.

The measurement of the intensity of the scattered radiation to analyze the shape of the scatter curve can be carried out in the forward direction.

• 1 * β C «

- 18 -

tion under one or more 'scattering angles throughout Scattering angle range from 0.5 to 180 °. According to the invention, the incident light is preferably linear polarized, but elliptically polarized, circularly polarized or unpolarized light can also be used be used.

With the transcutaneous measurement of scattered intensities, ie with the measurement through tissue layers and blood vessels, part of the scattered radiation is present as incoherent radiation. Although this scattered radiation component is greatly weakened by secondary scattering on other layers, it is fundamentally unavoidable. The incoherent scattering can be partially suppressed by filters (eg polarization filters) if the primary radiation is polarized. Otherwise it must be subtracted from the signal as a background _c

An estimate of the theoretically expected change in the intensity of the scattered radiation with a change in the concentration of a component results from the calculations of G. Fournet (A. Guinier, X-Ray Diffraction, WH Freeman and Company, San Francisco, 1963). On this basis, the image shown in FIG. 2 results for the dependence of the change in intensity on the ratio V _{M / V.} The percentage change in the scattering intensity, based on the intensity at s = 0, is plotted on the ordinate, and the ratio of the volumes is plotted on the abscissa. With increasing glucose concentration, ie decreasing V / V, an increasing as well as a decreasing signal amplitude can in principle be achieved in the scattering angle range around 1 ", which also depends on the polarity of the subcomponents, for example when forming a difference °), however, according to equation (1), an increase in the intensity of the scattered radiation

VMiaa ^

lit · *. · .. ·· / iS

»(» · F «ft» β «· A y; J ^

- 19 -

development with the concentration of a low molecular weight substance, such as glucose, to be expected.

The change in the free volume, in particular the; Proteins and hemoglobin in the case of blood by |

a physiologically occurring change in the glucose concentration centration, for example in diabetics, of, for example, 5 mmol / 1 fi

to 15 mmol / 1 leads to a change of V ../ V by
about 0.4 in the range of 0.2 to 0.6- This is primarily
Approximation to expect an intensity change of 20%,

which is quite a respectable value. Γ is here- prerequisite for that is measured in the angle range of 1 °, | requires a very good measurement technique. With a coarser | Measurement technology, as it is based on the embodiment of FIG. 7 explained later, must therefore be provided with a
significantly reduced measuring sensitivity expected
will.

An additional fundamental difficulty with

the measurement, for example, of blood components by laser light scattering on a suitable part of the body, for example the ear lobe chen, results from its changing blood flow, jjj which can lead to completely different measurement signals being obtained with the same glucose concentration.

A corresponding correction is, however, technically easily possible with the device according to the invention. The intensity is advantageously used for this
of the central ray or the ratio of the intensity ;;

of the central ray to the intensity of the scattered radiation |

used. Thus, the intensity of the center beam is measured, for example, and the measuring signal corrected by difference with a predetermined desired value individually at a fixed pre-f given light intensity, wherein an empirically determining prefactor

can be used. )

- 20 -

The measurement of the concentration of one component of a multicomponent solution, e.g. the glucose concentration in the blood, according to the invention, as explained and derived above, by analyzing the shape of the scatter curve and determining that angular range of the scattered radiation in which the greatest change in intensity is dependent on the concentration of the component to be determined is available. The measurement can be carried out most simply in the method according to the invention Device can be carried out according to the so-called two-signal method, but is of course also an intensity measurement can be carried out with a continuous change in the scattering angle, which, however, is one in terms of apparatus requires greater effort. In the two-signal method, the intensity of the central beam and a second Intensity measured at a certain scattering angle. The angular range within which the second intensity is measured is advantageously chosen so that the change in the intensity of the scattered radiation with the change the concentration to be measured in this area is the maximum will.

The device according to the invention basically comprises an optical part, an electrical or electronic part as well as a mechanical part, it essentially comprises the following components:

A) Optical part

a) light source (laser, laser diode)

b) if necessary a deflection mirror (fixed or movable)

c) sample or sample holder + cuvette

d) if necessary a deflection mirror (fixed or movable)

e) optical receiver with separate

setting of at least two angular ranges,

1 »6 * β Λ Ρ " ■ ff · C *>'.

- 21 -

if the mirrors b) and / or d) are not movable,
and

f) one or more light detectors. 5

B) Electrical part

a) Power supply for the light source, optionally controllable or adjustable

b) Power supply for the light detectors

c) if applicable, intensity regulation for the light source

d) Amplifier for the signals from the light detectors of the various angular ranges, according to the sectoring of the optical receiving part

e) Difference generator, adder, quotient generator and / or multiplier

f) signal processing part (microprocessor, microcomputer or computer) with memory, Constants, input and output options

g) signal indicator

h) Output device (printer, writer, etc.).

