WO2006126154A1

WO2006126154A1 - Non-invasive measurement of blood analytes using thermal emission spectroscopy

Info

Publication number: WO2006126154A1
Application number: PCT/IB2006/051601
Authority: WO
Inventors: Antonius Van Gogh; Maarten Van Herpen; Marcello Balistreri
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2005-05-24
Filing date: 2006-05-19
Publication date: 2006-11-30
Also published as: CN101179983A; EP1887923A1; JP2008545515A

Abstract

A system is disclosed for the non- invasive measurement of an analyte concentration in body tissue. The system comprises means (16) for detecting a thermal emission spectrum (13) emitted by the body tissue, such as a finger, and interference filtering means (11) , for spatially separating the thermal emission spectrum to create a plurality of spectral patterns and measuring in respect of each of a plurality of said spectral patterns a spectral intensity at a first, reference set of wavelengths, and a second set of wavelengths dependent on the analyte being measured. The concentration of the analyte is then determined from the spectral measurements.

Description

Non-Invasive Measurement of Blood Analytes using Thermal Emission Spectroscopy

The present invention relates to the non- invasive measurement of blood constituents, and particularly but not exclusively to the non-invasive measurement of blood glucose concentrations.

The determination of the concentration of most blood constituents, such as cholesterol and glucose, is currently done by invasive means. A blood sample is typically taken from a patient and transferred to a lab or handheld device, where it is analysed. This presents an obvious discomfort to patients, particularly young children, and the sample taken from the patient can become contaminated resulting in the need for additional blood samples to be taken.

Several methods are being developed for the continuous, non-invasive analysis of blood, however, only a few have been clinically tested against invasive methods. In fact, most techniques still suffer accuracy limitations in their measurement.

One of the methods in which in-vivo (i.e. internal to the body) tests have been reported is a method called Thermal Emission Spectroscopy (TES). With this method, the thermal or blackbody radiation of the human body is measured in the infra-red part of the electromagnetic spectrum; the resulting intensity and spectral measurements are found to be characteristic of the temperature and state of the radiating object.

In International Patent Application No. WO97/43947 there is described a noninvasive blood glucose monitor prototype that derives the blood glucose levels from the thermal radiation in the mid infra-red spectral region of the tympanic membrane. The device measures thermal radiation at two wavelengths, 8.5μm and 9.6μm; the shorter wavelength is used for reference emission intensity measurements and the longer wavelength for glucose signature measurements. The clinical results obtained using the TES method are promising (CD. Malchoff, J.I. Landau, K. Shoukri, J.M. Buchert, "A novel non-invasive blood glucose monitor", Diabetes Care, 25 (12), 2268-2274 (2002)). However, they are not yet considered sufficiently clinically accurate. At low glucose concentrations, < 4.2mM or <75mg/dl, the standard deviation should be < 0.4mM or < 7.5mg/dl. At high glucose levels, >4.2mM or 75mg/dl, the standard deviation should be < 10%, e.g. for a physiological range of glucose of 3-30 mM and an average value between 10-15mM, the standard deviation should be < 1.0-1.5 mM. Malchoff et al found an averaged standard deviation of 1.5mM in the range 50-450mg/dl.

It is therefore an object of the present invention to provide a system for non- invasive measurement of an analyte concentration, e.g. glucose concentration, in a live subject using the above-mentioned thermal emission spectroscopy method, so as to improve the accuracy thereof relative to the prior art arrangement, without increasing costs significantly.

In accordance with the present invention, there is provided a system for non-invasive measurement of an analyte concentration in body tissue, the system comprising means for detecting a thermal emission spectrum emitted by said body tissue, interference filtering means for spatially separating said thermal emission spectrum to create a plurality of spectral patterns and measuring in respect of each of a plurality of said spectral patterns a spectral intensity at a first, reference set of wavelengths, and a second set of wavelengths dependent on the analyte being measured, and determining therefrom the concentration of said analyte.

