MXPA98001048A - Method for non-invasive measurement of an analyte in blood, with a better optic interface - Google Patents

Abstract

The present invention relates to a method for the non-invasive measurement of the concentration of an analyte, particularly a blood analyte in blood. The method uses spectrographic techniques together with an improved optical interphase between a detector probe (11) and the surface (12) of the skin or tissue surface of the body containing the blood to be analyzed. A coupling means (22) is described to improve the interface between the detector probe (11) and the surface (12) of the skin during the spectrographic analysis. In a preferred embodiment, the concentration of the blood analyte in blood is quantified using the partial square analysis in relation to a model incorporating a plurality of known blood samples.

Description

METHOD FOR NON-INVASIVE MEASUREMENT OF TJN ANALYTE BLOOD, WITH AN IMPROVED OPTICAL PHASE TECHNICAL CAMPQ The present invention relates generally to a non-invasive method for measuring a blood analyte, particularly glucose, using spectroscopic methods. More particularly, the method incorporates an improved input optical interface for irradiating biological tissue with infrared energy having at least several wavelengths and an improved optical output interface for receiving unabsorbed infrared energy as a measure of absorption differential by the biological sample to determine the glucose concentration. An index coupling means is described as a key element of the improved optical interface.

BACKGROUND OF THE INVENTION The need and demand for a non-invasive and accurate method to determine the blood glucose level has been well documented. Barnes et al., (U.S. Patent No. 5,379,764) describe the need for diabetics to frequently check the glucose levels in their REF: 26786 blood. It is also recognized that the more frequent the analysis, the less likely there are large swings in glucose levels. These large oscillations are associated with the symptoms and complications of the disease, whose long-term effects may include heart disease, arteriosclerosis, blindness, seizures, hypertension, renal failure and premature death. As described below, several systems have been proposed for the non-invasive measurement of blood glucose. However, despite these efforts, a lancet cut on the finger is still necessary for all currently commercially available forms of glucose verification at home. It is considered that compromising the diabetic patient in this way to a more effective use of any form of diabetic management is seldom achieved. The various proposed non-invasive methods for determining blood glucose level, discussed individually below, generally use quantitative infrared spectroscopy as a theoretical basis for analysis. Infrared spectroscopy measures electromagnetic radiation (0.7-25 μm) that absorbs a substance at various wavelengths. The molecules do not maintain fixed positions one with respect to the other, but they vibrate backwards and forwards around an average distance. The absorption of light at an appropriate energy causes the molecules to be excited at a higher level of vibration. The excitation of molecules to an excited state occurs only at certain defined energy levels, which are characteristic for that particular molecule. The primary states of primary vibration occur in the middle infrared frequency region (ie, 2.5-25 μm). However, the noninvasive determination of analytes in blood in this region is problematic, if not impossible, due to the absorption of light by water. The problem is solved by using shorter lengths of light which are not attenuated by water. The overtones of the primary vibration states exist at shorter wavelengths and allow quantitative determinations at these wavelengths. It is known that glucose absorbs at multiple frequencies in the middle and near infrared range. However, other infrared active analytes are found in the blood, which also absorb at similar frequencies. Due to the superimposed nature of these absorption bands, a single specific frequency can not be used for a reliable non-invasive measurement of glucose. Therefore, the analysis of the spectral data for the measurement of glucose requires the evaluation of many spectral intensities over a broad spectral range to obtain the sensitivity, precision, accuracy and reliability necessary for the quantitative determination. In addition to superimposing the absorption bands, glucose measurement is further complicated by the fact that glucose is a minor component, in terms of weight, in the blood, and that the resulting spectral data can show a non-linear response due to both the properties of the substance it is examined and / or the inherent lack of linearity in the optical instrumentation. A further common element for non-invasive glucose measurement techniques is the need for an optical interface between the body portion and the measuring point and the sensing element of the analytical instrument. Generally, the detector element must include an input element or means for irradiating the sample point with infrared energy. The detector element must additionally include an output element or means for measuring the transmitted or reflected energy at various wavelengths resulting from irradiation through the input element. Robinson et al. (U.S. Patent No. 4,975,581) describe a method and apparatus for measuring a characteristic of unknown value in a biological sample using infrared spectroscopy together with a multiple variation model that is derived empirically from a set of spectra of biological samples of known characteristic values. The above-mentioned characteristic is generally the concentration of an analyte, such as glucose, but it can also be a chemical or physical property of the sample. The method of Robinson et al., Involves a two-stage process that includes both calibration and prediction stages. In the calibration step, the infrared light is coupled to calibration samples of known characteristic values so that there is a differential attenuation of at least several wavelengths of the infrared radiation as a function of the various components and analytes comprising the shows with a known characteristic value. Infrared light is coupled to the sample by passing light through the sample or by reflection of light from the sample. The absorption of infrared light by the sample causes variations in light intensity that are a function of the wavelength of light. The resulting variations in intensity in at least several wavelengths is measured for the establishment of calibration samples of known characteristic values. The original or intensity-transformed variations are then empirically related to the known characteristic of the calibration samples using a multiple-variable algorithm to obtain a multiple-variable calibration model. In the prediction stage, the infrared light is coupled to a sample of unknown characteristic value, and the calibration model is applied to the original or transformed intensity variations of the appropriate wavelengths of light measured from this unknown sample. The result of the prediction stage is the estimated value of the characteristic of the unknown sample. The description of Robinson et al is incorporated herein by reference. Several of the modalities described by Robinson et al., Are non-invasive and incorporate an optical interface having a sensing element. As shown in Figures 5 and 6 of Robinson et al., The optical interface first includes an input element and secondly, an output element. The input element is a source of infrared light or a source of light close to infrared. The interface of the input element with the sample or portion of the body containing the blood to be tested includes transmitting the light energy or propagating the light energy to the surface of the skin by means of air. The output element includes a detector which receives the transmitted or reflected light energy. The exit interface with the sample also includes propagating transmitted or reflected light through the air from the skin.

