WO2006112837A1

WO2006112837A1 - Thermal emission non-invasive analyte monitor

Info

Publication number: WO2006112837A1
Application number: PCT/US2005/013118
Authority: WO
Inventors: Janusz Michal Buchert
Original assignee: Janusz Michal Buchert
Priority date: 2005-04-17
Filing date: 2005-04-17
Publication date: 2006-10-26

Abstract

An improved method and an improved instrument for analyte determination that uses naturally emitted infrared radiation of the subject are disclosed. The method is based on Thermal Emission Spectroscopy (TSA) where a spectral signal is measured in reference to the body’s physiological and ambient parameters. An instrument, that utilizes this method, incorporates temperature and humidity sensors. Ambient environmental parameters and subject parameters as disclosed allow for the normalization of the spectrally specific analyte signal for greater precision and accuracy of analyte concentration determination. This improvement leads to universal calibration in, for example, non-invasive blood glucose measurements in human subjects.

Description

THERMAL EMISSION NON-INVASIVE ANALYTE MONITOR

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an infrared spectral measurement method and instrument that uses infrared radiation naturally emitted by a subject in mid and far infrared spectral regions and is based on the mid-infrared Thermal Emission Spectroscopy (TES) analytical method for non-invasive determination of the concentration of analytes. It relates more specifically to a method and instrument that incorporates ambient temperature and humidity sensors as well as physiological temperature sensors. The said method and the said instrument allow for better normalization of the spectrally specific analyte signal for greater precision and accuracy of the determination of the concentration of analytes. It leads to universal calibration in, for example, non-invasive blood glucose measurement in human subjects.

2. Related Art

At least 170 million people suffer from diabetes worldwide and two thirds of them live in developing countries according to the World Health Organization (WHO). The number of newly diagnosed people with diabetes is increasing at all ages, and notably in younger persons. In many developing countries, the prevalence of diabetes in adults is now greater than 10%. Most of the health impact of diabetes is the result of its long-term complications and eye problems - retinopathy and cataracts are among the most distressing and costly to society. Sixteen million people in the United States live with this chronic disease; approximately 5-10% are children. The seminal Diabetes Control & Complications Trial (The Diabetes Control and Complications Trial Research Group, New Engl. J. Med. 329:977-1036, 1993) concluded that frequent glucose monitoring is necessary to reduce the complications of diabetes. A lack of compliance occurs despite strong evidence that tight control dramatically reduces long-term diabetic complications. However, all glucose monitors now available require invasive techniques. The most widely used method of self-monitoring, obtaining blood from a finger prick, causes pain and discomfort which results in poor compliance. A novel, hand-held, non-invasive glucose monitor will provide diabetics with the means for testing their glucose level more frequently, improving their quality of life, and reducing the costs and complications of this chronic disease.

The present invention is an improvement of a method and an improvement of an instrument based on the prior art discovery (U.S. Patent 5,666,956 and U.S. Patent 5, 823,966 issued to J.M. Buchert.) The entire contents of these patents are incorporated herein by reference and made a part of this specification that natural infrared thermal emission obtained from tissue or organs of a subject, any mammal species, is modulated by the state of the emitting source. The thermal infrared radiation from any matter at a temperature above zero degrees Kelvin consists of spectral information defining the state of the emitting matter. Spectral information comprised in said emission consists of spectral information of the subject tissue. By measuring thermal emission spectral features of certain analytes, the concentrations of analytes can be established in a non-invasive manner.

Thermal emission was first applied medically in 1957 when Lawson (Lawson R: "Implication of Surface Temperatures in the Diagnosis of Breast Cancer," Can. Med. Assoc. J.: 75:309-310, 1956) discovered that skin temperature over a cancer in the breast was higher than that of normal tissue. Thermal imaging is a noninvasive diagnostic technique that allows the examiner to visualize and quantify changes in skin surface temperature. Thermography's major clinical value is in its high sensitivity to pathology in the vascular, muscular, neural and skeletal systems and as such can contribute to the pathogenesis and diagnosis made by the clinician. It has been used extensively in human medicine in the U.S.A., Europe and Asia for the past 20 years.

In 1987 Jacob Fraden patented (U.S. Patent No. 4,797,840) an instant ear thermometer that measured the intensity of infrared radiation emitted from the tympanic membrane (eardrum). Tympanic membrane thermometers are currently widely used at home and in the hospital environment. They determine temperature by utilizing total energy from a wide spectral range of human body heat infrared emission, which is usually contained between 8 and 14 micrometers.

Prior art (U.S. Patent 5,666,956 and U.S. Patent 5, 823,966) and the present invention further improve technology based on Thermal Emission Spectroscopy (TES), using a spectral analysis of the infrared thermal emission to measure a tissue's analyte concentration. This new cost-effective, painless blood glucose monitor will improve patient compliance and should thereby reduce diabetic complications as well as their high cost.

This technology can also be adapted for use as a continuous monitor (U.S. Patent 5, 823,966) and, with various control algorithms, could provide a closed-loop feedback system with insulin delivery devices.

Blood glucose concentrations may be measured by invasive or minimally invasive techniques. Some of these methods measure blood glucose directly and some measure interstitial fluid glucose. For example, Cygnus, Inc.'s GlucoWatch ("GlucoWatch Automatic Glucose Biographer and Autosensor": available from http://www.glucowatch.com/us/prescribing info/prescribing info.pdf) is the only minimally invasive instrument approved by the FDA as an adjunctive device to supplement blood glucose testing. This device transdermally extracts interstitial fluid from the skin using iontophoresis. A very weak electric current pulls interstitial fluid glucose through the skin. However, the GlucoWatch still requires daily calibration of the instrument using the invasive finger-stick method. MiniMed Inc.'s product ("Medtronic/MiniMed CGMS specifications", available from http://www.minimed.com/doctors/md products cgms specs.shtml ) is a subcutaneous, continuous blood glucose monitoring system that directly records and stores concentration values in memory. This invasive device does not provide measurements directly to the patient and is available for professional use only.