The mechanical structure is geared towards the special measurement on the earlobe; the mechanical According to the invention, part of the device is designed to be foldable in the manner of an ear clip and has a fixed or movable one Light source, fixed or movable deflection devices such as deflection mirrors, a fixed or movable optical receiving part, preferably with Angular area sectoring, as well as a fastening device for attachment to a suitable body

ι t># β β if ι »ι * « ι a «ν *» nt /

- 22 -

pteil, ζΒ on the earlobe.

The device according to the invention, the principle of which is shown in FIG. 9a, is characterized by - a basically U-shaped beam _T_ with a Joint provided in its base area with a Spring which presses the two side parts of the carrier against one another under spring pressure, and such a Distance of the two side parts from each other that in the spaces between the two side parts of the carrier_T_ inserted a human earlobe and can be held in it like an ear clip,

- One provided on or in a side part of the carrier T, optionally arranged in a cooling block K Laser diode _p_,

- a deflecting mirror attached above the laser diode _D_ U, the one at the laser diode I). emitted light around deflects about 90 ° in an approximately horizontal direction,

- An optical receiving part _E_ provided opposite the deflecting mirror U_ on the other side part of the carrier, which detects the central beam and the scattered radiation of the light of the laser diode_D_ passing or scattered through the earlobe inserted into the carrier T_ in at least one predetermined angular range and correspondingly via at least one light detector supplies electrical signals,

- an electronic signal processing device with amplifiers and devices for correcting the measurement signals,

- A signal display device and / or signal output device
as

- a power supply,

wherein the electronic signal processing device, the signal display device and / or the signal output

- 23 -

device and the power supply are each integrated with the carrier T_ or provided independently of it.

Depending on the embodiment, the optical receiving part receives up to four or more different signals Scattering angle ranges next to that of the central ray. The optical receiving part E and the optical The transmitter part with the light source also has corresponding electrical supply lines or connecting lines Power source and possibly to the Siynalververarbeitungeinrichtung on.

According to a particularly favorable embodiment the device according to the invention has an optical receiving part J! _, the basic structure of which is shown schematically in FIG. 3 is shown. This optical receiving part _E_ has a housing 5p, in the bottom surface of which a light detector 2p is provided centrally and its inner surface seen from the light detector 2p outward ko j ,; niche extended, |

one on the open side of the case 5p concentrically | Ring-shaped glass body $ 3p made of glass or another translucent material provided in the conical surface, whose inner surface narrows conically towards the outside as seen from the light detector 2p_, a radiopaque or radiopaque coating arranged concentrically in the glass body 3p; tete sleeve 4p, which at its outwardly directed end i:

is closed except for a central opening, <

and a light detector Ip provided concentrically in the sleeve 4p and in the optical axis of the arrangement, the diameter Dl _{1 of} the central opening of the sleeve 4p, the diameter D> 2_ of the outer bottom surface of the sleeve 4p and the diameter D_3 of the outer bottom surface

- 24 -

the surface of the glass body 3p and the cone half-angle QL of the sleeve 4p and the cone half-angle jß_ of the housing jj £ or the inner cone of the glass body ^ P. ^are designed so that the light detector 2p detects the scattered radiation falling in the underlying scattering angle range as completely as possible.

The inner surface of the housing 5p or the outer surface of the glass body 3p and / or the outer surface of the sleeve 4p or the inner surface of the glass body 3p are preferably designed with a parabolic curvature in cross section.

Furthermore, an optical receiving part in the form of a light whistle in the inventive device is particularly favorable Contraption.

With a particularly favorable alternative execution | Approximate form of the device according to the invention, the optical receiving part E_, as shown schematically in FIGS. 4a and 4b, has a flat design and is composed of four layers 1-4 arranged one above the other, of which the lowest layer _1_ is light-sensitive, the second layer _2_ above it is opaque to radiation and has a lying in the optical axis central opening with a diameter dL, the overlying third layer _3_ is light sensitive and a central Ie, concentric opening with the diameter D2. and the overlying fourth layer j4_ has a concentric central opening with the diameter Ό3_ , the diameters Ol_ or Ό2_ and D3_ being chosen so that the layer ^ 1_ the central ray and the layer _3_ the scattered radiation falling in the scattering angle range on which the measurement is based, if possible capture completely.

- 25 -

Layers _2_, 3_ and _4_ can generally either be light-sensitive or only have a mask function, depending on whether measurements are to be carried out using a two-signal method, a three-signal method or a multi-signal method.