Barnes et al., (U.S. Patent No. 5,379, 764) describe a spectrographic method for analyzing glucose concentration, where near infrared radiation is projected onto a portion of the body, the radiation includes a plurality of wavelengths, followed by detection of the resulting radiation emitted from the body part affected by the absorption of the body. The method described includes pre-processing the resulting data to minimize the influences of deviation and entrainment to obtain an expression of the magnitude of the detected radiation as it has been modified. The detector element described by Barnes et al. , includes a double-conductor fiber optic probe which is placed in contact or close contact with the skin of the body. The first conductor of the double-conductor fiber optic probe acts as an input element which transmits near infrared radiation to the surface of the skin while in contact with it. The second conductive fiber of the double conductor probe acts as an output element which transmits the reflected energy or non-absorbed energy back to the spectrum analyzer. The optical interface between the sensing element and the skin is obtained by simply contacting the surface of the skin with the probe, and may include the transmission of light energy through the air to the skin and through the air back into the skin. the probe based on the degree of contact between the probe and the skin. Irregularities in the surface of the skin and at the measuring point can alter the degree of contact. Dáhne et al., (American patent number 4,655,225) describes the use of near-infrared spectroscopy to non-invasively transmit optical energy in the near-infrared spectrum through a finger or the earlobe of a person. The use of near-infrared energy reflected diffusely from depth within tissues is also discussed. The responses are derived at two different wavelengths to quantify glucose in the subject. One of the wavelengths is used to determine the background absorption, while the other wavelength is used to determine the absorption of glucose. The optical interface described by Dáhne et al., Includes a detector element having an input element which incorporates a light directing means which is transmitted through the air to the surface of the skin. The light energy which is transmitted or reflected from the body tissue as a measure of absorption is received by an output element. The interface for the output element includes transmitting the light energy reflected or transmitted through the air to the detector elements. Caro (U.S. Patent No. 5,348,003) describes the use of electromagnetic energy temporarily modulated at multiple wavelengths such as radiant light energy. The dependence of the wavelength derived from the optical absorption per unit path length is compared with a calibration model to derive analyte concentrations in the medium. The optical interface described by Caro includes a detector element having an input element, wherein the light energy is transmitted through a focusing means on the surface of the skin. The focusing means may be close to or in contact with the surface of the skin. The detector element also includes an exit element which includes an optical collection means which may be in contact with the surface of the skin or near the surface of the skin to receive the light energy which is transmitted through the tissue . Again, a portion of the light energy propagates through the air to the surface of the skin and back to the output element due to lack of contact with the detector and irregularities in the surface of the skin.

Problems have been recognized with the optical interface between the tissue and the instrument. In particular, problems have been recognized in the optical interface associated with the coupling light and return to exit tissue by Ralf Marbach as published in his thesis entitled "MeBverfahren zur IR-spektroskopishen Blutglucose Bestimmung" (English translation: "Measurement techniques for IR spectroscopic determination of blood glucose"), published in 1993. Marbach states that the requirements of the optical accessory for measuring the diffuse reflection of the lip are: 1) A high optical "performance" for the purpose to optimize the S / N ratio of the spectra, 2) Intensity suppression for Fresnel or specular reflection in the surface area of the skin. The mention accessory proposed by Marbach tries to solve both requirements through the use of a hemispherical immersion lens. The lens is made of a material which closely resembles the refractive index of the tissue, calcium fluoride. As stated by Marbach, the important advantages of the immersion lens for transcutaneous diffuse reflection measurements are an almost complete coupling of the refractive indices of CaF2 and the skin and the successful suppression of Fresnel reflection. However, calcium chloride does not present an ideal index coupling for tissue, since it has an index of 1.42, in relation to tissue that is approximately 1.38. Therefore, there is an index matching in the lenses for the tissue interface assuming full contact between the lens and the tissue. The optical efficiency of the sampling accessory is further compromised by the fact that the lenses and the fabric are not in perfect optical contact due to the roughness of the fabric. The result is a significant mismatch of refractive indices when light is forced to travel through the lens (N = 1.42) to the air (N = 1.0) and then to the tissue (N = 1.38). Therefore, the inherent roughness of the fabric results in small air spaces between the lens and the fabric, which decreases the optical performance of the system, and consequently compromises the operation of the measuring accessory. The magnitude of the problem associated with the mismatch of the refractive index is a complicated issue. First, a fraction of light, which would otherwise be available for spectroscopic analysis of blood analytes, is reflected in the limits of mismatch returning to the entrance or to the optical collection system without questioning the sample. The effect is governed by the Fresnel equation: R = W ~ 2. { N '+ N) 2 For randomly polarized, normally incident light, where N and N 'are the refractive indices of the two media. When solving for the air / CaF2 interface, an R = 0.03, or a 3% reflection is obtained. This interface must be traversed twice, which provides a 6% reflected component, which does not interrogate the sample. These bad interface matches are multiplicative. Then the fraction of light that enters the tissue successfully must be considered. In some regions of the spectrum, for example, under a strong band of water, almost all of the transmitted light is absorbed by the tissue. The result is that this apparently small reflected light component of the poor refractive index match can virtually clean and darken the desired signal from the sample. Finally, it is useful to consider the effect of the critical angle on the light fabric trying to get out of the tissue. The tissue is highly dispersed and in this way the light rays which reach the tissue at normal incidence can leave the tissue at a high angle of incidence. If the coupling lens is not in intimate contact with the tissue, these high angle light rays are lost for a total internal reflection. The equation which defines the critical angle, or point of total internal reflection, is as follows: ? "Sin -1 N When light propagates through a higher index material such as tissue (N '= 1.38) and approaches an interface with a lower refractive index, such as air (N = 1.0), a critical angle of total internal reflection. Light that approaches such an interface at an angle greater than the critical one will not propagate in the most rarefied medium (air), but will reflect fully inward, into the tissue. For the tissue / air interface mentioned above, the critical angle is 46.4 °. The light will not escape when it encounters a greater inclination than this angle. Therefore, an optimal intimate contact is essential for an efficient capture of light from the tissue. As detailed above, each of the prior art apparatus for the non-invasive measurement of glucose concentration uses a detector element. Each detector element includes an input element and an output element. The optical interface between the input element, the output element and the surface of the skin of the tissue to be analyzed, in each apparatus, is similar. In each case, the input light energy is transmitted through the air to the surface or potentially through the air due to a gap in the contact surface between the input detector and the surface of the skin. Likewise, the output detector receives the transmitted or reflected light energy by means of transmission through the air to the output detector, or potentially through a gap between the detector element and the surface of the skin although the made attempts to place the exit detector contact with the skin. It is considered that the optical interfaces described in the prior art alter the accuracy and consistency of the data that is acquired using the methods and apparatuses of the prior art. Therefore, the accuracy of these methods for the non-invasive invasion of glucose are compromised. Accordingly, there is a need for a method and apparatus for non-invasively measuring blood glucose concentrations which incorporates an improved optical interface. The optical interface should produce consistent repeatable results so that the concentration of the analyte can be calculated accurately from a model such as that described by Robinson et al. The optical interface should minimize the effects of input and output light energy due to transmission through the air both in and out of the tissue being analyzed. In addition, the harmful effects of spaces due to irregularities in the surface of the skin or the presence of other contaminants must be reduced or eliminated. The present invention solves these needs as well as other problems associated with existing methods for the non-invasive measurement of blood glucose concentration using infrared spectroscopy and the optical interface associated therewith. The present invention also offers additional advantages over the prior art and solves the problems associated therewith.