There are a number of reviews (Klonoff DC, "Non-invasive Blood Glucose Monitoring," Diabetes Care 20:433-437, 1997; Koshinsky T, Heinemann L, "Sensors for Glucose Monitoring: Technical and Clinical Aspects," Diabetes Metab. Res. Rev. 17: 113-123, 2001) on approaches for non-invasive BG measurements. In recent years, infrared (IR) spectroscopy has emerged as the analytical method of choice founded on the spectrum of IR frequencies characteristic of the analyte itself instead of relying on reagents and color reactions. Kaiser (U.S. Patent No. 4,169,676) showed the possibility of a non-invasive method of glucose measurement by analyzing the infrared absorption spectrum through an attenuated total reflection (ATR) prism. Others (Kajiwara et al. "Spectroscopic Quantitative Analysis of Blood Glucose by Fourier Transform Infrared Spectroscopy with an Attenuated Total Reflection Prism", Med. Prog. Technol. 18: 181-189, 1992) reported using Fourier transformed infrared spectroscopy (FT-IR) methods for quantitative measurements of glucose concentration in blood and serum samples at characteristic absorbance peaks. Varous approaches in infrared absorption are described in the following references: Bauer et al., "Monitoring of Glucose in Biological Fluids by Fourier-Transform Infrared Spectrometry with a Cylindrical Internal Reflectance Cell," Analytica Chimica Acta 197: 295-301, 1987; Bhandare et al, "Glucose Determination in Simulated Plasma Blood Serum Solutions by FTIR Spectroscopy: Investigation of Spectral Interferences," Vibrational Spectroscopy 6: 363-378, 1994; Heise et al., "Multicomponent Assay for Blood Substrates in Human Plasma by Mid-Infrared Spectroscopy and its Evaluation for Clinical Analysis," Applied Spectroscopy, 48: 85- 95, 1994; Cadet F, "Method for the Classification of Biological FT-IR Spectra Prior to Quantitative Analysis," Applied Spectroscopy 50: 1590-1596, 1996; Budinova et al., "Application of Molecular Spectroscopy in the Mid-Infrared Region to the Determination of Glucose and Cholesterol in Whole Blood and in Blood Serum," Applied Spectroscopy 51 :631-635, 1997; Vonach et al., "Application of Mid-Infrared Transmission Spectrometry to the Direct Determination of Glucose in Whole Blood," Applied Spectroscopy 52: 820-822, 1998. None of these devices are commercially available. They utilize absorption, transmission, and reflection methods for spectroscopically analyzing BG concentration. Near-infrared spectroscopy techniques, developed by companies such as Instrumentation Metrics (Sensys), and LifeTrac, are fundamentally different from Infratec's methodology. These methods require an outside near-infrared (NIR) excitation source to measure the resulting radiation after interaction with the tissue. The near-infrared spectrum is not very selective for blood glucose determination because it relies on overtone and combinational absorption and not on the fundamental spectral fingerprint of glucose in the mid-infrared region.

Argose Inc. is trying to develop another optical technology based on UV- induced fluorescence where the target is not glucose itself, but a molecular component of skin (e.g. tryptophan or collagen cross-links) that fluoresces in relation to its glucose concentration. This indirect spectral method is poorly correlated with blood glucose and the chronic use of UV light could be harmful to human tissue.

Knudson, in U.S Patents 5,115,133; 5,146,091 and 5,179,951, discloses a method for measuring blood sugar that involves testing body fluid constituents by measuring light reflected from the tympanic membrane. The testing light and a reference light at a glucose sensitive wavelength at about 500 to about 4000 wave numbers (cm^'1) are directed toward the tympanic membrane which contains fluid having an unknown concentration of a constituent. A light detector is provided for measuring the intensity of the testing light and the intensity of the reference light, both of which are reflected and spectrally modified by the fluid. A light path distance measurer is provided for measuring the distance of a light path traveled by the testing light and a reference light. A circuit is provided for calculating the level of the constituent in the fluid in response to a reduction in intensity in both the testing light and the reference light and in response to the measured distance. Knudson teaches that measurements on a body fluid constituent can be performed by measurements across the tympanic membrane using the absorption method characterized by light generating means for generating a testing light of known intensity with said testing light including at least one wavelength absorbable by said constituents and further determining the amount of said testing light absorbed by said constituent.

Optiscan's Biomedical Corporation (U.S. Patents No. 5,515,847 and 5,615,672) technology relies on monitoring the infrared absorption signal through the wrist. Measurements are made by monitoring infrared absorption of the desired blood constituent in the long infrared wavelength range. It uses human body heat radiation as a source radiation for measurements of resulting transmission through arterial blood in the wrist. It consists of an infrared detector, which detects light at infrared wavelengths and has passed through the arterial blood vessel of the patient and been selectively absorbed by at least one predetermined constituent at characteristic infrared absorption wavelengths for these constituents. Unfortunately, the thick skin of the wrist is not penetrable to infrared radiation, so the skin must be cooled down and then warmed up (Optiscan issued U.S. Patents: 55,900,632; 6,025,597; 6,049,081; 6,072,180; 6,161,028; 6,198,949; 6,556,850; 6,577,885; 6,580,934) to obtain glucose spectral information from the dermis's vasculature. Optiscan's device captures thermal gradient spectra from living tissue by periodic temperature modulation and phase detection. The instrument is the size of a desktop computer and consists of mechanical parts and a complicated design, limiting its portability. Its portability would be also limited by the size of the energy source (battery) required for frequent warming up and cooling down of the tissue.

U.S. Patent No. 6,002,953 issued to Block, discloses a non-invasive infrared transmission measurement of analytes in the tympanic membrane. The invention cools a segment of the subject's tympanic membrane and employs thermal radiation emitted by the subject's inner ear which is transmitted through this cold segment to directly obtain absorption information related to the concentration of various constituents of blood flowing through the membrane. In particular, the invention uses optical devices inserted into the external ear cavity to direct a portion of the transmitted radiation onto an infrared detection and analysis device. The signal from the detection device is analyzed to obtain the concentration of the constituent of interest. The invention is similar in approach to Optiscan's method of cooling the measured tissue to obtain analyte concentration information using absorption spectrum analysis. It is impractical; it will require substantial cooling (as one can note from Optiscan's patent' information) of the ear canal that could be uncomfortable to a user. The dynamics of physical phenomena during the process of tissue cooling additionally complicate the analysis and contribute to the uncertainty of the results.