According to a further advantageous embodiment of the invention, which is shown in Fig. 4c, the optical receiving section E_ is also flat and made up of three superposed layers 5, 6, 7, wherein the uppermost layer 5_ is opaque and an annular opening with the diameters Ό2_ and p_3_ and a central opening with the diameter £ l_, under the top layer _5_ a light-sensitive layer J5_ with a central concentric opening, the diameter of which is between .Dl and D2_ and an underlying light-sensitive layer _7_ are provided, the layer _5_ acts as a mask for the underlying layers Jj ^ and J_ and the diameters _D1 ^ or _D2 and E> j $ are chosen so that the layer J7_ covers the central ray and the layer 6_ the scattered radiation falling in the scattering angle range on which the measurement is based as completely as possible .

For a very simple structure of the device according to the invention, an optical receiving part E_ with only one light detector and an associated deflecting mirror is favorable, which is arranged so that it can occupy two fixed positions, in one position the central beam and in the other position the Scattered radiation reflected on the light detector.

Parts of the device according to the invention, in particular the electronic signal processing part, can also be in a spectacle frame or in the usual way

- 26 -

Jewelry (wristwatch, bangle, collar, necklace, etc.) be integrated.

According to the invention, the individual electrical or electronic components can also be different Device parts distributed and partially or fully integrated with these.

The electronic part itself is preferred according to the invention partially or entirely formed in an integrated form. Advantageously, the optical part, especially the optical receiving part, in integrated Form be formed.

Commercially available components can be used for the components of the optical transmitter part.

Compared to the embodiment shown in FIG of the optical receiving part, the devices of FIGS. 4a and 4c have the advantage of being considerably less Installation depth; however, these flat receiving parts can cannot be constructed from commercially available discrete components.

The electrical or electronic part of the device according to the invention, on the other hand, can be made from commercially available Be constructed components. That part which is provided for regulating the intensity of the light source can if necessary, a regulator with a special shape of the control characteristic, since laser diodes, for example, are known to have a strongly non-linear current-intensity characteristic exhibit.

The signal processing in the signal processing device can according to the invention both digitally and

- 27 -

take place analogously. ^v ··

digital signal processing

FIG. 5 shows a basic circuit diagram of the electrical part of a device according to the invention with digital signal processing. The arrangement comprises a power supply _8_, a variable gain amplifier _9_ for the light source, a light source ₁ J O _- and various light detectors 1_2 / which detect the light transmitted through the sample or scattered light 2_1 and provide corresponding measurement signals. In the simplest case, only two light detectors 12 are provided, from whose measurement signals in conjunction with a reference signal up to a maximum of five signal quantities (two absolute and three relative) can be derived. The generation of the relative signal quantities can take place before or after the conversion of the measurement signals into digital signals,

The measuring signals of the light detectors 1_2_ are amplified by assigned signal amplifiers] ^ 3_ to 1J [and passed via analog-digital converter 2A ^ to a measured value processing part Γ7, which can consist of a microprocessor, a microcomputer or other computer.

One or more differential amplifiers or the like supply the relative intensities. The measured value processing part generates signals from the measured signals that control the signal output on the basis of predetermined functions or programs, corrects the measured signals by comparing them with entered constants and / or in some other way, for example by forming differences, forming quotients, adding or subtracting, and also generates the required control variables, which then reach the control amplifier _9_ via digital-to-analog converter 21_, for example. The measured value processing part Γ7 is also designed so that there are rising or falling tendencies of the

- 28 -

Detects and displays the measurement signal or the output signal; the measured value processing part furthermore generates acoustic and / or optical signals, preferably by means of suitable peripherals, in the case of adjustable upper and / or lower limit values, for example warning signals. The device can also be designed so that it is compatible with other data processing devices and can be connected to other data processing devices. The results are output via a display instrument 18 , for example a digital voltmeter or other display devices; The device further comprises an output device \ 3_ which represents a measured value printer, a writer or a similar recording and / or displaying instrument.

Analog signal processing

FIG. 6 shows a block diagram of an embodiment of the electrical part of a device according to the invention, in which the signal processing takes place analogously. Like the circuit shown in FIG. 5, the circuit comprises a power supply _8_, a control amplifier _9_ for the light source, a light source 1_0_ and two light detectors 1_2_ which detect the central beam or the scattered radiation coming from the sample 1JL_.

The circuit shown in FIG. 6 is designed for the two-signal method; Procedures based on the Acquisition of three or more signals are based on analog signal processing quickly lead to very extensive Circuits. The device accordingly has only two light detectors ji_2_.

