WO2007060583A2

WO2007060583A2 - Method and apparatus for determining concentrations of analytes in a turbid medium

Info

Publication number: WO2007060583A2
Application number: PCT/IB2006/054311
Authority: WO
Inventors: Gert 't Hooft; Wouter H. J. Rensen; Gerhardus W. Lucassen
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2005-11-28
Filing date: 2006-11-17
Publication date: 2007-05-31
Also published as: WO2007060583A3

Abstract

A method of non-invasively measuring the concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μeff(λ). The proposed method comprises the steps of: irradiating the turbid medium with a spectrum of electromagnetic radiation by means of a number of radiation sources (8a, 8b), detecting a reflection spectrum of said electromagnetic radiation reflected from the turbid medium by means of a number of detectors (10), such that the reflection spectrum is detected at at least two different source-detector distances pu, said distances being chosen such that pi,2»l/μeff, determining a first quantity representative of a relative change in reflection with respect to the source-detector distance (p) and deriving from said first quantity a second quantity representative of the effective attenuation coefficient μeff, and determining said concentration from said second quantity. Thus the proposed method effectively makes the measured spectrum linear in the various analytes present in the turbid medium, allowing for a simple linear regression analysis. This is accomplished by a judicious choice of effective medium thickness and alternative definition of the effective absorption coefficient.

Description

Method and apparatus for determining concentrations of analytes in a turbid medium

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to non- invasive monitoring of analytes in turbid media. More specifically, the present invention relates to a method and an apparatus for non-invasively monitoring the concentration of at least one analyte in a turbid medium, such as glucose in human blood.

BACKGROUND OF THE INVENTION

When people with diabetes can control their blood sugar (glucose), they are more likely to stay healthy. People with diabetes use two kinds of management devices: glucose meters and other diabetes management tests. Glucose meters help people with diabetes check their blood sugar at home. Most methods of monitoring blood glucose require a blood sample, usually obtained by using an automatic lancing device on a finger. Some meters use a blood sample from a less sensitive area, such as the upper arm, forearm, or thigh. Other devices use a beam of light instead of a lancet to pierce the skin. Over the years, scientists have been trying to find non- invasive ways for people with diabetes to measure their blood glucose. A potential way to non-invasively determine the glucose level is to measure the diffuse optical reflection spectrum of skin and tissue in the near infrared wavelength regime. A typical example of such a spectrum measured on the forearm is given in Fig. 1 as taken from Ref. [I]. In the wavelength range from 1.1 to 1.7 micron (μm) the main absorption peaks (in arbitrary units) are due to water and fat, as indicated in Fig. 1 by means of arrows. On the shoulders of these peaks small features can be distinguished which are caused by the presence of glucose. A reliable non- invasive glucose monitor is able to determine from these features the glucose concentration with an absolute accuracy of about 20% and a detection limit of about 30 mg/dl.

In a classical absorption measurement as described, for instance, in prior art documents WO 03/079892 A2, US 6,865,408 Bl, and EP 0 613 652 A2, the intensity I of the transmitted light is assumed to decrease exponentially with distance z according to the Lambert-Beer law: l = Oe-^az . (1)

Consequently, the logarithm of the intensity, In(I), is linearly proportional to the absorption coefficient, α. The absorption coefficient depends on the wavelength λ and is a summation of the absorption coefficients of the individual constituents (hereinafter also referred to as "analytes") weighted with their respective concentration. When the absorption is measured as a function of the wavelength with enough accuracy and the absorption spectra of the individual constituents are known with enough precision, all the concentrations can be derived from a single measured spectrum. Mathematically, this can be viewed as a simple matrix inversion. Consider a number of n different analytes, each having an absorption spectrum at unit concentration of μ^λ), with i=l,...,N. A medium with analyte concentrations C₁ will exhibit an absorption at wavelength λ, which is equal to:

w α(λ_y) = ∑ ς μ,(λ_y) . (2)

/ =1

This can be interpreted as a matrix multiplication, i.e., α = M c. Here α is an array of the logarithms of measured absorption values, c is an array of concentrations while M_j1 is a matrix of known absorption spectra (a column of which represents a wavelength index, and a row of which represents an analyte index). In order to find the concentrations from a measured absorption spectrum, the matrix M has to be inverted and multiplied with α(λ). When only one analyte concentration is to be determined, only the inner product of the measured spectrum with the proper row of inverse matrix M_j1 ^"1 has to be taken.