BRIEF DESCRIPTION OF THE INVENTION The present invention is a method for non-invasively measuring the concentration of an analyte, particularly glucose in human tissue. The method uses spectroscopic techniques together with an improved optical interface between a detector probe and the surface of the skin or the tissue surface of the body containing the tissue to be analyzed. The method for non-invasively measuring blood glucose concentration includes first providing an apparatus for measuring infrared absorption by an analyte contained in the tissue. The apparatus generally includes three elements, a power source, a detector element and a spectrum analyzer. The detector element includes an input element and an output element. The input element is operatively connected to the power source by a first means for transmitting infrared energy. The output element is operatively connected to the spectrum analyzer by a second means for transmitting the infrared energy. In the preferred modalities, the input element and the output element comprise lens systems which focus the infrared light energy towards and from the sample. In a preferred embodiment, the input element and the output element comprise a system of simple lenses which is used both for the input of infrared light energy from the power source and for the output of both specular and reflected light energy. diffuse manner from the sample containing the analyte. Alternatively, the input element and the output element may be constituted of two lens systems, placed on opposite sides of a sample containing analyte, wherein the light energy of the energy source is transmitted to the input element and the light energy is transmitted through the sample containing the analyte and then passed through the output element to the spectrum analyzer. The first means for transmitting the infrared energy, in the preferred embodiments, simply includes placing an infrared energy source close to the input element so that the light energy from the source is transmitted through the air to the input element. Furthermore, in preferred embodiments, the second means for transmitting the infrared energy preferably includes a single mirror or a system of mirrors which direct the light energy leaving the output element through the air to the spectrum analyzer. In carrying out the method of the present invention, an analyte is selected that contains a tissue area as the point of analysis. This area may include the surface of the skin on the finger, earlobe, forearm or any other surface of the skin. Preferably, the tissue containing the analyte in the sampling area includes blood vessels close to the surface and a relatively regular skin surface without callus. A preferred sample position is the lower part of the forearm. Subsequently a quantity of a medium or index coupling fluid is placed on the area of the skin to be analyzed. It is preferred that the index matching means be non-toxic and have a spectral signature in the near infrared region which is minimal. In the preferred embodiments, the index coupling means has a refractive index of about 1.38. In addition, the refractive index of the medium must be constant throughout the composition. The composition of index coupling means is detailed below. The detector element, which includes the input element and the output element, is subsequently placed in contact with the index coupling means. Alternatively, the index coupling means may first be placed on the detector element, followed by positioning of the detector element in contact with the skin, with the index coupling means, placed between them. In this way, the entry element and the exit element are coupled to the tissue containing the analyte or the surface of the skin via the index coupling means which eliminates the need for light energy to propagate through the air or from air pockets due to irregularities in the surface of the skin. By analyzing the glucose concentration in the tissue containing the analyte, the light energy of the energy source is transmitted via the first means to transmit infrared energy to the interior of the input element. The light energy is transmitted from the input element through the index coupling means towards the surface of the skin. Part of the light energy that makes contact with the sample containing the analyte is differentially absorbed by the various components and analytes contained therein at various depths within the sample. Some light energy is also transmitted through the sample. Nevertheless, a quantity of light energy is reflected back to the output element. In a preferred embodiment, the light energy not absorbed or not transmitted is reflected back to the output element before propagation through the index coupling means. This reflected light energy includes both the reflected light energy in a diffuse way and the reflected light energy in a specular manner. The reflected light energy in a specular manner is that which is reflected from the surface of the sample and contains little or no information of the analyte, while the diffused reflected light energy is that which is reflected from the deepest within the shows, where the analytes are present. In the preferred embodiments, the specularly reflected light energy is separated from the reflected light energy in a diffuse manner. Subsequently, the unabsorbed diffuse reflected light energy is transmitted via a second means to transmit the infrared energy to the spectrum analyzer. As detailed below, the spectrum analyzer preferably uses a computer to generate a prediction result using the measured intensities, a calibration model and a multi-variable algorithm. A preferred device for separating reflected light specularly from diffused reflected light is a specular control device as described in the co-pending application and commonly assigned serial number 08 / 513,094, filed on August 9, 1995 and entitled "Apparatus of diffuse reflex monitoring ". The above application is incorporated herein by reference. In an alternative embodiment, the input element is placed in contact with a first quantity of index coupling means on a first surface of the skin, while the exit element is placed in contact with a second quantity of coupling means of index on the opposite skin surface. Alternatively, the index coupling means may be placed on the entry and exit elements before contact with the skin so that the medium is placed between the elements and the surface of the skin during the measurement. With this alternative embodiment, the light energy propagated through the input element and the first quantity of the index coupling medium are absorbed differentially by the tissue containing the analyte or are reflected therefrom, while a quantity of the light energy at various wavelengths it is transmitted through the analyte containing tissue to the second skin surface or opposite skin surface. From the second skin surface, the unabsorbed light energy is propagated through the second amount of index coupling medium towards the output element with subsequent propagation to the spectrum analyzer for calculation of the analyte concentration. The index coupling means of the present invention is a key to the improved accuracy and repeatability of the method described above. The index coupling medium is a composition containing perfluorocarbons and chlorofluorocarbons. Preferably, the compound contains a hydrophilic additive such as isopropyl alcohol. It is considered that the hydrophilic compound picks up moisture on the surface of the skin to improve the interface between the fluid and the skin. In addition, the index coupling means may contain cleaning agents for binding the oil to the skin at the sample point and reducing the effect thereof. Finally, a surfactant can also be included in the fluid composition. The surfactant improves the wetting of the tissue, which generates a uniform interface. An antiseptic material can also be added to the index coupling medium. In an alternative embodiment of the present invention, the index of coupling between the optical detector elements and the fabric can be carried out by a deformable solid. The deformable solid can alter its shape so that air spaces are minimized, due in part to irregular skin surfaces. Deformable solids may include at least gelatin, adhesive tape and substances that are liquid when applied but that solidify with time. The index coupling means preferably has a refractive index between 1.35 and 1.40. It has been found that the use of a refractive index in this range improves the repeatability and accuracy prior to improve optical performance and reduce variations spectroscopic unrelated to the analyte concentration method. In addition, the index coupling means must have a consistent refractive index throughout the composition. For example, no air bubbles must be present which cause changes in the direction of light. In a preferred embodiment, the glucose concentration in the tissue is determined by first measuring the intensity of light received by the output detector. These intensities measured in combination with a calibration model are used by a multiple variable algorithm to predict the glucose concentration in the tissue. The calibration model empirically relates the known concentrations of glucose in a set of calibration samples to the measured intensity variations obtained from the calibration samples. In a preferred embodiment, the multiple variable algorithm used is the partial least squares method, although other multiple variable techniques may be used. The use of an index coupler means for coupling the input element of the optical detector and the output element to the surface of the skin reduces the probability of aberrant data being acquired. The index coupling means increases the repeatability and precision of the measurement method. Adverse effects on the entry and exit of light energy by transmission through the air or irregular surfaces of the skin that have air pockets are eliminated. These and other additional advantages and novel features which characterize the present invention are particularly emphasized in the appended claims to which form a part thereof. However, for a better understanding of the invention, reference to its advantages will be done and the target obtained by using the drawings which form a further part hereof and the accompanying descriptive matter in which there is illustrated and described modalities preferred of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, in which similar reference numbers indicate corresponding parts or elements of the preferred embodiments of the invention through the various views: Figure 1 is a partial cross-sectional view of a detector element coupled to the surface of the skin by means of an indexing coupling fluid; Figure 2 is a partial cross-sectional view of an alternative embodiment of a sensing element coupled to opposite sides of the skin surface by means of an indexing coupling fluid; and Figure 3 is a graphical representation of experimental data showing the improvement in accuracy and repeatability of a detector coupled to the skin via an index coupling means.