The device also includes a differential

stronger with integrator ^ 2, which is the difference signal of the j

- 29 -

Signals a ^ and _b_ of the light detectors I ^ integrated (time constant X = 1 to 10 s); the resulting signal is used in amplifiers 2_3_ and 2A. again amplified and displayed with a display device 18. The amplifier 2_3_ is determined by the ratio of the two measured values a / b via the quotient generator 25_ and the amplifier 2_4. controlled by the difference between the measured value a_ amplified by the signal amplifier 13 and the voltage that can be set at the resistor _R_. The measurement signal is given by the in Fig.

The circuit shown in FIG. 6 is correspondingly corrected relatively by the amplifier 23 and absolutely corrected by the amplifier 24; the resulting signal is displayed with the display device 1_8.

The absolute intensity of the signal _b_ can, if necessary, also be used via a control amplifier 21_ to stabilize the intensity of the light source IjO. The circuit of FIG. 6 also includes a limit value transmitter 2J [which signals an upper and / or lower limit value of the signal (it consists, for example, of two Schmitt triggers). The increasing or decreasing tendency of the signal can be derived from the integrator 2_2_. Finally, the circuit also includes an output device Γ9_, that is to say, for example, a measuring instrument that records and optionally also displays, for example a printer or a writer.

The circuit of FIG. 6 can also be designed in such a way that it can be combined with other, possibly independent Data processing devices or systems is compatible and can be connected.

The circuits shown in FIGS. 5 and 6 can also be designed so that they with the help of the resulting signals, which are sent by the display device

It »)

• I 1

- 30 -

device J_8 displayed or registered by the output device ljj_ become independent devices such as infusion devices and in particular devices for Insulin dosing, which can optionally also be implantable, can be controlled.

In Fig. 7 is the basic circuit diagram of the electronic part of an embodiment of the invention Device shown based on analog signal processing is based.

This embodiment also contains all the functions of the circuit of FIG. 6 with the exception of the control amplifier 21_, the limit value transmitter _2_8_ and the output device JL_9. The functions are, however, partly simplified or combined, wherein the measuring amplifier 30, which is explained in more detail in Fig. 8, the functions of the signal amplifier 1_3, the integrator 2 ^., The amplifier 22 and 2J, the quotient former 2_5 and the differential amplifier _1_6 of Fig. 6 takes over.

The power supply is based on the mains voltage (e.g. 220 V), which is initially divided into several, e.g. four, low voltage is implemented.

An alternative power supply by batteries can be provided. The circuit comprises a power supply 29_ that with a stabilized voltage, for example the sense amplifier .30 - 6 V, supplied. Furthermore, the two light detectors Ί \ 2 and T_3 are separately supplied by the power supply 29_ with a highly stabilized voltage, for example +30 V. The resistors R16 and RI7 are the signal resistances of the light detectors TJ2 and T_3. The CW laser diode D5 as a light source is powered by the power supply 8- with an electronically controlled,

- 31 - I.

also supplied highly stabilized voltage, whereby
the power supply 8 is designed in particular so that
that it also keeps voltage peaks of the mains voltage away from the diode in any case. The current of the laser

diode D5, which flows through the bypass resistor R18 ,

can, if necessary, be displayed by the display device J £ with the aid of the series resistor R1_9 and
be monitored. The measuring amplifier 3 (3 works both as a differential amplifier and as a single

stronger, as explained in more detail below. S.

The measuring amplifier 3 () receives EJ_ | at its inputs

and Ej2 the corresponding signals from the light detectors |: T2 ^ or T_3 supplied. It has the outputs AJ [and_A2_,

which are connected to the display device \ J3 kön- \

nen. I.

In Fig. 8, the measuring amplifier ^ O is in detail
shown schematically. It combines the addressed at the inputs) E_1_ and E_2 incoming signals over ICi and IC2 |

f, with the help of resistor R11, is the difference between the inputs Γ

output signals. This difference is shown via IC4 and R15 ί

to output A2. The input signal arriving at EI ^ is also amplified directly by IC1 and IC3 and passed to output AI ^ via R8_.

The amplification of the signal channel for the difference ^ signal, i.e. the branch E2- IC2 - IC4 - R15 , is shown in Ab- ί

depending on the voltage at W \ _ . The effective?

The ability of this scheme is determined by the resistors RS
and R14 as well as determined by the potentiometer P2 ^,
that is the operating point of the operational amplifier IC4
specifies. With IC5 , the transistor T1_, the
Diode D'4 and the resistor R14 the voltage at the output

transition from IC3 into a control current for the one in his

• ·· · ♦ ·· mm t

•:.

- 32 -

# ** · «tit" t · 1 Ö

Gain adjustable operational amplifier 1C4 converted. The potentiometer P1_. serves to set the setpoint for this control, with which, for example, a 'blood flow correction' can be set in the transcutaneous blood glucose determination on the earlobe.