However, in transmission or reflection spectroscopy on turbid media, e.g. human blood, the simple relation of Eq. 1 is not valid. As an example consider a semi- infinite medium characterised by a total absorption coefficient μ_a and reduced scattering coefficient μ_s'. The intensity reflection coefficient or reflectance, R, for a point source and a point detector separated by a distance p on the boundary of the medium is given by [2,3]:

1 1 ø^~μ<#Λi 1 Q^~μ"*^r2 K=^[z_o(Aⁱ _rf+-)-p- + (²b+2z_/,)(Aⁱ _rf + -)-p-] . (3)

The various quantities in Eq. 3 are defined by: Z₀ = (4)

Va ⁺ Vs

1

D =

3μ_a{μ_a + μ_s') ' (5) z_ή~5,9&D (6)

The variable zo represents the effective position of the point source, D is the diffusion coefficient, z_\, is the effective position of the boundary of the turbid medium (the value of 5.96 is derived for a refractive index of the turbid medium equal to 1.36), and μ_eff is the effective attenuation coefficient of the turbid medium. Since μ_a is much smaller than μ_s' the attenuation coefficient is approximately proportional to the square root of the absorption, and hence proportional to the square root of the concentration of any of the analytes. Moreover, the pre-exponential factors in Eq. 3 are also dependent on the attenuation coefficient. Therefore, the logarithm of the reflection does not follow a simple power law as a function of the absorption. A true absorption spectrum cannot be derived from a reflection spectrum, so that a linear regression analysis on spectra of turbid medium is prone to errors thus leading to an effective reduction in measurement accuracy. In practise, only the concentration of one analyte is determined while keeping all the other concentrations the same as in corresponding reference samples. E.g., in a non-invasive glucose monitor the water and fat peaks in the diffuse reflectance spectrum are kept as constant as possible between measurements.

Thus, there is a need in the art for a method and an apparatus which ensure non- invasive measurement of analyte concentrations in turbid media, e.g. glucose in human blood, with improved accuracy and without relying on over-simplified theoretical assumptions.

It is the object of the present invention to provide a method for non-invasively measuring the concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μ_eg(λ) which obviates the above-mentioned disadvantages. It is also an object of the present invention to provide an apparatus for the non- invasive measurement of a concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μ_eg(λ), in particular blood, which obviates the above-mentioned disadvantage of limited measurement accuracy. Furthermore, the present invention has for its object to provide a non-invasive biological analyte monitor, in particular a glucose monitor, which can be used by a patient for to monitor his/her blood sugar in accordance with the present invention.

SUMMARY OF THE INVENTION

According to a first aspect of the invention the object is achieved by providing a method of non-invasively measuring the concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μ_eg(λ), comprising the steps of:

- irradiating the turbid medium with a spectrum of electromagnetic radiation by means of a number of radiation sources,

- detecting a reflection spectrum of said electromagnetic radiation reflected from the turbid medium by means of a number of detectors, such that the reflection spectrum is detected at at least two different source-detector distances p_li2, said distances being chosen

- determining a first quantity representative of a relative change in reflection with respect to the source-detector distance and deriving from said first quantity a second quantity representative of the effective attenuation coefficient μ_eff, and

- determining said concentration from said second quantity. According to a second aspect of the invention the object is achieved by providing an apparatus for the non- invasive measurement of a concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μ_efi(λ), in particular blood, comprising:

- at least one radiation source adapted to generate a spectrum of electromagnetic radiation and to transmit said spectrum of electromagnetic radiation to the turbid medium,