DESCRIPTION t t.?T.T.?n.1 OF THE PREFERRED MODALITIES The detailed embodiments of the present invention are described herein. However, it should be understood that the embodiments described are only exemplary of the present invention which may be constituted in various systems. Therefore, the specific details described herein should not be considered as limiting, but rather as a basis for the claims and as a representative basis for the teachings for a person familiar with the technique that can be practiced in a manner variable the invention. The present invention is directed to a method for non-invasive measurement of tissue constituents using spectroscopy. It has been found that a sample is a complex matrix of materials with different refractive indices and absorption properties. In addition, because blood constituents of interest are present at very low concentrations, it has been found that it is imperative to couple light in and out of the tissue in an efficient manner. The method of the present invention incorporates an indexable coupling means, a fluid or a deformable solid, to improve the coupling efficiency of light inside and outside the tissue sample. The present invention uses the light energy in the near infrared region of the optical spectrum as a power source for analysis. Water is by far the largest contributor of tissue uptake in the near-infrared region due to its concentration as well as its strong absorption coefficient. It has been found that the total absorption spectrum of the tissue, therefore, closely resembles the water spectrum. For example, less than 0.1% of light absorption is from a constituent such as glucose. It has also been found that the tissue largely scatters light because there are many discontinuities in the refractive index in a typical tissue sample. The water is irrigated through the tissue, with a refractive index of 1.33. Cell walls and other tissue characteristics have refractive indices close to 1.5 and 1.6. These discontinuities in the refractive index result in inspection. Although these discontinuities in the refractive index are frequent, they are also typically of small magnitude and the dispersion generally has a strong directionality towards the forward direction. This forward dispersion has been described in terms of anisotropy, which is defined as the cosine of the average dispersion angle. Therefore, for a complete backward scatter, it means that all scattering events must cause a photon to deviate from its travel direction by 180 °, and the anisotropy factor would be -1. Likewise, for a complete forward dispersion, the anisotropy factor would be +1. In the near infrared, it has been found that the tissue has an anisotropy factor of about 0.9 to 0.95, which is a forward scatter. For example, an anisotropy factor of 0.9 means that an average photon of light only scatters through an angle of up to 25 ° as it passes through the sample. When carried out in analysis for a tissue analyte, measurements must be made in at least two different ways. It is recognized that the transmitted light can be measured through a section of tissue or the reflected or remitted light can be measured from the tissue. It has been recognized that transmission is the preferred method of analysis in spectroscopy due to the forward scattering of light as it passes through the tissue. However, it is difficult to find a part of the body that is optically thin enough for light from the near infrared to pass through it, especially at longer wavelengths. Therefore, the preferred method for measurement in the present invention focuses on the reflectance of light from the sample. The photons are reflected and refracted at refractive index discontinuities, and in this way the light that hits the tissue immediately has a small reflectance on the surface of the tissue. This is known as specular reflectance. Since light does not penetrate the tissue, it contains little information about the constituents of the tissue. This is especially valid when considering the physiology of the skin, which has an outer layer which is essentially dead and lacks concentration values of the analytes that are generally considered of interest in a sample. Therefore, the reflected light energy that contains the analyte information is that light which is reflected back to the surface through the discontinuities of the refractive index deeper within the tissue sample. This reflected light energy is referred to as diffuse reflected light.