The maximum amplification in the signal branch is at least 10,000, for the amplification of the branch El - A1 a gain of around 1000 is sufficient. Naturally, this factor is also sensitive of the display instrument.

The operating points of the operational amplifiers are determined by the following resistors, which also determine the gain: for IC 1 of RJL and R2 , for IC 3 of R5_, IU5 and R7 \ for IC 2 of RlQ and Rl2 , for IC 4 except for P. 2 also from R13 . In addition, the usual offset zero potentiometers and capacitors, not shown in the figure, are provided for frequency compensation. The capacitors ^ l and QA_ serve to reduce the input interference voltages. The capacitors C ^, Cj3 and C_5 reduce the tendency of the amplifier to oscillate and at the same time serve to integrate the respective signal.

9b shows a photograph of an earlobe provided for transcutaneous blood glucose determination in vivo Device according to the invention, which corresponds to the device principle of FIG. 9a.

The actual device is shown with solid lines; the dashed lines correspond decorative elements that can be freely chosen and are only determined by design considerations and by which the device can be tailored to the individual taste of the wearer.

I · »■

h · t

• · ttt

- 33 -

The device is similar to a conventional ear clip by a simple folding mechanism on the earlobe attached, wherein the device is preferably made as light and small as possible. The power supply for the light source and the signal processing device are preferably independent of the ear clip-like actual measuring device is provided and, for example, at a suitable location, for example in a bag or under clothing.

Parts of the device according to the invention, for example the output device j_9 or the display device JJJ, can furthermore, for example, in the form of a wristwatch or wristwatch-like device or about one necklace-like device similar to a, shoulder watch.

Mathematical structure of the measurement data and its correction

The expected course of the signal amplitude as a function of the concentration of the substance to be determined, for example glucose, does not completely correspond in the experiment to the theoretical signal course shown in FIG. 2, since the signal amplitude also depends on the dimensioning and the properties of the components of the respective device. For example, with a device according to the invention, which corresponds approximately to FIG. 9, a scattering angle range of approximately 10 ° to be assigned to the glucose concentration results compared to the theoretical ideal value (with maximum sensitivity) of approximately 1.5 °. If one examines _m under these circumstances the basic course

the signal amplitude as a function of the intensity of the central ray, a power function can be approx

«» ■ β

• * β

- 34 -

the form

Δΐ (8) = aI (o) ^b (7)

I (ο) = intensity of the central ray after passage through the rehearsal

be set. This approach initially applies to any sample. The sample properties are through the constants _a__ and b_ are taken into account. While the constant _a_ mainly due to the transmission properties is influenced, the constant b mainly influences the structure and in the case of biological samples characterizes the concentrations of the subcomponents.

A paper sample with a thickness such that the resulting mean intensity is equal to that of a biological sample (paper thickness about 0.15 mm) leads to a value for the constant a of 0.19 and for the constant b of 1.15. This means an almost linear relationship between AI and I (o) (cf. equation (7)), as is also to be expected ^{for a 'physical 1 sample.} In comparison, the measurement on the earlobe, for example, results in an average value for _a_ of 0.0O3 and for b_ of 1.5.

It is therefore suitable for the evaluation of transcutaneous measurements of the blood glucose concentration in vivo a mathematical approach in the simplest form such as

b = d + e ■ S or S = (8),

where the constants d_ and _e_ are determined empirically!

- 35 -

can. S means the glucose concentration. Measurands

are ΔΙ (ξ) and I (o). ;

The constants a_ and_b_ result from an I.

curve fitting with value pairs |

of the above-mentioned measurands when measuring several |

Intensities. The constants ä_ and _e_ are in principle | to be determined once for each sample; surprisingly
However, it has been found that they vary from sample to sample

are only slightly different. <,

The measurement value correction when measuring biological samples, eg with regard to the correction due to f changing blood flow to the earlobe, must be

see that the 'effective' sample thickness x ¹ changes. It can therefore not be carried out simply by forming a ratio, as is the case, for example, with
usual optical two-beam method is possible.
The formation of the relationship provides independence from.; of the absolute intensity, but no compensation for | variable sample thickness. The correction function, for example | to correct different blood flow must im
generally have an exponential form.

On the other hand, according to the invention, a difference is always necessary for signal formation, since
this is the only way to make a statement about the shape of the scatter curve j with simple means. ;

To derive the correction function, such as
proceed as follows:

The dependence of the light intensity when shining through an absorbing medium is known in FIG

»F

- 36 -

Way through the law of absorption

5 given, where

χ the sample thickness and m the absorption coefficient

mean.

2 Tt k 10 The absorption coefficient m is defined as ~ -

with k = in '- £ * μ,

whereby
15th

Λ the wavelength of the light used, 5 the dielectric constant and μ is the permeability

20 mean.