- at least one detector adapted to detect a spectrum of reflected radiation from the turbid medium and to generate detection signals representative of the detected radiation, wherein irradiation areas of said radiation source and detection areas of said detector on the turbid medium are arranged for to generate detection signals with respect to at least two different source-detector distances p_li2, wherein said source-detector distances are defined as the respective distances between the irradiation areas and the detection areas, said source- detector distances being chosen such that P_{1 j2} » l/μ_eff, and - data processing means adapted to determine from the detection signals a first quantity representative of a relative change in reflection with respect to the source-detector distance and deriving from said first quantity a second quantity representative of the effective attenuation coefficient μ_eff, and to determine said concentration from said second quantity. According to a third aspect of the invention the object is also achieved by providing a non-invasive biological analyte monitor, in particular a glucose monitor, comprising:

- an apparatus adapted to non-invasively measure a concentration of at least one analyte in the blood of a patient according to said second aspect of the present invention, and - a display in operative connection with said apparatus and adapted to display the determined concentration to an operator and/or the patient.

According to a fourth aspect of the present invention the object is further achieved by providing a computer program product comprising program code for execution by a data processing means, in particular the data processing means of the apparatus according to said second aspect of the present invention, for non-invasively determining the concentration of at least one analyte in a turbid medium with an effective attenuation coefficient μ_eg(λ), operable to: enter data descriptive of a reflection spectrum of electromagnetic radiation reflected from the turbid medium into the data processing means, wherein the reflection spectrum comprises reflection data from at least two different source-detector distances,

- determine a first quantity representative of a relative change in reflection with respect to the source-detector distance, derive from said first quantity a second quantity representative of the effective attenuation coefficient μ_eff, and - determine said concentration from said second quantity.

In accordance with a general idea of the present invention, in order to obviate the above-described non-linearity, it is proposed to increase the distance p between radiation source and detector (source-detector distance) such that zo and Zb (cf. Eqs 4 and 6, respectively) can be neglected with respect to p in Eqs 3, 8, and 9. The magnitude of the extrapolated boundary position and source position are approximately zo = 2 mm and Zb = 1 mm, respectively. Hence, for source-detector distances p larger than, e.g., 10 mm, Eq. 3 can be approximated by (T₁ ~ r₂):

Taking the logarithm of the reflectance, R, and the derivative with respect to the source-detector distance, p, one obtains:

dln(f?) _ 2 1

^~Z - ^~ V* T^~ . (11)

For source-detector distances, p, which are large enough the first term on the right hand side of Eq. 11 dominates. Knowing that scattering, i.e. μ_s', dominates over absorption, μ_a, using Eq. 7 one finally obtains a definition of a quantity, Sr, which is linear in the absorption, μ_a, of the constituents, viz.:

In accordance with the present invention the measurement scheme for determining the concentration of an analyte is thus:

1. Take the reflection spectrum, R, at two source-detector distances which are large enough, i.e. p _lj2 » l/μ_eff.

2. Compute the derivative of In(R) with respect to p (Eq. 11) and square the result, thus obtaining said first quantity representative of a relative change in reflection with respect to the source-detector distance. This is equivalent to saying that the first quantity is determined by computing the derivative of In(R), R being the intensity reflection coefficient, with respect to the source-detector distance and squaring the result of said computation.

3. According to Eq. 12, derive from said first quantity a second quantity, Sr, representative of the effective attenuation coefficient, μ_eff, and determine said concentration from said second quantity.

Computing a relative change in reflection with respect to the source-detector distance has the additional advantage that no absolute calibration of the employed equipment is necessary, i.e. day-to-day variation of source strength or detector efficiency is not important. The equipment should only be able to produce repeatable results during the measurement of the two required spectra at respective source-detector distances, i.e. on a rather short time interval.

With reference to the above-described step 2, in an embodiment of the apparatus in accordance with the present invention the data processing means are adapted to determine said first quantity by computing the derivative of In(R), R being the intensity reflection coefficient, with respect to the source-detector distance and to determine the second quantity from the first quantity by squaring the result of said computation.

In a variant of the method according to the present invention, in the above step 3 a ,,classical" regression analysis is applied on the second quantity for to determine the concentration of analytes in question, i.e. the concentration is determined from the second quantity by linear regression, which is an easy mathematical approach and valid in the context of the present invention owing to the above-described unique choice of measurement conditions. Correspondingly, in an embodiment of the apparatus in accordance with the present invention the data processing means are adapted to determine the concentration from the second quantity by linear regression.