Applicants have found that a large fraction of incident photons are absorbed in the tissue. Those photons which are available for back coupling out of the tissues are probably deflected in their angular trajectory. In fact, by definition, a photon must change direction in order to excite the tissue in a direction toward the optical input. However, applicants have found that a major problem associated with detection is related to the discontinuity in the refractive index between the average tissue refractive index and the refractive index of the air outside the tissue. It has been found that this discontinuity acts on the incident light which leads to a fraction network and a small specular reflectance of less than about 5 percent. However, in the exit path, discontinuity results in a critical angle phenomenon. Because the photon travels from a medium of high refractive index to one of lower refractive index, there is a critical angle after which a photon is fully reflected inward and will not escape from the tissue sample. It has been found that the critical angle for photons traveling from the tissue to the air is about 46 °, which is a problem. A photon normally incident on the surface of the tissue must deviate through a large angle to come out. Due to the forward direction of the dispersion, it is difficult for a photon to do this, and it is very likely that it will make a rub or a high angle of incidence with the tissue and the air interface. The friction index photons do not escape because the critical angle is exceeded. Applicants have found a solution for the differences in the refractive index associated with the luminous coupling energy that leaves the tissue for an analytical instrument. The solution is the use of an immersion fluid which has very little absorptivity in the spectral range of interest, and has a viscosity compatible with a good flow and coating capacity, and at the same time has a refractive index which closely matches with the tissue A preferred material is a fluorinated, chlorinated hydrocarbon polymer oil manufactured by Occidental Chemical under the trade name FLUOROLUBE. These oils have a refractive index of approximately 1.38, are non-toxic and have a spectral signature in the near infrared region which is minimal. Now with reference to Figures 1 and 2, partial cross-sectional views of two preferred embodiments of an apparatus for the non-invasive measurement of the concentration of an analyte in blood are shown. The drawings in Figures 1 and 2 are schematic to show the concept of using an index coupling means 22 together with a non-invasive sensing element 11 operatively connected to a power source 16 and a spectrum analyzer. The relative size, shape and detail of the physical components are not shown. The apparatus shown in Figure 1 and the apparatus shown in Figure 2 generally include three elements, a power source 16, a detector element 11 and a spectrum analyzer 30. The embodiment of Fig. 1 shows the detector element including an input element 20 and an output element 26, which may include a single lens system for both input and output light energy. The entry element 20 and the exit element 26 are in contact with a common skin surface 12 of a tissue 10 containing the analyte. The alternative embodiment of Figure 2 shows an arrangement or arrangement of an alternative detector element 11, in which the entrance element 20 and the exit element 26 are placed on opposite surfaces 12, 14 of a tissue 10 containing the analyte. Both modes work to give a measure of the absorption of infrared energy with the tissue 10 containing the analyte. Nevertheless, the modality of Figure 1 is used to measure the amount of light energy which is reflected from the tissue 10 containing the analyte by the analyte components therein. In contrast, the embodiment of Figure 2 measures the transmission of light energy through the tissue 10 containing the analyte. In both embodiments, the absorption at various wavelengths can be determined by comparing the intensity of the light energy from the energy source 16. The power source 16 is preferably a wide-band infrared black body source. The optical wavelengths emitted from the power source 16 are preferably between 1.0 and 2.5 μm. The power source 16 is operatively coupled to a first means for transmitting infrared energy 18 from the power source to the input element 20. In the preferred embodiments, the first means 18 is simply the transmission of light energy to the input element 20 through the air by placing a source 16 of energy next to the input element 20. The input element 20 of the detector element 11 is preferably an optical lens which focuses the light energy to a point of high energy density. However, it should be understood that other beam focusing means can be used in conjunction with the optical lenses to alter the illumination area. For example, a system of multiple lenses, tapered fibers or other devices for forming a conventional optical beam can be used in order to alter the input light energy. In both embodiments shown in Figures 1 and 2, an output detector 26 is used to receive the light energy reflected or transmitted from the tissue 10 containing the analyte. As described in connection with a method of analysis below, the embodiment of Figure 1 has an output detector 26 which receives the reflected light energy, while the embodiment of Figure 2 includes an output detector 26 which receives the light transmitted through the tissue 10 containing the analyte. As with the input element 20, the output element 26 is preferably an optical lens. Other means of optical pickup can be incorporated within the output element 26, such as a multi-lens system, a tapered fiber or other beam collection means to help direct light energy to the spectrum analyzer. A second means for transmitting the infrared energy 28 is operatively connected to the output element 26. The light transmitted through the second means for transmitting infrared energy 28 is transmitted to the spectrum analyzer 30. In a preferred embodiment, the operative connection to the output element includes the transmission of reflected or transmitted light energy leaving the output element through the air to the spectrum analyzer. A mirror or a series of mirrors can be used to direct this light energy to the spectrum analyzer. In a preferred embodiment, a specular control device is incorporated to separate the reflected specular light from the reflected light in a diffuse manner. This device is described in the copending application and commonly assigned serial number 08 / 513,094, filed on August 9, 1995 and entitled "Diffuse Reflectance Verification Apparatus", the description of which is incorporated herein by reference. In carrying out the method of the present invention, a tissue area 10 containing the analyte is selected as the point of analysis. This area may include the surface 12 of the skin on the finger, the earlobe, the forearm or any other surface of the skin. Preferably, the area for sampling includes blood vessels near the surface, on a relatively regular surface without callus. A preferred sample position is the lower part of the forearm. Subsequently, a quantity of index coupling means 22 is placed on the surface 12 of the skin., either a fluid or a deformable solid, in the area to be analyzed. The detector element 11, which includes the input element 20 and the output element 26, as shown in the embodiment of FIG. 1, is subsequently brought into contact with the index coupling means 22. Alternatively, a quantity of index coupling means 22 may be placed on the sensing element 11, which is then brought into contact with the surface 12 of the skin, with the index coupling means 22 positioned therebetween. In any of the methods, the entry element 20 and the exit element 26 are coupled to the tissue 10 containing the analyte or the surface 12 of the skin via the indexing means 22. The coupling of the detector element 11 to the surface of the skin via the indexing means 22 eliminates the need for light energy to propagate through the air or air pockets due to a space between the probe and the surface 12 of the skin or irregularities on the surface 12 of the skin. When performing the analysis to determine the glucose concentration in the tissue 10 containing the analyte, the light energy of the energy source 16 is transmitted through the first medium to transmit infrared energy 18 into the input element 20. The light energy is transmitted from the input element 20 through the index coupling means 22 to the surface 12 of the skin. The light energy that contacts the surface 12 of the skin is differentially absorbed by the various components and analytes contained beneath the surface 12 of the skin with the body therein (eg, blood within the vessels). In a preferred embodiment, the unabsorbed light energy is reflected back to the output element 26 before propagation again through the index coupling means 22. The unabsorbed light energy is transmitted via the second means to transmit infrared energy to the spectrum analyzer 30. In the alternative embodiment of Figure 2, the input element 20 is brought into contact with a first quantity of index coupling means 22 on a first surface 12 of the skin, while the exit element 26 is placed in contact with a second amount of index coupling means 24 on an opposite surface 14 of the skin. As with the previous embodiment, the index coupling means 22 can be placed first on the inlet element 20 and the outlet element 26 before contact with the surface 12 of the skin. With this alternative embodiment, the light energy propagated through the input element 20 and the first quantity of index coupling means 22 is differentially absorbed by the tissue 20 containing the analyte, while the amount of light energy in various lengths of The wave is transmitted through the tissue 10 containing the analyte to the second surface 14 of the skin or the opposite surface. From the second surface 14 of the skin, the unabsorbed light energy is propagated through the second quantity of the index coupling means 24 towards the output element 26 with subsequent propagation to the analyzer 30 of the spectrum for the calculation of the concentration of the analyte. As previously stated, the index coupling means 22 of the present invention is a key to an improvement in the accuracy and reproducibility of the method described above. Preferably, the index coupling means can be a fluid composition containing perfluorocarbons and chlorofluorocarbons. A preferred composition includes chlorotrifluoroethene. The compound preferably contains a hydrophilic additive, such as isopropyl alcohol. It is considered that the hydrophilic additive collects moisture on the surface of the skin to improve the interface between the medium and the skin. further, the index coupling means may contain cleaning agents to bind the oil to the skin at the sample point and reduce the effect thereof. A surfactant can also be included in the composition. The surfactant improves the wetting of the tissue, so that contact is improved. Finally, an antiseptic compound can be added to the index coupling medium. In an alternative embodiment of the present invention, the index coupling between the optical detector elements and the fabric can be carried out by a deformable solid. The deformable solid can alter its shape such as air spaces, in part because the irregular surfaces of the skin are minimized. Deformable solids may include at least gelatin, adhesive tape and substances that are liquid when applied, but that become solid over time. Preferably, the index coupling means has a refractive index of 1.35-1.41. It has been found that the use of a refractive index in this range improves the repeatability and accuracy of the above method. It is recognized that the refractive index of the index coupling means must be consistent throughout the composition to avoid refraction of light energy as it passes through the medium. For example, there should be no air bubbles present in the index coupling medium which can cause a discontinuity in the refractive index. In a preferred embodiment, the glucose concentration in the tissue is determined by first measuring the intensity of light received by the output detector. These intensities measured in combination with a calibration model are used by a multi-variable algorithm to predict the concentration of glucose in the tissue. The calibration model empirically relates the known glucose concentrations in the calibration samples to the measured intensity variations obtained from the calibration samples. In a preferred embodiment, the multiple variable algorithm used is the partial least squares method, although other multiple variable techniques may be used. The infrared input energy from the input element detector is coupled to the sample containing the analyte or blood via the index coupling means 22. Therefore, there is a different absorption at different wavelengths of infrared energy as a function of the composition of the sample. The different absorption causes variations in the intensity of the infrared energy that passes through the samples that contain the analyte. Intensity variations derived from infrared energy are received by reflectance or transmittance through the sample containing the analyte by the detector output element, which also couples to the blood or to the sample containing the analyte through the analyte. index coupling means 22.