The invented technology relates to a unique analytical method based on Thermal Emission Spectroscopy (TES reference: Willis HA, "Laboratory Methods in Vibrational Spectroscopy," New York, J. Wiley & Sons, 1987; Chase DB, "The Sensitivity and Limitation of Condensed Phase Infrared Emission Spectroscopy," Applied Spectroscopy, 35:77-81, 1981; DeBlase et al., FJ, "Infrared Emission Spectroscopy: a Theoretical and Experimental Review," Applied Spectroscopy, 45: 611-618, 1991; Sullivan et al., "Surface Analysis with FT-IR Emission Spectroscopy," Applied Spectroscopy 46: 811-818, 1992; Keresztury et al., "Quantitative Aspects of FT-IR Emission Spectroscopy and Simulation of Emission- Absorption Spectra," Analytical Chemistry 67: 3782-3787, 1995; Friedrich et al., "Emission Spectroscopy: An Excellent Tool for the Infrared Characterization of Textile Fibers," Applied Spectroscopy 52:1530-1535, 1998), which was used, for example, during the Mars expedition (by NASA) to analyze the chemistry of Martian rocks and is used in astronomy to analyze the chemical components of stars.

Various spectroscopic methods and instruments that aim to monitor sample temperature for spectral non-invasive blood glucose monitoring are described in the prior art.

For example, Braig et al., in U.S Patent 5,615,672, describe a glucose monitor that non-invasively measures glucose concentration by performing absorption analysis based on body heat infrared radiation and its transmission through arterial blood in the wrist. The described device includes a temperature-sensing device for measuring a person's internal temperature, in the arm, to adjust the constituent concentration measurement for temperature dependent effects. However, the sensor measures temperature at the skin surface. Therefore, the calculated compensation for internal body temperature to be applied to the measured spectral signal introduces a significant source of error in the analyte concentration estimate.

In another U.S Patent Application Publication, U.S. 2002/0038080 Al by Makarewicz et al., a method and apparatus for minimizing effects in a noninvasive in- vivo near-infrared spectral measurement caused by fluctuation in a tissue's state are described. Selected tissue state parameters are monitored spectroscopically, which allows one to maintain these parameters within a target range. The invention provides a method and apparatus for minimizing the effects in near infrared (NIR) spectral measurements variation due to skin temperature changes at a tissue measurement site. This is an especially dominant problem in the near infrared spectral region as shown by Jensen et al. in their paper, "Influence of Temperature on Water and Aqueous Glucose Absorption Spectra in the Near- and Mid-Infrared Regions at Physiologically Relevant Temperatures," Applied Spectroscopy: 57(1) 28- 36, 2003. The ear non-invasive blood glucose monitor (prior art method and instrument described in U.S. Patent No. 5,666,956 and U.S. Patent 5,823,966) is an infrared spectral monitor, which measures infrared radiation from a subject's tympanic membrane naturally emitted as heat in a manner similar to a non-contact ear tympanic thermometer. While an infrared thermometer measures the total infrared spectrum over a wide range of wavelengths emitted by the tympanic membrane, the infrared glucose monitor distinguishes between different spectral lines to correlate their properties with glucose concentration. In the case of the invented instrument, the spectral signatures (e.g. of glucose) contained in such broadband infrared energy emission from human tissue are used to perform constituent composition and concentration analysis. The device is a very sensitive, portable, hand held filtometer. The device is passive and does not damage human tissue by chronic external radiation.

The use of an invented improved method and an invented improved instrument will prevent the instability and uncertainty of proper universal calibration of the non-invasive analyte (e.g. blood glucose) monitor and will allow for reducing the influence of environmental conditions such as ambient temperature and humidity as well as physiological subject parameters.

SUMMARY OF THE INVENTION

In the infrared spectral monitor an appropriate infrared sensor detects the emission spectral line's features, which is an integral part of the measurement and/or acquisition system. A signal from the system is usually converted into useful information about analyte concentration in tissues after the calibration process is performed on real subjects. The calibration process involves the monitoring of environmental and physiological subject parameters such as temperature and ambient humidity. It has the purpose of providing spectrally specific analyte signal normalization for different subjects allowing for universal calibration. All the above parameters must be included in non-invasive blood glucose measurements calibration calculation and further for predictive blood glucose measurements. The body temperature of the subjects as a calibration parameter will compensate, for example, for changes of the body thermal emission intensity changes that are independent of glucose emission intensity changes due to concentration changes. Measurements of these environmental and subjects' parameters and incorporation of them into the calibration and prediction algorithm will allow us to compensate for their influence, on the thermal emission signal, spectrally specific to glucose, in various subjects and also will allow for universal calibration.

If spectral measurements are performed in well controlled ambient conditions as described in an in vitro experiment in Diabetes Care: 25(12) 2268-2275, 2002, it is not necessary to include additional parameters in the calculation of glucose concentration from the intensity of glucose thermal emission spectral lines. The above is also true for any other laboratory experiment that uses absorption, fluorescence, or Raman lines, etc. for the purpose of quantitative substance concentration measurements in vitro. For measurements in real life conditions, especially for in vivo and non-invasive conditions, one must incorporate the necessary environmental and physiological parameters of the subjects to compensate for their influence on spectral measurements.

Thus, a primary purpose of the present invention is to provide an infrared spectral monitor integrated with temperature and humidity sensors. A further objective is to provide an infrared spectral monitor integrated with an ambient temperature sensor. A further objective is to provide a body temperature sensor for a subject. There is yet a further objective, that is to provide a tympanic membrane temperature sensor for a subject. Another objective is to provide an ambient humidity sensor. Still another objective of the invention is to provide an infrared spectral monitor, which is not influenced by environmental conditions such as ambient temperature and humidity. A further objective of this invention is to provide an infrared spectral monitor not influenced by a subject's physiological condition such as body temperature or the size and physiological state of the ear canal. Yet another and further objective of this invention is to provide spectral analyte specific infrared measurements from this same spot of tissue as temperature measurements by infrared radiation sensor. Another objective of this invention is to provide spectral analyte specific infrared measurements in a continuous manner. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. Ia is the infrared absorption spectrum of D-glucose.

FIG. Ib is the infrared absorption spectra of: blood (59 mg/dL), blood added with glucose (371 mg/dL), and a glucose standard solution (1000 mg/dL) in the spectral range of glucose absorption.

FIG. 2a is one of the first emission spectra of chemical interest, that of aniline at

30 deg C; the upper spectrum shows the transmittance spectrum of aniline for a comparison with a lower trace that shows the thermal emission spectrum.