It will be appreciated by a person skilled in the art that step 3 can in principle be performed in the optical domain. This would circumvent the use of expensive detector arrays. However, there is no approach to perform step 2 in the optical domain. This means that at least two spectra have to be taken using a monochromator and a detector array set-up, as will be described in more detail below, and steps 2 and 3 have to be performed in the electronic domain.

A major advantage of the method according to the present invention is that a linear regression approach is valid. However, due to the relatively large proposed source- detector distances, a probe used to translate the method into practise will be of larger overall dimensions. Even more problematic is the necessary detection of an exponentially lower signal due to said relatively large proposed source-detector distances. This disadvantage can be partially compensated with a proper design of the irradiation and detection equipment, generally based on the use of light guides, i.e. waveguide fibres. Furthermore, instead of using only one waveguide fibre with diameter d at a distance p from an irradiation source leading to the detector, in another embodiment in accordance with the present invention a ring of waveguide fibres connected to a detector module. This increases the collection efficiency by a factor of 8p/d. For p = 10 mm and d = 1 mm, this amounts to an appreciable signal enhancement. In a related variant of the method according to the present invention the turbid medium is irradiated in at least two different irradiation areas, and the reflection spectrum is detected in one detection area located at different distances from the respective irradiation areas. For instance, the turbid medium can be irradiated in essentially concentrical circular areas extending around a central detection area. In a corresponding embodiment of the apparatus in accordance with the present invention the radiation source comprises at least two concentrical circular arrangements of a respective plurality of waveguide fibres essentially extending to the boundary of the turbid medium and arranged around a common central detection area on said boundary of the turbid medium, wherein the detector comprises at least one central waveguide fibre essentially extending to the boundary of the turbid medium and in operative connection with the data processing means.

In order to reduce manufacturing costs as well as overall system size, in a further embodiment of the apparatus according to the present invention the concentrical arrangements of waveguide fibres are coupled with a common radiation source by means of a switching means adapted for selectively exciting either one of the at least two concentrical circular arrangements of waveguide fibres. In this way only one (primary) radiation source, e.g. a lamp, has to be provided for to irradiate the turbid medium in two different irradiation areas.

In the above reasoning it is also admissible to interchange source and detector. All light paths, no matter how diffusive they are, are reversible, so that reciprocity holds. Therefore, in a related variant of the method in accordance with the present invention the turbid medium is irradiated in one irradiation area, and the reflection spectrum is detected in at least two detection areas located at different distances from the irradiation area. Again, the reflection spectrum from the turbid medium can be detected in essentially concentrical circular detection areas extending around a central irradiation area. In a corresponding embodiment of the apparatus in accordance with the present invention the radiation source comprises at least one central waveguide fibre essentially extending to the boundary of the turbid medium for irradiating a central irradiation area, and the detector comprises at least two concentrical circular arrangements of a respective plurality of waveguide fibres essentially extending to the boundary of the turbid medium and arranged around the central irradiation area and in operative connection with the data processing means.

In a variant of the apparatus in accordance with the present invention the irradiation areas and the detection areas are located on a boundary of the turbid medium, in particular on the skin of a patient. To enhance the signals even more it is best to use highly reflective boundaries [4]. One should however, take care that no optical short circuit exists on the boundary of the turbid medium between source and detector. Therefore a highly scattering gel, which adapts easily to the surface contours of the turbid medium, is a good solution. Given a particular source-detector distance, p, the average path of the light that is detected penetrates to a depth of about p/3 into the turbid medium. For non- invasive glucose monitors the large source-detector distance and the accompanying larger penetration depth means that not only the dermis is probed but also the tissue beneath it. Thus larger sized veins are probed, too. The measured glucose levels will therefore follow changes in the glucose concentration in the blood more directly, i.e. there will be no time lag due to the fact that glucose first has to be transferred from the veins to the upper tissue layers before it can be measured by means of devices with smaller source-detector distances.

The method and apparatus in accordance with the present invention can be employed advantageously in non-invasive biosensors. A primary candidate is a non-invasive glucose monitor. However, other analytes can be probed, too. In the wavelength regime between 650 nm and 850 nm the method and the apparatus according to the present invention can be employed to determine the blood content and oxygenation by monitoring deoxy- and oxy-haemoglobin concentrations.