The spectrum analyzer 30 of the present invention preferably includes a frequency scattering device and a detector photodiode array in conjunction with a computer to compare the data received from such devices to the model described above. Although it is preferable, other methods of analyzing the output energy can be used. The frequency scattering device and the photodiode array detectors are positioned so that the array includes multiple output electrodes, one of which is assigned to a particular wavelength or narrow range of wavelengths of the source 16 of Energy. The amplitude of the voltage developed at each of the electrodes can be measured with the intensity of the infrared energy incident at each particular detector in the array for the wavelength of the source associated with that detector. Typically, the photodiodes of the array detector are passive, instead of photovoltaic, although photovoltaic devices can be used. The diodes of the array detector must be supplied with a direct current power supply voltage derived from the power supply and coupled to the diodes of the array detector by means of a cable. The impedance of the diode elements of the array detector is changed as a function of the intensity of the optical energy incident thereto in the pass band of the power source 16 associated with each particular photodiode element. The impedance changes can control the amplitude of the signal supplied by the array detector to a random access memory computer. The computer includes a memory that has stored in it a multivariate calibration model that empirically relates the known concentration of glucose in a set of calibration samples with the variations in the intensity of the measurement from the calibration samples, at different wavelengths. Such a model is constructed using techniques known to people familiar with statistics. The computer predicts the analyte concentration of sample 10 containing the analyte by using the measured intensity variations, the calibration model and a multi-variable algorithm. Preferably, the calculation is performed by the partial least squares technique as described by Robinson et al., In U.S. Patent No. 4,975,581, incorporated herein by reference. It has been found that a considerable improvement in detection accuracy is obtained by simultaneously using at least several wavelengths from the entire spectral frequency range of the power source 16 to derive data for a multi-variable analysis . The multi-variable method allows both detection and compensation for interference, the detection of meaningless results, as well as the elaboration of models of many types of non-linear relationships. Since the calibration samples used to derive the models have been analyzed on a multivariate basis, the presence of unknown biological materials in the tissue containing the analyte does not prevent or alter the analysis. This is because the unknown biological materials are present in the calibration samples used to form the model. The partial least squares algorithm, the calibration model and the measured intensity variations are used by the computer to determine the concentration of the analyte in the tissue 10 containing the analyte. The indication derived by the computer is coupled to conventional alphanumeric visual screens.