FIG. 2b is:

A) the absorption and thermal emission spectra of 220 mg/dL glucose in a KBr sample at 41 deg C;

B) the thermal emission spectra from human plasma at 37 deg C with a different glucose concentration. Peak intensities of deconvoluted spectral bands are shown in the insert.

FIG. 3 is a diagram of vibronic and radiative transitions in absorption (a) and in emission (b) of photons.

FIG. 4 is a simplified diagram of an embodiment of an instrument of the invention.

FIG. 5 is a simplified diagram of an other embodiment of an instrument of the invention; a) a remote sensor assembly inserted in the ear canal b) analyzing an electronics microcomputer system and display

DESCRIPTION OF THE PREFERED EMBODIMENT

The present invention is directed at an instrument and method for the noninvasive detection of the concentration of analytes in human body tissues, for example, glucose in blood, using naturally occurring infrared radiation in the micrometer spectral region of the human body's heat emission. It relates more specifically to a method and instrument that incorporates additional temperature and humidity sensors and allows for a better normalization of spectrally specific analyte signals for greater precision and accuracy of an analyte's concentration determination and universal calibration in, for example, non-invasive blood glucose measurement in human subjects.

Scientific understanding that the glucose molecular signature frequency is focused in the mid-infrared region, as shown in FIG. 1 , and correspondence between the emission and absorption spectra, as shown in FIG. 2, lead to the invention.

Absorption of radiation is characterized by the selective removal or absorption of certain frequencies as radiation (incident radiation Φo) passes through a substance (sample: solid, liquid, or gas) as shown in the upper part of FIG 3ai A molecule transition from one energy level (lower E₀) to another (higher E₁) occurs as shown in the lower part of FIG. 3 a. At room temperature most substances (molecules) are in the ground electronic state but can be thermally excited (radiation less) into higher vibrational energy levels, and the process of thermal emission (radiation) characterized by radiant flux Φ_E will occur as shown in FIG. 3b. The emission of radiation is an inverse process of absorption. The relaxation of a molecule to a lower Eo (and more stable) energy state is accompanied by the release of a radiant photon of appropriate energy E₁ (frequency λi) as shown in the lower part of FIG. 3b. For a thermally excited molecule, at room or body temperature range, thermal emission occurs in the mid-infrared wavelength range.

Vibrational Spectroscopy could characterize molecules, which are composed of positive and negative ions that vibrate at quantized frequencies. When positive and negative ions move out of phase with each other, absorption or emission of radiant energy becomes possible at the wavelength corresponding to the vibrational frequency of the motions, as long as there is a net dipole moment. For example, in glucose molecule the primary spectral absorptions are due to the stretching motion modes of C-O and C-C and the bending modes of O-C-H, C-C-H and C-O-H. The exact frequencies, shapes, intensities, and number of features in a spectrum are dependent on the relative masses, radii, distances, and angles between atoms and their bond strengths. These parameters are determined by the structural arrangement of the anions (i.e., their polymerization), and the location and composition of the cations associated with them. Because all molecules consist of unique structures and/or compositions, virtually every molecule has a different suite of vibrational absorption/emission characteristics and thus a unique spectrum in the thermal infrared radiation.

Glucose has a very well defined vibrational spectral feature in the fingerprint infrared region as shown, for example in FIG. Ia for the infrared absorption spectrum of D-glucose and in FIG Ib for the infrared absorption spectra of blood with added glucose in the spectral range of glucose absorption as well as in the thermal emission spectra plots in FIG 2b. The correspondence between the emission and absorption spectra was theoretically predicted by Planck (Planck Max, "The Theory of Heat Radiation," New York, Dover Publications, 1991). Kirchhoffs law confirms that, for the entire body in the same temperature and for the same wavelength, absorptivity is equal to monochromatic emissivity. Thus one can conclude that tissue (e.g. blood) spectral characteristics with different contents of analytes (e.g. glucose) will change the emissivity of the tissue (e.g. the tympanic membrane) and make it possible to measure the concentration of an analyte (e.g. glucose) in the tissue (e.g. blood). Planck describes the difference between absorption spectroscopy and thermal emission phenomena where the entire volume of the emitting body is a source of radiation, which can be measured. One can observe the surface of a body as radiating heat to the surroundings but this does not imply that the surface actually emits heat radiation. The surface of a body never emits radiation but allows part of it coming from the interior to pass through. The other part is reflected inward. As the fraction transmitted is larger or smaller, the surface seems to emit more or less intense radiation. If one considers absorption, external radiation cannot be measured if the optical density of the sample is large (a combination of the thickness and absorption coefficient). In emission each and every infinitesimal internal part of a sample is a source of heat radiation. The surface allows the radiation to pass through from the interior and to be analyzed in the mid infrared region.

One of the first thermal emission spectra (shown in FIG 2a) of chemical interest, that of aniline at 30 deg C, was shown experimentally in 1965 (from Griffiths PR, "Chemical IR Fourier Transform Spectroscopy," New York, J. Wiley & Sons, 1975, Fig 12.1, pp. 312) with its transmittance spectrum for comparison. Infrared emission spectroscopy, while not commonly used, shows the promise of application in several areas of chemical analysis. It was used, for example, during the Mars expedition (by NASA) to analyze the chemistry of Martian rocks and is used in astronomy to analyze the chemical components of stars. For most of the samples measured there is excellent correspondence between band frequencies observed in the infrared emission spectrum and the absorption spectrum of the same material. For example, FIG. 2b shows the absorption and thermal emission spectra of 220 mg/dL glucose in KBr pellet at 41 deg C, and the thermal emission spectra from human plasma at 37 deg C with different glucose concentrations. This figure emphasizes two important features: the first is to show the spectral region of interest and the second is to present experimental proof of the thermal emission detection ability of current room temperature infrared detectors. Deconvolution shows bands sensitive and non- sensitive to glucose concentration changes in human plasma. For viewing clarity, the spectra are up-shifted along the vertical axis. Results from deconvolution in the inserted table show peak intensity changes versus glucose concentration. In the emission one can observe the corresponding bands of glucose absorption, e.g. the main band at 9.8 micrometers, a band at 10.9 micrometers (corresponding to 914 cm- 1 vibrational state of glucose) and a weaker band at around 11.9 micrometers. Peak intensities of deconvoluted spectral bands shown in the figure insert, part B of FIG. 2b, follow the glucose concentration changes.