Further advantages and characteristics of embodiments in accordance with the present invention can be gathered from the following description of preferred embodiments given by way of example only with reference to the enclosed drawings. The features mentioned above as well as below can be used in accordance with the invention either individually or in conjunction. The embodiments mentioned are not be be understood as an exhaustive enumeration but rather as examples with regard to the underlying concept of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a diagram of an absorption spectrum of human skin at irradiation wavelengths between 1,1 μm and 2,4 μm; Fig. 2 is a schematic diagram of a non- invasive biological analyte monitor consistent with the present invention;

Fig. 3 is a schematic diagram of an arrangement of waveguide fibres in the non-invasive biological analyte monitor according to Fig. 2; and

Fig. 4 is a flow chart of the method according to the present invention. DETAILED DESCRIPTION

The following detailed description of the invention refers to the accompanying drawings. The same reference numerals may be used in different drawings to identify the same or similar elements.

Fig. 2 shows a schematic diagram of a non- invasive biological analyte monitor 1 consistent with the present invention. The non-invasive biological analyte monitor 1 comprises a monitor console 2 and a probe 3 positioned on the turbid medium 4, i.e. on a boundary 5 of the latter, e.g. the skin of a patient in the case of a glucose monitor. Between the probe 3 and the boundary 5, a coupling agent, e.g. a highly scattering gel (not shown) can be provided. The monitor console 2 comprises a lamp 6, the light of which is focused via optics 7 onto waveguide fibre bundles 8 a, b (source fibre bundles) which essentially extend to the boundary 5 of the turbid medium 4. Between the optics 7 and an excitation extremity 8c of the waveguide fibre bundles 8a, b there is provided a shutter switch 9 controllable for exciting either fibre bundle 8a or fibre bundle 8b at a time. For glucose monitoring, spectroscopy will be performed in the wavelength range from 1.1-1.7 micron (μm). Light with shorter wavelengths than 1.1 micron can be filtered out with a semiconductor filter formed of a Si substrate (not shown in the figure) arranged in the path of light between the lamp 6 and the excitation extremity 8c of the waveguide fibre bundles 8a, b. Heating of such a semiconductor filter causes a shift in transmission edge. It is therefore preferred to apply an oxide-based coating (not shown) on the lamp 6 and/or on the optics 7 with appropriate transmission characteristics, as known to a person skilled in the art.

In the detection path, the non-invasive biological analyte monitor 1 further comprises a waveguide fibre bundle 10 (detector fibre) connected at a first extremity with the probe 3 - thus extending essentially to the boundary 5 of the turbid medium 4 - and at a second extremity with a monochromator 11 comprised within the monitor console 2. The monochromator 11 is operatively connected with a detector array 12, the latter being further connected with an electronics unit 13. For a wavelength range from 1.1-1.7 micron the preferred detector material is InGaAs. Furthermore, in operative connection with the monitor console 2 there is provided a display 14. The electronics unit 13 further comprises a data processing means 15 adapted to operate on the output of the detector array 12. In addition, the monitor console 2 is operatively connected with an input means 16, e.g. a CD-ROM drive or a network card, adapted to read a suitable data carrier medium 17, e.g. a CD-ROM and a data stream from a computer network, respectively, for providing a computer program product with executable instructions for the data processing means 15, as will become apparent later.

Fig. 3 shows a schematic diagram of an arrangement of the waveguide fibres 8a, b in the probe 3 of the non- invasive biological analyte monitor 1 according to Fig. 2. In Fig. 3, the probe 3 is shown as seen from below, i.e. with its side facing the boundary 5 of the turbid medium 4 in Fig. 2. In the depicted embodiment the source fibre bundles 8a, b are arranged concentrically around a central detector fibre 10, such that the respective distances pi and p₂ are different between the outer fibre ring 8a and the detector fibre 10 (with a radius of the outer fibre ring 8a defining first source-detector distance pi) and the inner fibre ring 8b and the detector fibre 10 (with a radius of the inner fibre ring 8b defining second source- detector distance p₂). The detector fibre 10 is a multimode fibre with a core diameter d of about 1 mm. The source fibre bundles 8a, b have a diameter di,₂ of about 22 and 20 mm, respectively. I.e., the diameters di,₂ of the circular arrangements of waveguide fibres are chosen such that p_lj2 » l/μ_eff, in particular by a factor of about 10. Furthermore, the source fibre bundles 8a, b each consist of a multitude of multimode fibres (not explicitly shown) arranged in said circular fashion around the central detector fibre 10, each of the individual fibres in the source fibre bundles 8a having a core diameter d of about 1 mm, similar to that of the detector fibre 10.