Experimental part Comparative tests are carried out to document the effect of using an index coupling means in comparison with a medium that does not allow index matching in the same apparatus. The reference should be made with figure 3, which is a graphical representation of the results of the experiment, where line 50 represents the analysis without the index coupling means, and line 52 documents the improved precision of the result when the detector element is coupled to the surface of the skin via a means of index coupling. To carry out the test, the forearm is sampled with and without index coupling means with a separate data collection in two minutes. The apparatus used to carry out the experiment uses a Perkin-Elmer Fourier Transform infrared spectrometer (Norwalk, CT), system 2000 (FTIR) with a single indium antimonide element detector (InSb), 4 mm DAY. The light source is a 100 watt tungsten and quartz halogen light lamp from Gilway Technical Lamp (Woburn, MA). The interferometer used is an infrared transmitting quartz beam splitter. The data collection is done via a transport link to a PC that develops Perkin-Elmer TR-IR programming elements. The data visualization is carried out in Matlab (Math orks, Natick, MA). Home optical sampling systems are constructed, which consist, in part, of the optical system described in copending application 08 / 513,094, filed on August 9, 1995, entitled "Diffuse reflectance verification apparatus". All parameters of the instrument were identical for the collection of both spectra. The experimental procedure is as follows. The sampling surface consists of a semi-sphere of MgF2 mounted with its radius side facing downwards, and its flat surface placed horizontally. Light is incised in the hemisphere from the bottom. The flat surface of the hemisphere, the assembly for the hemisphere and the support for the assembly are all made up of a horizontal sampling surface in the same plane. The patient's arm is placed down on this surface so that the lower side of the forearm rests against the sampling surface of the hemisphere. The area of the forearm has previously been shaved and washed with soap and water, and then rubbed with isopropyl alcohol. The arm is then covered with a blood pressure cuff that is inflated to a pressure of 30 mmHg. The fist acts to hold the arm in place and to prevent movement of the arm in relation to the hemisphere. The sampling surface is maintained at a constant temperature of 28 ° C with resistance heating elements and a thermobar feedback device. After the arm has been placed on the device, it is allowed to equilibrate for 30 seconds before sampling. With reference to Figure 3, upper trace, with the number 50 mark, the result obtained is shown when the sampling is carried out in the manner previously described in the absence of index coupling means. In the lower trace, marked with the number 52, 100 microliters of chlorotrifluoroethene are applied to the surface of the hemisphere before the placement of the arm. There are several notable differences. The most evident is the dispersion of the data. Lines 50 and 52 each consist of multiple spectra. With FLUOROLUBE, the entire spectrum overlaps each other very closely. This indicates that the interface is very stable. Without FLUOROLUBE, the interface is extremely unstable. In addition, it is remarkable in the reading data near 5200 cm "1. This is the position for the strongest water band.Without FLUOROLUBE, this band appears weaker, since it is contaminated with specular light. Note that the dispersion of the data is larger under this band.In fact, the difference between the two traces can be attributed mainly to the spurious energy from the specular contamination.

The novel characteristics and advantages of the invention encompassed by this document have been established in the preceding description. However, it will be understood that this description is, in many aspects, only illustrative. Changes can be made in the details, particularly in terms of shape, size and placement of the parts, without exceeding the scope of the invention. Of course, the scope of the invention is defined by the language in which the appended claims are expressed.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, it is -1-3 claims as property what is contained in the following:

Claims (32)

1. A non-invasive method for measuring the concentration of a blood analyte in human tissue, characterized in that it comprises the steps of: (a) providing an apparatus for measuring infrared absorption, the apparatus includes a power source that emits infrared energy at wavelengths multiple placed operatively to an input element, the apparatus further includes an output element operatively connected to a spectrum analyzer; (b) providing an index coupling means and placing a quantity of medium between the human tissue and the entry element and the exit element for coupling the detector element with the tissue containing the analyte through the index coupling means; and (c) irradiating the tissue through the input element with multiple wavelengths of infrared energy so that there is differential absorption of at least part of the wavelengths; and (d) collecting at least a portion of the infrared energy not absorbed with the output element followed by measuring the wavelength intensities of the unabsorbed infrared energy with the subsequent calculation of the blood analyte concentration using an algorithm and a model.

2. The method according to claim 1, characterized in that the input element and the output element are incorporated into a single detector element.

3. The method according to claim 1, characterized in that the index coupling means has a refractive index that closely matches that of the tissue that is irradiated.

4. The method according to claim 3, characterized in that the index coupling means has a refractive index between 1.30 and 1.45.