The invented method and instrument is an improvement of a prior art analytical means of Thermal Emission Spectroscopy (TES) to measure infrared radiation emitted naturally by the human body. This infrared radiation contains spectral information of the emitting body tissue. The radiation thermometer measures the integral energy of infrared radiation from the body through the entire infrared wavelengths without spectral discrimination. In the case of the prior art instrument the signal from the detector is proportional to the difference between the intensity of the spectrum emitted from the body passing through the filter with the spectral characteristic of the measured analyte, for example, glucose in blood, and the intensity of the infrared spectrum emitted from the body passing through the filter with spectral characteristics which do not include spectral bands of the analyte. If a signal passing through both filters is well balanced than the measured signal should be independent from the overall temperature of the emitting body because this information is canceled out by subtraction. This same applies to other spectral intensity changes independent of analyte concentration changes.

It was discovered that the above assumptions are valid only for well-balanced intensities passing through both filters of the infrared detector. Additionally, infrared detector signal dependence on ambient and on detector base temperature has influenced the resulting differential signal. Other parameters that have an influence on the detector glucose spectral signal are the size and shape of the ear canal (e.g. the detector distance from the tympanic membrane) and ambient humidity. The invented improved method and improved instrument is aimed at minimizing the effects of these parameters on the spectral analyte signal of thermal emission from the tissue.

The prior art method and instrument follow up independent clinical studies are described in the publication "A NOVEL NONINVASIVE BLOOD GLUCOSE MONITOR" by Malchoff et al., Diabetes Care, 25(12) 2268-2275, 2002, which are also hereby incorporated herein as a reference. In this study two-widow infrared non-invasive blood glucose ear monitors were used, according to U.S. Patent No. 5,666,956. The subject's oral and ear temperature, room temperature, and room humidity were recorded during the study. Measurements of infrared ear temperature were made after each spectral thermal infrared emission glucose measurement. Environmental parameters as well as physiological parameters were measured using outside instruments. Ambient temperature and humidity were measured using the Radio Shack Digital Thermo-Hygro (Cat. No. 63-1013) thermometer and humidity gauge. The subjects' oral temperature was measured using a mercury thermometer and their ear tympanic temperature was measured using an OMRON MC-505 infrared thermometer.

Ear temperature, as well as body temperature measured by conduction, has an important role in the ability to achieve universal calibration. For different lengths of the ear canal, e.g. a different distance between the detector and the tympanic membrane, these measurements normalize the variability of such differences in the use of the device. The intensity of infrared heat radiation measured by the detector is defined by the temperature of the radiating body according to Planck's/Kirchoff s laws, its emissivity and the distance between a detector and the emitting tissue, e.g. the tympanic membrane. Due to various shapes and sizes of the ear canal in different subjects, the distance between the detector and the tympanic membrane vary. By introducing the ear temperature of the subject and his body temperature as normalization factors, the normalized signal becomes independent of these physiological differences. Previously both measurements were made using two separate instruments, an electronic ear thermometer and an oral mercury thermometer. Errors in these measurements that were not performed at the same time and were not performed in the same place on the tissue contributed to the increased error in resulting concentration values. Both of these temperature measurements are integrated into the novel and improved invented instrument. The replacement of the independent electronic ear thermometer will be accomplished in a two-window design by using a differential amplifier connected to two (reversibly polarized), for example thermopile, detector sensors designed to generate two output signals. One will be a differential signal of glucose signature; the other signal will be the background, the so called quasi-isosbestic point of the spectrum, whose intensity is not changing with analyte concentration changes and is proportional to ear temperature. In a four- window detector design, ear temperature measurements will be accomplished by measuring the infrared radiation over a wide range of energy from 8 to 14 microns in one of the four windows. The remaining windows will incorporate infrared filters for the glucose signature and quasi-isosbestic point of the spectrum.

The quasi-isosbestic point (indicated approximately in FIG. Ib) in the emission/absorption mid infrared spectrum of glucose solution was derived from well- controlled spectral studies of various glucose concentrations in water (ATR) solution and in blood plasma (absorption). The intensity (of mid infrared absorption or by correspondence thermal emission) at this isosbestic point of the spectrum is not changing with changes of glucose concentration. In the real world, the intensity of the measured spectrum is influenced by many factors such as: the sample (tissue, blood, or body) temperature, water contents of the sample (the glucose spectral signature is on top of every broad water spectrum), a sample from other constituencies (other chemicals, or interfering substances), and also by the device detection system's emissivity, efficiency and throughput. It is why one needs some normalization point to compare different spectra if the needed information relates to spectral line intensities. In the invented novel device, the spectrum isosbestic point is used as a reference in the differential detection system (double windows filtometer) to normalize and reduce the influence of the above described factors. The difference between the laboratory situation for spectrum normalization and real world conditions depends on many additional factors. If, for example, the distance between the device detector and the tympanic membrane is constant in every measurement case, if the relationship between thermal emission intensity at an isosbestic point and intensity at a glucose signature wavelength with target (tissue) temperature is known, and well defined, if the relationship between the_emissivity of the optical system including the thermopile detector_is known and well defined, etc., it will not be necessary to measure all outside parameters to achieve universal calibration. The isosbestic point compensates only for a portion of factors that are responsible for the difference between well-controlled laboratory conditions (laboratory measured thermal emission spectra in FIG. 2b) and the real world situation (different subjects with wide ranges of subject conditions, e.g. the shape of the ear canal in a wide range of ambient conditions).