It should be noted however, that the invention is not limited to a particular value of the diameter/radius of the fibre rings or to the exact core diameter of fibres. The ring diameters should be large enough so that μ_eff pi,₂ » 1 but small enough to retrieve as much signal as possible. The value of the core diameter d of the detector fibre 10 should be as large as possible for reasons of signal magnitude, but small with respect to l/μ_eff, i.e. d « l/μ_eff.

In operation, the lamp 6 is used as a primary source of radiation for to irradiate the turbid medium 4 via the waveguide fibre bundles 8a, b in accordance with a switching state of the shutter switch 9, thus creating two irradiation areas in accordance with the arrangement of the source bundles 8a, b on the boundary 5 of the turbid medium. The irradiated light is attenuated, i.e. absorbed and scattered, in the turbid medium 4 and reflected therefrom in various directions. Part of the light emitted by the turbid medium 4 is collected by fibre bundle 10, which is connected to monochromator 11 and detector array 12 for to measure a reflection spectrum, R(λ), of the turbid medium 4. The output of the detector array 12 is transferred to the electronics unit 13 which will take care of the amplification, signal processing (by means of the data processing means 15), and user display (via display 14). To this end, the data processing means 15 is adapted - e.g., by providing suitable program code by means of the input means 16 and said medium 17 for execution by the data processing means - to operate on the output signals of the detector array 12 in order to perform - either individually or in conjunction - the various data processing steps in accordance with the method of the present invention, i.e., entering measured data descriptive of the reflection spectrum of electromagnetic radiation reflected from the turbid medium into the data processing means, wherein the reflection spectrum comprises reflection data from at least two different source-detector distances, deriving said first and second quantities from the measured reflection spectrum and performing a linear regression for to determine the analyte concentration in question, as described in detail above. Said signal processing with now be further described with reference to Fig. 4.

Fig. 4 shows a flow chart of the method for determining the concentration of an analyte, e.g. glucose, in a turbid medium such as human blood according to the present invention. The method starts in step 400. In a subsequent step 402 the reflection spectrum R(λ) is measured for a first source-detector distance pi by selectively exciting fibre bundle 8a (Fig. 2) and detecting the light reflected from the turbid medium 4 (Fig. 2) by means of the detector fibre 10, monochromator 11, and detector array 12 (Fig. 2). Then in step 404 said measurement is repeated for a second source-detector distance p₂ by selectively exciting fibre bundle 8b (Fig. 2). From said two measurements of R(λ), the data processing means 15 (Fig. 2) computes said first quantity representative of a relative change in reflection with respect to the source-detector distance p, i.e. the derivative of In(R) with respect to p, in step 406 (cf. Eq. 11). In subsequent step 408 the data processing means 15 (Fig. 2) derives from said first quantity said second quantity representative of the effective attenuation coefficient μ_eff, i.e. by computing the square of the derivative of In(R) with respect to p (cf. Eq. 12), thus obviating all non-linearities which might influence accuracy of measurement in a negative way. Then in step 410, a linear regression is performed on said second quantity in analogy to Eq. 2 in order to determine the analyte concentration in question. Finally, in step 412 the result is displayed to a user and/or operator by means of the display 14 (Fig. X). The inventive method terminates in step 414.

Thus, the present invention provides a method and an apparatus which ensure non-invasive measurement of analyte concentrations in turbid media, e.g. glucose in human blood, with improved accuracy and without relying on over-simplified theoretical assumptions. REFERENCES

Stephen F. Malin, Timothy L. Ruchti, Thomas B. Blank, Suresh N. Thennadil, and Stephen L. Monfre, "Noninvasive Prediction of Glucose by Near-Infrared Diffuse Reflectance Spectroscopy", Clinical Chemistry 45 (1999) 1651-1658. Thomas J. Farrell and Michael S. Patterson, "A diffusion theory model of spatially resolved, steady- state diffuse reflectance for the non- invasive determination of tissue optical properties in vivo", Med. Phys. 19 (1992) 879-888.