The present invention facilitates the measurement of the reference or analyte signal at more than one wavelength, preferably at a plurality of wavelengths, in various parts of the spectrum in a low cost manner. This flexibility has two advantages. First, measuring the reference and glucose signals at a plurality of wavelengths and in other parts of the spectrum means that more information is obtained, resulting in a better accuracy of the glucose concentration. Secondly, measuring parts of the spectrum containing information of other analytes allows for the correction for the interference from other analytes, thereby further increasing the accuracy of the measurement. Accordingly, the extraction of information relating to other analytes enables the invention to be applied in the determination of other analyte concentrations, e.g. haemoglobin or cholesterol.

Preferably, said system comprises a thermal emission spectroscopy system.

Preferably, said interference filtering means comprises a spatial light modulator.

Preferably, said interference filtering means comprises a multivariate optical element.

Preferably, said multivariate optical element comprises a liquid crystal display.

Preferably, said multivariate optical element comprises a digital mirror display.

Preferably, said multivariate optical element comprises a liquid crystal on silicon display.

Preferably, said thermal emission spectrum is detected using a photodetector.

Preferably, said system utilises multivariate calibration methods such as partial least squares regression.

Preferably, said analyte is glucose, haemoglobin, or oxygenated haemoglobin..

It is also known to employ a so-called metabolic heat conformation (MHC) method for the non- invasive measurement of blood glucose concentration in body tissue. The MHC method is used to estimate the blood glucose levels by measuring the body heat and the oxygen supply to the tissue sample. Body heat generated by glucose oxidation is based on the subtle balance of capillary glucose and oxygen supply to the cells of a tissue, and can be summarised in an equation:

[Glucose concentration] = Function[Heat generated, Blood flow rate, Hb, HbOi] where Hb and HbO₂ represent the haemoglobin and oxygenated haemoglobin concentrations, respectively.

In a preferred embodiment therefore, where the analyte is glucose, MHC means may be integrated or otherwise provided in the TES system defined above. The factors influencing the glucose concentration measurements are different for each of the TES and MHC methods, because TES gives a direct glucose concentration measurement and MHC gives an indirect measurement. Accordingly, inaccuracies in the glucose measurement are recognised when there is a large discrepancy between the MHC and TES measurements

Preferably, said thermal emission spectroscopy system incorporates a metabolic heat conformation method for independently determining blood glucose concentration.

Preferably said metabolic heat conformation method comprises self-mixing interferometry.

Preferably, said glucose concentration measurement determined using thermal emission spectroscopy, and said glucose concentration measurement determined using the metabolic heat conformation method, are compared to determine the accuracy in the glucose concentration measurement.

Preferably, the heat generated from said body tissue is determined using the Planck energy distribution formula.

These and other aspects of the present invention will be apparent from and elucidated with reference to the embodiments described herein.

Embodiments of the present invention will now be described by way of examples only and with reference to the accompanying drawings in which:

Figure 1 is a schematic representation of a thermal emission spectroscopy based glucose sensor in accordance with the first embodiment of the present invention; Figure 2 is a schematic representation of the thermal emission spectroscope and self- mixing interferometric unit, in accordance with the second embodiment of the present invention; and

Figure 3 is a schematic representation of the self-mixing interferometric apparatus.

Referring to Figure 1 there is shown a simplified thermal emission spectroscopy (TES) based device 10 in which a spatial light modulator (SLM) 11 such as a liquid crystal panel, a digital mirror display or a liquid crystal on a silicon display (LCOS display), is used in conjunction with a diffraction grating 12.

The blackbody radiation 13 (i.e. thermal emission spectrum) emanating from the tissue sample (not shown) is spatially organised according to the constituent wavelengths 14, by the diffraction grating 12. The grating 12 splits the spatially mixed spectrum of wavelengths 13 and spatially re-arranges the spectrum in order of the wavelengths constituting the spectrum. This "organised spectrum" 14 is then focussed onto the SLM 11 by a first lens system 15.