Furthermore applies

n ² = 1 + 4 TT-cc-N,

25 where <x is the polarizability and

N is the number of scattering

Mean particles per ml. I.

With changes in blood flow naturally changes

30 also measured the number of scattering particles per ml:

If a blood vessel with a linear dimension x _o (e.g. the diameter) is assumed that is at a distance x. to the next blood vessel,

35 applies to the volume without blood ¹ : '■

t · ι ti * · i '' · · Ά

• so to

- 37 -

for the volume 'with blood ¹ applies
V ₁ ~ (X ₁ + x _o ) ³ .

From this it follows for the ratio of the volumes

(X ₁ + x _o ) ³ x _o ^x o ο χ

V ₁ / V ₀ = - = —- or V ₁ = V ₀ (1 + 3 —- +3 (—-) * + (_1)

Ί ο ι ^Λ 1 ^Λ 1 ν

^X 1 11 X ₁

(10}.

The volume in which there is blood is thus •
15th

V = V ₁ - V ₀ = V ₀ (3— ° + 3 (- °) ² + (- ⁰ ) ³ ) (11)

. ^{1 1 1}

in the area

· O ^ x ₀ < X ₁ .

If one examines the ratio x _o / x, as it is present on average in the tissue of the earlobe, for example, a value of about 0.5 to 0.8 results. In this area, the volume in which there is blood changes to a good approximation by the square of the square, as follows from equation (11). This results in an approximation for the number of scattering particles

30th

and from this the relationship with equation (9)

Ic ^ x ₀ Zx ₁ (12)

• ft · · ·

JtIII I · 11 ■ > · ',

it »ι j ι · ι · · -, i

IJtI, I. J IJ · J \?

ι ι · · ι ι ι J ι t ι · ../ ■

. ι ■ j. j ι /

1 JIII Il) 1 '«·'

- 38 -

As the sample thickness χ in equation (9), x _o is also to be used, so that the relationship

I = I ₀ .e " ^{ß x} o ² (13)

results, in which JJ_ means a corresponding coefficient.

For the mathematical calculation, equation (13) must be differentiated, whereby the simple relationship

(14)

shows that x _o itself is very small and the exponential function also changes only slightly as a result of the only small changes.

By reversing equation (14), the variable x _{o, which is unknown per se, is obtained} from the change in intensity 20

Xo = / (I - Io ¹ ) (15),

where Io 'means the intensity with normal blood flow.
25th

It follows as a correction function

2 Δΐ ¹ = Ai (s) * e "^ ^(I " ^Iol) (16).

Compared to normal blood flow, there can be both a stronger and a weaker blood flow, so that the correction can be both positive and negative - the sign of the correction must be determined accordingly. This is best done again with the quantity I - I ₀ 'that has already been used, so that the final

- 39 -

valid correction formula results in:

ΔΙ = Δΐ ( ₅ ). (1 + δ · (Ι-Ιο ·) e "^ ^(I " ^{Iol) ] (17)} ·

The constants δ, Ζ 'and I ₀ ' can be determined experimentally; in simple cases they can also be determined theoretically, since their physical meanings are clearly defined.

!. From the measured data, eg from the tensions of El and E 2 ^ in Figure 7, the measured variable, for example, the glucose concentration can be determined in three different ways, namely:

1. from equation (8), where the constant b from equation

(7) with JSL = ₁ Ai (s) and 122 = I (o), is calculated using egg * 'nes average value for a;

2. from equation (7) with one or more pairs of values ( E1; E2 ) to determine the constants a and b according to the "best-fit" method and by iterative adjustment of S according to equation (8);

3. by measuring _E_1 and J32 at a fixed reference intensity I and using the mean values of the constants a and b and Al (s) from equation (7), where _E2_ = I (o) is set. Then by a linear Approach (or in other cases through some other mathematical context) the direct relationship between the measured variable and the signal variable.

This relationship can, for example, be the form

S = K ΔΙ (s) - A (18)

own in the

S is the glucose concentration

and

- 40 -

A and K constants
mean.

All three corrections should lead to the same result. Since, however, the measurement data even with a careful measurement method in the case of biological samples are naturally subject to particular fluctuations, this is the case in many cases expedient to use all three evaluation methods in parallel and to combine their results in order to do so to achieve a measured value display that is largely independent of individual measurement errors. The easiest way to do this is to do this by a suitable averaging.

A simple and at the same time very cheap way of correcting the measurement signals for different blood flow for measurements in vivo on the earlobe, the skin temperature at the measuring point is taken into account, which is in a relatively direct relationship to the tissue perfusion at the relevant measuring point. By a corresponding mathematical correction function, e.g. can be empirically determined, the measurement signals can be based on the measured skin temperature in the signal processing device corrected for a specific blood flow condition. The device according to the invention therefore conveniently has a temperature sensor that shows the skin temperature of the earlobe or in the immediate vicinity Detected near the measuring point.