Alwin Kienle and Michael S. Patterson, "Improved solutions of the steady- state and the time-resolved diffusion equations for reflectance from a semi- infinite turbid medium", J. Opt. Soc. Am. A. 14 (1997) 246-254.

Jeroen Paasschens and G. W. 't Hooft, "Influence of boundaries on the imaging of objects in turbid media", J. Opt. Soc. Am. A. 15 (1998) 1797-1812.

Claims

CLAIMS:

1. A method of non-invasively measuring the concentration of at least one analyte in a turbid medium (4) with an effective attenuation coefficient μ_eg(λ), comprising the steps of:

- irradiating the turbid medium (4) with a spectrum of electromagnetic radiation by means of a number of radiation sources (6, 8a, 8b),

- detecting a reflection spectrum (R) of said electromagnetic radiation reflected from the turbid medium (4) by means of a number of detectors (10), such that the reflection spectrum (R) is detected at at least two different source-detector distances p_lj2, said distances being chosen such that p_lj2 » l/μ_eff, - determining a first quantity representative of a relative change in reflection (R) with respect to the source-detector distance (p) and deriving from said first quantity a second quantity (Sr) representative of the effective attenuation coefficient μ_eff, and

- determining said concentration from said second quantity.

2. The method according to claim 1, characterised in that the first quantity is determined by computing the derivative of In(R), R being the intensity reflection coefficient, with respect to the source-detector distance, and in that the second quantity is determined from the first quantity by squaring the result of said computation.

3. The method according to claim 1, characterised in that the concentration is determined from the second quantity by linear regression.

4. The method according to claim 1, characterised in that the turbid medium (4) is irradiated in at least two different irradiation areas, and in that the reflection spectrum (R) is detected in one detection area located at different distances (pi,₂) from the respective irradiation areas.

5. The method according to claim 1, characterised in that the turbid medium (4) is irradiated in essentially concentrical circular areas extending around a central detection area.

6. The method according to claim 1, characterised in that the turbid medium (4) is irradiated in one irradiation area, and in that the reflection spectrum (R) is detected in at least two detection areas located at different distances (pi,2) from the irradiation area.

7. The method according to claim 1, characterised in that the reflection spectrum (R) from the turbid medium (4) is detected in essentially concentrical circular detection areas extending around a central irradiation area.

8. The method according to claim 1, characterised in that the turbid medium (4) is tissue.

9. The method according to claim 1, characterised in that the determined concentration is that of glucose.

10. The method according to claim 1, characterised in that the turbid medium (4) is irradiated with electromagnetic radiation at wavelengths between 1 , 1 μm and 1 ,7 μm.

11. The method according to claim 1 , characterised in that the determined concentration is that of deoxy-haemoglobin and oxy-haemoglobin.

12. The method according to claim 1, characterised in that the turbid medium (4) is irradiated with electromagnetic radiation at wavelengths between 650 nm and 850 nm.

13. An apparatus for the non- invasive measurement of a concentration of at least one analyte in a turbid medium (4) with an effective attenuation coefficient μ_efi(λ), in particular blood, comprising: at least one radiation source (6, 8a, 8b) adapted to generate a spectrum of electromagnetic radiation and to transmit said spectrum of electromagnetic radiation to the turbid medium (4), at least one detector (10, 11, 12) adapted to detect a spectrum of reflected radiation (R) from the turbid medium (4) and to generate detection signals representative of the detected radiation, wherein irradiation areas of said radiation source (6, 8a, 8b) and detection areas of said detector (10, 11, 12) on the turbid medium (4, 5) are arranged for to generate detection signals with respect to at least two different source-detector distances p_lj2, wherein said source-detector distances are defined as the respective distances between the irradiation areas and the detection areas, said source-detector distances being chosen such

- data processing means (15) adapted to determine from the detection signals a first quantity representative of a relative change in reflection with respect to the source- detector distance and deriving from said first quantity a second quantity (Sr) representative of the effective attenuation coefficient μ_eff, and to determine said concentration from said second quantity.