The various parts of the organised spectrum 14 can be analysed by assigning grey levels to specific pixels of the SLM 11. For example, making a collection of pixels black at a given location on the SLM 11, will prevent those wavelengths of the

"organised spectrum" 14, incident upon the blackened pixels, from passing through the SLM 11. Conversely, making a collection of pixels white will allow those wavelengths incident thereon to pass through the SLM 11. The wavelengths passing through the SLM 11 are focussed onto a detector 16 using a second lens system 17. In this manner, parts of the spectrum 14 can be transmitted and others blocked. Thus, by switching certain wavelengths on and off, glucose signature spectral bands and spectral bands for reference measurements can be measured sequentially.

Alternatively, by using more than one detector or a detector array, many signals can be measured simultaneously.

The present embodiment is also amenable to multivariate calibration methods such as partial least squares regression. Such methods take into account the variation in the entire thermal emission spectrum 13 signal to allow the maximum amount of information to be extracted from the spectrum.

The multivariate calibration procedure produces a regression vector

where r(λ_n) is a weighting function as applied to wavelength X_n of the thermal emission spectrum 13, for the analyte of interest, e.g. glucose. (Wavelengths Xi to X_n correspond to those wavelengths present in the emission spectrum). Subsequently taking the inner product of the regression vector with the measured thermal emission spectrum s=[s(λi),....,s(λ_n)] gives the concentration of the analyte of interest, in this case glucose.

The multivariate calibration method proceeds by displaying the weighting factors r(λi) to r(λ_n) on the pixels of the SLM 11 and subsequently focussing those wavelengths transmitted through the SLM 11 onto the detector 16 using the second lens system 17. Similarly, other desired signal patterns can also be extracted by displaying other regression vectors on the SLM 11. In this way, the glucose absorption and reference measurements can be made at more than one wavelength to improve the accuracy in the measurements. The SLM 11 acts as a so-called Multivariate Optical Element (MOE). However, when only one signal component is required, the MOE does not need to be adjusted and so the cheaper alternative of an interference filter can be used as a MOE.

It is to be noted that this embodiment contains no moving parts; selecting spectral regions or changing regression vectors is all done electronically. Furthermore, whilst the present invention has been exemplified by the non- invasive measurement of blood glucose concentration, the skilled addressee will also recognise its potential in measuring the concentration of other blood constituents, such as haemoglobin and oxygenated-haemoglobin.

In a further embodiment as illustrated in figure 2, there is shown a system for measuring the blood glucose levels in a tissue sample, i.e. a finger 20. The system incorporates a thermal emission spectroscopy based device 10, and a self-mixing interferometry unit 30 as applied to the Metabolic Heat Conformation (MHC) method. The system may further comprise thermometers to measure for example the room and skin temperature. The blood flow rate is determined using the self-mixing interferometry unit as identified in figure 2, and shown in detail in figure 3. The unit comprises a laser cavity 31, a lens system 32 to focus the laser beam 33 onto the tissue sample, i.e. the finger tip surface 20, and a photodetector 34. The laser beam 33 is focussed onto a focal plane which contains a surface 35 to which the finger 20 is applied. This ensures the surface of the finger 20 is suitably positioned at the focal plane of the lens system 32.

The beam emanating from the laser cavity 31 reflects off the surface of the finger 20 and is entrained back into the laser cavity 31 by the lens system 32. The interference of the laser beam 33 with the reflected beam within the laser cavity 31, sets up power fluctuations in the laser output, which is measured using the photodetector 34. The technique bears the name self-mixing interferometry due to the fact that the light reflected back into the laser cavity 31 interferes with the light resonating within the cavity.

If no blood flows in the finger 20 and the finger 20 is not moved, then everything is static, and the resulting signal from the photodetector 34 will be a constant in time (zero if DC filtered). If the finger 20 moves, or the amount of blood changes in the finger 20, then the amount of reflected light is changed and this will create fluctuations in the laser 31. The measured fluctuations will mirror these movements, and so the heartbeat will be an implicit part of the signal.