For this correction according to the skin temperature, it is necessary that the measuring device is at all measurements is located unchanged at a certain measuring point or can be attached in a reproducible manner. Such a one Determination is particularly in the case of female users of the measuring clips shown in FIG. 9, which are used for jewelry purposes have pierced earlobes, in particularly simple

α β ο s

• ■ ·

- 41 -

Way possible if the measuring device is inserted into the hole in the earlobe. The inventive Apparatus according to the principle of FIG. 9 therefore advantageously has a corresponding one for such applications Thorn that is pushed through the hole in the earlobe.

The mathematical operations explained above are, for example, on conventional programmable pocket calculators feasible. Of course, microprocessors or other computers and Computing systems are used. A program in a 'low level' programming language is required for the combination of the three methods including averaging around 220 program steps.

example

In Fig. 10, experimental results are one with

a device according to the invention carried out continuous transcutaneous blood glucose measurement using a device similar to that of FIG. 9 became. The measurements were carried out on a healthy test person who was used to generate a glucose load orally 400 ml Dextro O.G.-T. were administered. (Dextro O.G. T. solution for oral glucose loading (Boehringer Mannheim GmbH) corresponds to a physiological amount of 100 g of anhydrous glucose. In 400 ml of juice contains 17 g of anhydrous glucose, 13 g of maltose, 11 g of maltotriose and 53 g of higher oligosaccharides.

• at ·· «·« t - <9 res »-. * · _T '«

I III * * · · -ft *

- 42 -

i,
th. After hydrolysis in the intestinal tract, this mixture corresponds to the amount of glucose indicated above (BM tolerance test, Boehringer Mannheim GmbH, 6800 Mannheim 31).

The device, in the form of an ear clip, was attached to the test subject's earlobe. the Device worked according to the two-signal method, with the absolute intensity of the central beam for correction was used. The resulting difference signal of the two measurement signals was determined by the signal processing processing device generated and recorded with a pen.

For comparison purposes, the difference between the two Measurement signals also recorded without prior correction. It was found that the invention performed correction is required to achieve quantitative measurement results.

Blood samples were taken from the test subject every 20 minutes, which were routinely performed after the clinical trial Analysis of the usual hexokinase method with an autoanalyzer were examined for the content of blood glucose. The ones with the auto analyzer after the conventional one Measurement results obtained by the method are entered as crosses in FIG. 10. From this methodology is known to give the highest values when compared with other conventional methods, such as for example from H. Förster and M. ' Haslbeck, Diagnostics 5

(1972) 311-315. The measurement results obtained continuously with the device according to the invention are shown as a solid line. The results show that the method according to the invention and the device according to the invention to one quantitative blood glucose determination are suitable, since excellent agreement of the obtained measurement

V ^^

- 43 -

results with the comparative values.

In addition to these measurements, continuous measurements according to the method according to the invention were carried out on a sick test person (diabetic), and in the case of the patient, blood glucose determinations according to the above were also carried out on an ongoing basis
performed conventional procedure indicated
became. As the measuring clip goes from measurement to measurement
changed attached or because of the decrease between the

Measurements cannot be applied in a completely reproducible manner, can be made by such measurements, j where there is definitely one | in each measurement

other irradiation point is detected, the corresponding | determine the corresponding correlation coefficient. A correlation coefficient of
r = 0.4 is reached, which corresponds to an excellent reproducibility of the measurements even with a changed irradiation point. ^;

The device according to the invention is suitable for =. due to their underlying technical concept, especially for miniaturization, especially of the $

electronic part and the light source as well as the opti- f see receiving part. ■

The device according to the invention is not based on the
quantitative determination of glucose in vivo limited,
because with a suitable selection of the scattering angle ranges
also other blood components in basically the same way

have se determined quantitatively. f

The device according to the invention can also be due to of the underlying general technical concept to a very large extent within the scope of the inventive concept be modified. j

β H * *
■ · Λ

ft * k

• · · ♦ ■ * ·

- 44 -

The technical concept of the performance according to the invention provides a completely new alternative
previous methods and devices for blood glucose determination as well as for the transcutaneous determination of other blood components and blood values (e.g. erythrocyte count, Hb values, etc.).