5. A non-invasive method for measuring the concentration of blood analyte in human tissue, characterized in that it comprises the steps of: (a) providing an apparatus for measuring infrared absorption, the apparatus includes a power source that emits infrared energy at multiple wavelengths operatively connected to an input element of a detector element, the apparatus further includes an output element within the detector element operatively connected to a spectrum analyzer; (b) selecting a sample area on a skin surface of a tissue containing analyte; (c) providing an index coupling means and placing a quantity of medium between the detector element and the sample area; (d) placing the input element and the output element in contact with the amount of index coupling means for coupling the detector element with the tissue containing the analyte through the index coupling means; and (e) irradiating the tissue containing the analyte through the input element such that there is differential absorption of at least some of the wavelengths and measuring the differential absorption of the wavelengths through the connected output element. with the spectrum analyzer.

6. The method according to claim 5, characterized in that it additionally comprises the step of calculating a concentration of the blood analyte in the analyte-containing tissue with the spectrum analyzer by comparing the differential absorption with a model that includes differential absorption data in a plurality of known samples of tissue containing analyte.

7. The method according to claim 6, characterized in that a partial least squares analysis is used to compare the differential absorption of the analyte-containing tissue with the model.

8. The method according to claim 5, characterized in that the input element and the output element include optical lenses.

9. The method according to claim 5, characterized in that the sample area is a surface of the skin on the underside of a forearm of a patient.

10. The method according to claim 5, characterized in that the index coupling means comprises a mixture of perfluorocarbons and chlorofluorocarbons.

11. The method according to claim 10, characterized in that the index coupling means has a refractive index of about 1.30 to about 1.40.

12. A non-invasive method for measuring the concentration of blood analyte in a human tissue, characterized in that it comprises the steps of: (a) providing an apparatus for measuring infrared absorption, the apparatus includes a power source that emits infrared energy at wavelengths Multiple operatively connected to an input element of a detector element, the apparatus further includes an output element inside the detector element operatively connected to the spectrum analyzer; (b) selecting a sample area on a skin surface of a tissue containing analyte; 10 (c) providing an index coupling means and placing a first amount of the medium between the input element and the sample area, and a second amount of index coupling means between the element 15 exit and an opposite surface of the sample area; (d) placing the input element in contact with the first quantity of index coupling means and the element of Outlet in contact with the second quantity of the index coupling means for coupling the detector element with the analyte-containing tissue through the first and second quantity of coupling medium. 25 of index; and irradiating the analyte-containing tissue through the input element so that there is differential absorption of at least part of the wavelengths and measuring the differential absorption by transmittance of a portion of the wavelengths through the tissue that contains the analyte to the output element connected to the spectrum analyzer.

13. The method according to claim 12, characterized in that it further comprises the step of calculating a blood analyte concentration in the analyte-containing tissue with the spectrum analyzer by comparing the differential absorption with a model that includes differential absorption data in a plurality. of known tissue samples containing analyte.

14. The method according to claim 13, characterized in that the partial least square analysis is used to compare the differential absorption of the analyte-containing tissue with the model.

15. The method according to claim 12, characterized in that the input element and the output element include optical lenses.

16. The method according to claim 12, characterized in that the sample area is a surface of the skin on the underside of a forearm of a patient.

17. The method according to claim 12, characterized in that the index coupling means comprises a mixture of perfluorocarbons and chlorofluorocarbons.

18. The method according to claim 17, characterized in that the index coupling means has a refractive index of about 1.30 to about 1.40.

19. A fluid composition for providing an optical interface between the surface of the skin in a body and a spectrographic detector element when measuring the absorption of infrared energy by constituents under the surface of the skin within the body at multiple wavelengths, the composition of fluid is characterized in that it comprises: (a) about 80% to about 99% of a mixture of perfluorocarbons and chlorofluorocarbons; and (b) about 1% to about 20% of a hydrophilic additive.

20. The fluid composition according to claim 19, characterized in that the hydrophilic additive is isopropyl alcohol.

21. The fluid composition according to claim 19, characterized in that the mixture of perfluorocarbons and chlorofluorocarbons comprises approximately 90% chlorotrifluoroethene and approximately 10% other fluorocarbons.

22. The fluid composition according to claim 19, characterized in that it additionally comprises about 1% to about 10% cleaning agents, the cleaning agents include at least mineral oil.

23. The fluid composition according to claim 19, characterized in that it additionally comprises about 1% to about 5% of a surfactant, the surfactant includes at least sodium dodecylsulfate.

24. The fluid composition according to claim 19, characterized in that the refractive index of the fluid is from about 1.30 to about 1.40.

25. The fluid composition according to claim 19, characterized in that the refractive index of the fluid is about 1.38.

26. The fluid composition according to claim 15, characterized in that it also comprises an antiseptic additive.

27. A fluid for providing an optical interface between a surface of the skin and a detector element for the non-invasive measurement of analytes in blood, the fluid is characterized in that it has the characteristics of: (a) being non-toxic to the human body; (b) not damaging the detector element; and (c) being able to fill the regular surface of the fabric and at the same time maintain a constant refractive index through the fluid.

28. The fluid according to claim 27, characterized in that the fluid has a refractive index that matches that of the tissue.

29. The fluid according to claim 28, characterized in that the fluid has a refractive index between 1.30 and 1.45.

30. A quantitative analysis instrument for the non-invasive measurement of a blood analyte in human tissue, the instrument is characterized in that it comprises: (a) a source of at least three wavelengths of light, the wavelengths are in the range from 500 to 2500 nm; (b) an input detector element for directing the wavelength of light into the tissue, and an output detector element for collecting at least a portion of the light unabsorbed from the tissue; (c) the input and output detectors are adapted to allow the placement of an index coupling means across its surface and between them and the tissue containing the analyte; (d) at least one detector for measuring the intensities of at least a portion of the wavelengths collected by the output detector element; (e) electronic systems for processing the measured intensities to estimate the value of the analyte in blood; and (f) means for indicating the estimated value of the blood analyte.

31. The analysis instrument according to claim 30, characterized in that the detector elements are adapted for use with an index coupling means so that the thickness of the index coupling means remains constant during the measurement period.

32. The analysis instrument according to claim 30, characterized in that the detector elements are adapted for use with an index coupling means so that the thickness of the index coupling means is relatively constant from a tissue measurement to the next measurement of tissue.