14. The apparatus of claim 13, characterised in that the irradiation areas and the detection areas are located on a boundary (5) of the turbid medium (4), in particular on the skin of a patient.

15. The apparatus according to claim 13, characterised in that the data processing means (15) are adapted to determine said first quantity by computing the derivative of In(R), R being the intensity reflection coefficient, with respect to the source-detector distance (p) and squaring the result of said computation.

16. The apparatus according to claim 13, characterised in that the data processing means (15) are adapted to determine the concentration from the second quantity by linear regression.

17. The apparatus according to claim 13, characterised in that the radiation source comprises at least two concentrical circular arrangements (8a, 8b) of a respective plurality of waveguide fibres essentially extending to the boundary (5) of the turbid medium (4) and arranged around a common central detection area on said boundary (5) of the turbid medium (4), wherein the detector comprises at least one central waveguide fibre (10) essentially extending to the boundary (5) of the turbid medium (4) and in operative connection with the data processing means (15).

18. The apparatus according to claim 13, characterised in that the radiation source comprises at least one central waveguide fibre essentially extending to the boundary (5) of the turbid medium (4) for irradiating a central irradiation area, and in that the detector (11, 12) comprises at least two concentrical circular arrangements of a respective plurality of waveguide fibres essentially extending to the boundary (5) of the turbid medium (4) and arranged around the central irradiation area and in operative connection with the data processing means (15).

19. The apparatus according to claim 17 or 18, characterised in that the waveguide fibres are coupled with the boundary (5) of the turbid medium (4) by means of a highly scattering substance, in particular a highly scattering gel.

20. The apparatus according to claim 18, characterised in that the concentrical arrangements (8a, 8b) of waveguide fibres are coupled with a common radiation source (6) by means of a switching means (9) adapted for selectively exciting either one of the at least two concentrical circular arrangements (8a, 8b) of waveguide fibres.

21. The apparatus according to claim 17 or 18, characterised in that a diameter (I₁ ,₂ of the circular arrangements (8a, 8b) of waveguide fibres is chosen such that di,₂ » l/μ_eff, in particular by a factor of about 10.

22. The apparatus according to claim 17 or 18, characterised in that a diameter d of the individual waveguide fibres is chosen such that d « l/μ_eff.

23. The apparatus according to claim 13, characterised in that the wavelengths in the radiation spectrum (R) are comprised between 1,1 μm and 1,7 μm, and in that the data processing means (15) is adapted to determine a glucose concentration.

24. The apparatus according to claim 13, characterised in that the wavelengths in the radiation spectrum (R) are comprised between 650 nm and 850 μm, and in that the data processing means (15) is adapted to determine a deoxy-haemoglobin and an oxy- haemoglobin concentration.

25. A non-invasive biological analyte monitor (1), in particular a glucose monitor, comprising:

- an apparatus adapted to non- invasive Iy measure a concentration of at least one analyte in the blood of a patient according to any one of claims 13 to 24, and

- a display (14) in operative connection with said apparatus and adapted to display the determined concentration to an operator and/or the patient.

26. A computer program product comprising program code for execution by a data processing means, such as the data processing means (15) of the apparatus according to any one of claims 13 to 24, for non-invasively determining the concentration of at least one analyte in a turbid medium (4) with an effective attenuation coefficient μ_efi(λ), operable to: enter data descriptive of a reflection spectrum (R) of electromagnetic radiation reflected from the turbid medium into the data processing means, wherein the reflection spectrum comprises reflection data from at least two different source-detector distances p_lj2,

- determine a first quantity representative of a relative change in reflection (R) with respect to the source-detector distance (p), derive from said first quantity a second quantity (Sr) representative of the effective attenuation coefficient μ_eff, and

- determine said concentration from said second quantity.

27. The computer program product according to claim 26, further operable to determine the first quantity by computing the derivative of In(R), R being the intensity reflection coefficient, with respect to the source-detector distance, and to determine the second quantity from the first quantity by squaring the result of said computation.

28. The computer program product according to claim 26, further operable to determine the concentration from the second quantity by linear regression.