The signal on the photodetector 34 can also be understood on the basis of the speckle pattern when the blood flows. If no blood flows in the finger 20, then the speckle pattern will remain constant and the signal will be constant. When the blood flows, the speckle pattern will change in proportion to the blood flow velocity. The larger the velocity of the blood, the faster it changes the speckle pattern and the faster the signal on the photodetector 34 will oscillate (the oscillation period being typically between 0.1ms and 2ms). Thus, if the pattern is Fourier transformed, then as the signal oscillation rate increases, so will the number of high frequency components in the transform. By measuring the signal from the photodetector 34, the heartbeat and blood velocity can be measured simultaneously. This allows for a real time- varying rate of blood flow to be viewed, instead of a time-averaged view, as with the thermal diffusion method. More importantly however, the direct optical determination of blood velocity provides a more accurate determination of the blood velocity than the known thermal diffusion method associated with the MHC method and also provides for a more rapid measurement.

Thus, having determined the heat generated, the Hb and HbO₂ concentrations and blood velocity, the blood glucose concentration can be determined.

The TES device can be used to determine the blood glucose, Hb and HbO₂ concentrations as described in the first embodiment. In addition, as an alternative to a thermometer, the TES measurement system can also be used to determine the heat generated in the skin, using the temperature dependence of the blackbody curve given by the Planck energy distribution formula:

Because TES gives a direct glucose measurement and the MHC method gives an indirect measurement, the factors influencing the glucose measurements are different. Therefore the independent measurements can be compared to improve accuracy and combined to provide an average for the blood glucose concentration.

It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be capable of designing many alternative embodiments without departing from the scope of the invention as defined by the appended claims. In the claims, any reference signs placed in parentheses shall not be construed as limiting the claims. The word "comprising" and "comprises", and the like, does not exclude the presence of elements or steps other than those listed in any claim or the specification as a whole. The singular reference of an element does not exclude the plural reference of such elements and vice- versa. The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In a device claim enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

Claims

CLAIMS:

1. A system (10) for non-invasive measurement of an analyte concentration in body tissue (20), the system (10) comprising means (16) for detecting a thermal emission spectrum (13) emitted by said body tissue (20), interference filtering means (11) for spatially separating said thermal emission spectrum (13) to create a plurality of spectral patterns and measuring in respect of each of the plurality of said spectral patterns a spectral intensity at a first, reference set of wavelengths, and a second set of wavelengths dependent on the analyte being measured, and determining therefrom the concentration of said analyte.

2. A system as claimed in claim 1, wherein said system comprises a thermal emission spectroscopy system.

3. A system as claimed in claims 1 or 2, wherein said interference filtering means (11) comprises a spatial light modulator.

4. A system as claimed in claims 1 or 2, wherein said interference filtering means (11) comprises a multivariate optical element.

5. A system as claimed in claim 4, wherein said multivariate optical element comprises a liquid crystal display.

6. A system as claimed in claim 4, wherein said multivariate optical element comprises a digital mirror display.

7. A system as claimed in claim 4, wherein said multivariate optical element comprises a liquid crystal on silicon display.

8. A system as claimed in any preceding claim, wherein said thermal emission spectrum (13) is detected using a photodetector (16).

9. A system as claimed in any preceding claim, wherein said system (10) utilises multivariate calibration methods such as partial least squares regression.

10. A system as claimed in any preceding claim, wherein said analyte is glucose, haemoglobin, and/or oxygenated haemoglobin.

11. A system as claimed in any preceding claim, wherein said thermal emission spectroscopy system is incorporated in a metabolic heat conformation method for independently determining blood glucose concentration.

12. A system as claimed in claim 11, wherein said metabolic heat conformation method comprises self-mixing interferometry.

13. A system as claimed in claims 11 or 12, wherein said glucose concentration measurement determined using thermal emission spectroscopy, and said glucose concentration measurement determined using the metabolic heat conformation method are compared to determine the accuracy in the glucose concentration measurement.

14. A system as claimed in any preceding claim in which the heat generated from said body tissue is determined using the Planck energy distribution formula.