FIG. 4 shows a simplified diagram of an embodiment of the invented instrument. Infrared radiation from the object target 1, such as a human body, or for example its tympanic membrane, is optically received by the invented instrument. The instrument consists of: speculum 3 (for example, for insertion into an ear canal) with an optional plastic cover 2 (for hygienic reasons, fabricated of a thin polymer material that is transparent to radiation in the far infrared spectral region); the infrared optical system which can include: infrared wave guide 4 such as a hollow tube polished and/or gold plated inside, or in another form selected from the group consisting of a mirror, reflector, lens, and a fiber optic transmitting infrared radiation made, for example, from ATRIR special glass produced by Amorphous Materials, Inc.; optional optical valve 5; and a detecting system with electronics 8, microcomputer 9, a display system 10, a body temperature sensor 11 and sensors for ambient temperature 12 and humidity 13. The said infrared wave guide 4 can be in the form of any directing device such as a mirror, reflector, lens, etc. At the end of the receiving wave guide 4 an optional optical valve 5 could be positioned in the form of a shutter or chopper that optionally activates measurement of infrared radiation by a detecting system. The detecting system consists of an optical infrared filter set 6 and a detector 7 sensitive in the infrared region of human body radiation. This infrared sensor (detector 7) can be of any type known to the art. This sensor generates an electrical signal, which is representative of the received radiation. It includes a signal of infrared specific analyte emission and a signal related to the body's infrared temperature. Another detector 7 signal received by conditioner electronics 8 is a signal from the detector base thermistor (not shown) required for normalization of detector 7, and other infrared radiation signals. The electronics 8, microprocessor 9 and display system 10 must stabilize the temperature dependent parts of the instrument, compensate for ambient and body temperature changes, compensate for ambient humidity changes, and then correlate, calculate and further display the concentration of the analyte from the spectral intensity measurements of infrared radiation emitted by the body.

The detection system comprises an infrared energy sensor 7 for infrared energy measurements and could consist, for example, of the dual element pyroelectric or thermopile detector or any other infrared energy detector known to the art. The infrared energy sensor could be comprised of two sensing areas covered by a silicon window (optical infrared filter set 6) with a long pass filter to pass only infrared radiation, which corresponds to emission in the range of the internal temperature of a human body. The said infrared sensor could comprise more sensing areas such as three, four, etc. Any combination of infrared filters 6 could cover the sensing elements. In the case of an infrared sensor with two sensing areas, the spectrally modified infrared radiation from, for example, the tympanic membrane illuminates both windows (sensing areas), one with a negative correlating filter which blocks radiation in the absorption bands for the analyte to be measured and the other which passes through a neutral density filter capable of blocking radiation equally at all wavelengths in the range of interest. This is to compensate for the overall attenuation by the negative correlating filter in the first sensing area. The two sensing areas are connected so that their outputs are subtracted. The difference in the radiation intensity between the two radiation paths provides a measure proportional to the analyte concentration. The electrical signal from the infrared detector, also including the body infrared temperature, is then sent to the forming electronics 8 system. The signal from body temperature sensor 11, ambient temperature sensor 12 and ambient humidity sensor 13 is also input into the forming electronics. Then all signals are further sent to microcomputer 9 and to the display 10 system as shown in FIG. 4. Any combination of interconnections of sensors with forming electronics and a microcomputer can be used. Microcomputer 9 has the role of correlating , calculating and further displaying the concentration of the analyte from the spectral intensity measurements of infrared radiation emitted by the body.

One can also use a narrow band filter with a spectral characteristic specific to analyte infrared signature in front of one of the windows (sensing elements) and cover the other by an appropriate attenuation filter or other narrow band filter with a spectral characteristic at a wavelength not sensitive for analyte concentration (for example at the isosbestic point). Careful adjustment of the peak wavelength and transmission of both narrow band filters can compensate for changes in body temperature but is not necessary if other compensation means for normalization are used. In a multiwindow system, one can use, for example, one of the sensing elements for body infrared temperature measurements in, for example, the 8 to 14 micrometer spectral range of the infrared spectrum.

An infrared wave-guide 4, as a part of the optical detection system, must scramble and direct infrared radiation from the tympanic membrane to detector windows. One possible design could be a wave-guide made of an inner diameter that is a gold plated, polished tube attached mechanically to the detector housing. The diameter of the tube must be sufficiently wide to equally illuminate all detector windows. Additionally, it must be sufficiently small to be accommodated into the speculum designed for insertion into the ear canal (a diameter of 5-6 mm). Scrambling of the radiation to discard its directional properties is achieved by choosing the optimized length to diameter ratio of the infrared tube. The design of the assembly of detector and infrared wave-guide must fit different diameters of the speculum required for both adult and younger pediatric use. Separate modules could to be used to accommodate different size ranges of ear canals. The said infrared wave-guide could also be selected from other optical elements such as a mirror, reflector, lens, or a fiber optic The directional properties of the infrared wave-guide and the incorporation of the infrared temperature sensor into the infrared emission analyte detector system will assure that both spectral analyte specific emission intensities and ear temperature is measured from the same spot of the emitting tissue, e.g. the tympanic membrane. In prior art measurements performed by two instruments, the non-invasive glucose monitor and the ear thermometer, both contributed to the increased uncertainty of the resulting analyte concentration.

To stabilize and normalize for environmental and subject variability, the invented instrument will include sensors for ambient temperature 12, humidity 13 and for measurement of a subject's body temperature 11 by conduction. In the prior art instrument, there were no "built in" sensors for ambient temperature, humidity and body temperature. Temperature measurements are important to compensate for changes in the thermal emission spectra that are not related to analyte concentration changes. Humidity measurements are important to compensate for the possible interference of water vapor in the measured infrared spectral radiation range. Water vapor could influence, in the same manner as a neutral density filter, the overall spectral infrared signal intensity in the region of the glucose spectral signature. The water spectrum in the glucose infrared signature region is not specific but changes due to its concentration variation could influence the glucose signature baseline. For a higher humidity, the detected infrared spectral signal is weaker. A wide selection of commercially available sensors can be used. A mechanical design incorporates the sensors into the monitor housing and into speculum 3 or the optional speculum plastic cover 2. Electronics 8 and signal conditioners will support the sensors' requirements.

Temperature sensing chips such as the AD592 by Analog Devices as well as standard thermistors for ambient temperature measurements can be used. Humidity sensors such as the HIH-3602 Monolithic Integrated Circuits can be used. Body temperature measured by conduction can be made using a temperature sensor known in the art. This can be achieved, for example, by thermistor(s) incorporated into the speculum 3 or into the optional speculum plastic cover 2, the resistant (e.g. platinum) wire placed around the distal part of the speculum 3 or the optional speculum plastic cover 2 or using appropriate heat flux sensors placed on speculum 3 or on its plastic cover 2. The thermal mass of the temperature sensor, for example, the thermistor, resistant wire, heat flux sensors and appropriate construction materials of speculum 3 and optional speculum plastic cover 2 must satisfy the requirements for rapid thermal conduction. It is preferable for reproducible temperature measurement to be completed within a short time period (e.g. 6 to 10 seconds) after the speculum 3 insertion into the ear canal.