Claims (8)

Expectations 1. Device for the quantitative determination of dissolved low molecular weight and certain high molecular weight substances in single or multi-component systems, with the individual components in the linear dimensions of the molecules, sufficiently differentiate their structure and / or composition and / or molecular weight, marked by - a basically U-shaped carrier (_T_) with a Joint (G.) provided in its bottom area with a spring that underneath the two side parts of the support a spring pressure against each other, and such a distance between the two side parts that a human earlobe inserted into the space between the two side parts of the wearer (_TJ and can be held in it like an ear clip, - one on or in a side part of the girder (TJ in front seen, possibly arranged in a cooling block (_KJ Laser diode (JJ.), - a deflecting mirror attached to the laser diode (jp_) (_yj that emitted that from the laser diode (_D_) Light by about 90 ° in an approximately horizontal direction 25 steers, - a opposite the deflection mirror (JJJ provided on the other side portion of the carrier optical receiving part (J !.), which the central beam and the scattered radiation of which passes through the inserted into the carrier (T_) earlobe or scattered light of the laser diode 709-X2145 G-SF-CH 9 «t ■ · 9 j ft «· ·« ( D ) detected in at least a predetermined angular range and supplies corresponding electrical signals via at least one light detector, - an electronic signal processing device with amplifiers and devices for correcting the measurement signals, - A signal display device and / or signal output device as - a power supply, wherein the electronic signal processing device, the signal display device and / or the signal output device siwie the power supply is either integrated with the carrier (_T_) or provided independently of it are (Fig. 9). 2. Device according to claim 1, characterized by an optical receiving part (E) with a housing (5pJ, in the bottom surface of which a light detector (2jd) is provided centrally and the inner surface of which, viewed from the light detector (2p), widens conically outwards, one on the open side of the housing (5p) provided concentrically in the conical surface of an annular glass body (3jP) made of glass or another light-permeable material, the inner surface of which narrows conically towards the outside as seen from the light detector (2p), one in the glass body (3jd) concentrically arranged radiation-opaque or radiation-opaque coated sleeve (4p), which is closed at its outwardly directed end except for a central opening, and a light detector (Ip) provided concentrically in the sleeve (4p) and in the optical axis of the arrangement, where the diameter (_D1) of the central opening of the sleeve c ·· a t * r * (4p), the diameter ( D2) of the outer bottom surface of the sleeve (4p) and the diameter (DJ3) of the outer bottom surface of the glass body (3p) and the cone half-angle (U) of the sleeve (4p_) and the cone - | Half-angle (J3_) of the housing ( 5p) or the inner cone of the I glass body (3p ) are designed so that the Lichtdetek- '. tor (2p) in the underlying scattering angle range
falling scattered radiation recorded as completely as possible
(Fig. 3). 3. Apparatus according to claim 1, characterized
characterized in that the inner surface of the I housing (J> p_) or the outer surface of the glass body (3p ) | and / or the outer surface of the sleeve (4p_) or the inner surface of the glass body (_3_p) in cross-section parabolic are slightly curved. : 4. Device according to one of claims 1 to 3,
characterized in that the optical receiving part (_E_) in the form of a light whistle is trained. ;; 5. Apparatus according to claim!, Characterized by a flat design optical receiving part (_E_), which consists of four on top of each other
arranged layers ( 1 to 4 ), of which the lowest layer (JJ is photosensitive, the; overlying second layer (_2_) is radiopaque and one lying in the optical axis $ central opening with the diameter (Dl _- ), the I overlying third layer (_3_) is light-sensitive 'and a central, concentric opening with the
Diameter ( D2 ) and the overlying fourth layer (_4_) has a concentric central opening with; the diameter (D3), the diameter I ■ ⁴ ■ ι ( Dl or D_2_ and Ε) 3_) are chosen so that the layer (JJ the central beam and the layer (_3_) cover the scattered radiation falling in the scatter angle range on which the measurement is based as completely as possible (Fig. 4a , 4b). 6. The device according to claim 1, characterized by a flat optical receiving part (_E), which is composed of three layers ( 5, 6, 7 ) arranged one above the other, the top layer (J5) being opaque and an annular opening with the diameters (D2. And DJ3) and a central opening with the diameter (DJU has, under the top layer (J5_) a photosensitive layer (_6J with a central concentric opening, the diameter of which is between (JDl ₁ and DJ2), and an underlying layer light-sensitive layer (JJ are provided, the diameters (JDl or D2 ^ and D3) being chosen so that the layer (7) covers the central ray and the layer (Jj_) covers the scattered radiation falling in the scattering angle range on which the measurement is based as completely as possible (Fig . 4c). 7. The device according to claim 1, characterized by an optical receiving part (_EJ with only one light detector and one associated Movable deflecting mirror with two fixed positions, the deflecting mirror in one position reflects the central beam and in the other position the scattered radiation onto the light detector. 8. Device according to one of claims 1 to 7, further characterized by polarization filters in front of the light detector or the light detectors of the optical receiving part (E).