The molded speculum 3 of the invented instrument with an imbedded temperature sensor 11, covered by an optional plastic cover made of material transparent to radiation in the infrared spectral region, with an optional imbedded temperature sensor 11, is inserted into the ear canal. The output signals of the sensors such as the infrared emission differential signals of analyte signature, the body internal temperature, the ear temperature and humidity sensor output signals stand for the completed necessary information to achieve universal calibration. All the signals in the form of an electrical signal are than inputted into conditioning electronics 8, and finally into the microcomputer 9 for signal evaluation. Results of the signal evaluation are then displayed on the instrument display 10 as a concentration of the measured analyte.

The present invention is directed at an improved instrument and an improved method for the continuous non-invasive detection of the concentration of analytes in human body tissues, for example, glucose in blood, using naturally occurring infrared radiation in the micrometer spectral region of the human body. The invented instrument will continuously measure infrared radiation naturally emitted by the human body and normalize the measured signal using signals from a variety of temperature and optional humidity sensors for analyte concentration determination in a continuous manner.

In FIG. 5a and Fig. 5b a simplified diagram of the further embodiment of the invented instrument is shown. A remote sensor assembly inserted in a subject's ear canal optically receives infrared radiation from the object target 14 such as a human body tympanic membrane. The infrared radiation sensor is contained within an earplug remote assembly 15, that is connected with an electronic analyzing unit 16 by cable or by a telemetric transmitting and/or receiving system. The instrument consists of the ear plug 15 for insertion into an ear canal with the infrared radiation sensor detecting system, and the electronic analyzing unit 16 consisting of: electronics with a microcomputer 17 and a display system 18. The earplug assembly 15 would consist of optional telemetric transmitting electronics while the electronic analyzing unit 16 would consist of optional telemetric receiving electronics. The infrared radiation sensor detecting system consists of an optional infrared wave-guide 23, of an optical infrared filter set 19 and an infrared detector 20 sensitive in the infrared region of human body radiation. This infrared radiation sensor (detector 20) can be of any type known to the art that allows for continuous measurement of infrared energy including the thermopile sensor. This sensor generates an electrical output signal that is representative of the received infrared radiation. It includes a signal of infrared specific analyte emission and a signal related to infrared body temperature. Still another detector 20 signal received by forming electronics and microcomputer 17 is a signal from the detector base thermistor (not shown) required for normalization of detector 20's various infrared radiation signals. Earplug 15 consists of an ambient temperature sensor 21 and an optionally ambient humidity sensor 22. The electronics with microprocessor 17 and the display system 18 must stabilize the temperature dependent parts of the instrument, compensate for the ambient temperature changes detected by the ambient temperature sensor 21, optionally compensate for ambient humidity changes detected by ambient humidity sensor 22, and then correlate, calculate and further display the concentration of the analyte from the spectral intensity measurements of infrared radiation emitted by the body. The electronics with microprocessor 17 can optionally be directly connected to a regulated insulin reservoir, such as an insulin pump, or an artificial pancreas for an automatic insulin control system.

The present invention reduces variability to the spectral signal of the analyte of interest due to environmental conditions such as ambient temperature and humidity, physiological body conditions, such as body temperature, infrared radiation measured tissue temperature, the varying distance between the spectral detector and the emitting tissue, the varying spot of the tissue's non-contact temperature measurements in comparison to the spot where that spectral information is collected. It is aimed at reducing the number of variables of data analysis by mathematical methods. The mathematical methods of analysis include partial least squares, principal component analysis, artificial neural networks, a mixture of expert's algorithm, chemometric techniques, mathematical models, and other similar methods.

The present invention provides an optimal means for measurement of the concentration of the analyte of interest from the infrared energy emissions of the tissue by means of evaluation of the temperature and humidity parameters' influence on analyte concentration derived from an infrared spectral emission signal. The method and instrument senses the infrared thermal emission analyte signal level, senses the body and ambient temperature, senses the ambient humidity, produces output electrical signals representative of the said physical quantities, converts the resulting input, and sends the converted input to a processor. The microcomputer is adapted to provide the necessary analysis of the signal to determine the concentration of the substance of interest. It displays the concentration of the substance of interest.

The invention is aimed at monitoring ambient conditions and multiple physiological variables of a patient at a single site, using multiple sensors integrated into a single instrument. The instrument has an infrared spectral sensor, a detector base temperature sensor, an infrared temperature sensor, and a body temperature conduction sensor, an ambient temperature sensor, a humidity sensor and a communication circuit for outputting information produced by said sensors. These elements are integrally placed within the housing of the instrument or within speculum 3, or within the optional speculum plastic cover 2 or within the earplug mold made to fit the ear of the patient.

The embodiments of the present invention are intended to be merely examples and those skilled in the art will be able to make numerous variations and modifications without departing from the spirit of the present invention. All such variations and modifications are intended to be within the scope of the present invention as defined in the appended claims.

Claims

What is claimed is:

1. An improved method for determining a human body tissue analyte concentration by non-invasive measurement of the emission spectral lines characteristic to a body tissue analyte in an infrared spectral region emitted naturally by a human body as heat, comprising: a) measuring a spectral intensity of said emission lines; b) said emission spectral lines having a wavelength dependence of tissue - constituents; c) detecting the emission spectral lines at a predetermined emission wavelength; d) analyzing the emission spectral lines in the said infrared spectral region; e) measuring ambient temperature; f) measuring optionally ambient humidity; g) measuring body temperature by means of heat conduction; h) measuring body temperature in a non-contact manner by means of radiation; i) correlating the said spectral intensity of emission spectral lines, the said ambient temperature and the said optional humidity, the said body temperature measured by means of conduction and by means of radiation with body analyte concentrations.

2. The improved method as in claim 1, for determining blood glucose concentration by non-invasive measurement of emission spectral lines characteristic to a body tissue analyte in an infrared spectral region emitted naturally by a human body's tympanic membrane in an infrared wavelength spectrum as heat including the measuring of ambient and body temperature and optionally ambient humidity.

3. An improved instrument for determining a human body tissue's analyte concentration by non-invasive measurement of emission spectral lines characteristic to a body tissue analyte in an infrared spectral region emitted naturally by a human body as heat, comprising: a) a means for detecting said emission spectral lines at a predetermined infrared wavelength; b) a means for detecting the spectral intensity of the emission spectral lines; c) a means for measuring ambient temperature; d) an optional means for measuring ambient humidity; e) a means for measuring body temperature by means of heat conduction; f) a means for measuring body temperature in a non-contact manner by means of radiation; g) a means for correlating the said spectral intensity of emission spectral lines, the said ambient temperature and the said optional humidity, the said body temperature measured by means of conduction and by means of radiation with body analyte concentrations.

4. The improved instrument of claim 3 wherein the detecting means comprises: a) a detector means; and, b) an analyzing means in the form of a wavelength selecting means for the emission spectral lines; said detector means comprising means for detecting the intensity of the received emission spectral lines from the said analyzing means producing an electrical output signal; the said wavelength selecting means comprising means for allowing only significant wavelengths of tissue analyte emission spectral lines in natural infrared radiation emitted by the human body to reach the detector means.

5. The improved instrument of claim 3 wherein the measuring means comprises sensors for said temperature and optionally for said humidity measurements.

6. The improved instrument of claim 4, wherein the detector means comprises an infrared energy sensor for infrared energy measurements.

7. The improved instrument of claim 4, wherein the analyzing means comprises filter means for filtering the emission spectral lines to allow only for wavelengths significant to the tissue analyte emission spectral lines to pass or to be absorbed before reaching the detector means.

8. The improved instrument of claim 3, where the correlating means is an electronic means comprising electronics and a microcomputer for correlating the electronic output signal from the detecting means and measuring means with the tissue analyte concentration.

9. The improved instrument as in claim 3, for determining blood glucose concentration by non-invasive measurements of emission spectral lines characteristic to blood glucose as a body tissue analyte.

10. An improved instrument for non-invasive tissue analyte concentration measurements based on measurements of emission spectral lines characteristic to a human body tissue analyte in an infrared spectral region emitted naturally by a tympanic membrane as heat, comprising: a) an ear plug assembly for insertion into an ear canal; b) said ear plug assembly comprising an infrared radiation detecting system comprising an optical infrared filter set and a detector, sensitive in an infrared region of human body heat radiation, for detecting the emission spectral lines, and providing an output based thereon; c) said ear plug assembly comprising a body temperature measurement sensor by means of conduction; d) said ear plug assembly comprising a body temperature measurement sensor in a non-contact manner by means of radiation; d) a sensor for ambient temperature measurements; e) an optional sensor for ambient humidity measurements; f) said ear plug assembly and said sensors comprising connection means whereby the output of the detecting system may be connected with electronics, a microcomputer and a display system for forming, calculating, and displaying an electrical signal from the said detecting system and said sensors to show a numerical value of the analyte concentration.

11. The improved instrument of claim 10 wherein said detecting system incorporating a body temperature sensor is adapted to be in thermal conductive contact with a human body.

12. The improved instrument as in any one of claims 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein said detecting of said emission spectral lines and said spectral intensity of the emission spectral lines and said detecting of temperature and optionally humidity are continuously affected.

13. The improved instrument of claim 12 wherein the emission spectral lines are the emission spectral lines of blood glucose.

14. The improved method as in any one of claims 1 or 2 wherein the measuring of the spectral intensity of said emission lines and the detecting of the emission spectral lines and said detecting of temperature and optionally humidity are affected continuously.

15. The improved method as in claim 14 wherein the emission spectral lines are the emission spectral lines of blood glucose.

16. An improved instrument for determining a human body tissue analyte concentration by a non-invasive measurement of emission spectral lines characteristic to a body tissue analyte in an infrared spectral region naturally emitted by a human body as heat, comprising: a) a speculum for insertion into an ear canal; b) an optional plastic cover made of material transparent to radiation in an, infrared spectral region; c) an infrared waveguide for receiving infrared radiation from the tympanic membrane and for illuminating all windows of a detecting system; d) the said infrared waveguide selected from the group consisting of a mirror, reflector, lens, hollow tube, and a fiber optic; e) the detecting system consisting of: i) an infrared filter set; and, ii) a detector sensitive in an infrared region of human body heat radiation; f) an optical infrared filter set consisting of a negative correlating filter or narrow band filters; g) a detector system sensitive in an infrared region of human body heat radiation consisting of at least two sensing areas electronically connected so that their outputs are subtracted; h) the detector system comprising a body temperature sensor by non-contact means, e.g. radiation; i) said speculum optionally comprising body temperature sensors by conduction; j) a sensor for ambient temperature measurements; k) an optional sensor for ambient humidity measurements; and,

1) said detector and said sensors having an output connected with electronics, a microprocessor and a display system for forming, calculating, and displaying the resulting electrical signal from the detector and sensors to show a numerical value of the analyte concentration.

17. An improved instrument for non-invasive tissue analyte concentration measurement based on measurement of emission spectral lines characteristic to human body tissue analyte in an infrared spectral region emitted naturally by the tympanic membrane as heat, comprising: a) a speculum for insertion into an ear canal and for receiving from an infrared wave-guide infrared radiation from the tympanic membrane and for illuminating all windows of a detecting system; b) the detecting system comprising: i) an optical infrared filter set consisting of a negative correlating filter or narrow band filters; and, ii) a detector sensitive in an infrared region of human body heat radiation, said detecting systems positioned to be illuminated by infrared radiation arriving from the said optical infrared filter set, or negative band filters, and having at least two sensing areas electronically connected so that their outputs are subtracted to produce a detection output; iii) a body temperature sensor by non-contact means, e.g. radiation; c) said speculum optionally comprising body temperature sensors by conduction; d) a sensor for ambient temperature measurement; e) an optional sensor for ambient humidity measurements; and, f) a said detector and said sensors having an output connected with electronics, a microprocessor and a display system for forming, calculating, and displaying an electrical signal from the detector and sensors to show a numerical value of the analyte concentration.

18. An improved instrument as in claim 17 wherein the infrared waveguide is selected from the group consisting of a mirror, reflector, lens, hollow tube, and a fiber optic.

19. The instrument as in any one of claims 17 or 18 wherein the emission spectral lines are the emission spectral lines of blood glucose.