JP2006525084A - Method and device for non-invasive analyte measurement - Google Patents

Abstract

The present invention relates to a non-invasive method and apparatus for detecting the level of analyte concentration in a tissue of a subject. The spectrum of mid-infrared radiation emanating from the subject's body is modified to correspond to the concentration of various compounds in the tissue being irradiated. In one aspect of the invention, the instrument (200) pours radiation in the mid-infrared range (150) onto a subject's body surface, such as the patient's eye (100), and reflects to the instrument (200). The analyte concentration is measured based on the returning mid-infrared radiation.

Description

(Field of Invention)
The present invention relates to optical non-invasive methods and instruments for detecting the presence or measuring the concentration of a wide range of analytes such as glucose in a subject's tissue. The spectrum of mid-infrared radiation emanating from the subject's body is modified in response to the presence, absence or concentration of the analyte in the subject's tissue. In one aspect of the invention, the device applies light in the mid-infrared range to the surface of the patient's body, such as the skin or any opening, such as the eye, mouth, ear or nose, perforation tube or cavity. The presence, absence or concentration of the analyte is determined based on the mid-infrared illumination signature characteristic of the analyte that is poured and reflected back to the instrument. In another aspect of the invention, the instrument measures the level of mid-infrared radiation from the surface of the patient's body, including but not limited to any opening such as skin or eyes, mouth, ears or nose. Includes mid-infrared radiation emanating from the surface of the patient's body, such as a perforated tube or cavity, and determines the presence, absence or concentration of the analyte based on the mid-infrared radiation signature characteristic of the analyte . In a preferred embodiment, the present invention relates to a non-invasive method for measuring the presence or concentration of a wide range of analytes such as glucose in a subject's conjunctiva. The spectrum of mid-infrared radiation emitted or reflected from the patient's conjunctiva is modified in response to the presence, absence or concentration of the analyte in the subject's conjunctiva. In one aspect of the invention, the conjunctiva of the patient's eye determines the presence, absence or concentration of the analyte based on the characteristic spectral characteristics of the analyte detected by an instrument capable of detecting an optical signal. It is used as a source of optical signals. The measurements made by the instrument on the conjunctiva or any other body part of the present invention do not require direct contact of the instrument with the surface of the patient body.

(Background of the Invention)
Diabetes remains one of the most serious and treated diseases facing the global health care system. Diabetes is a chronic disease in which the body cannot maintain normal levels of glucose in the bloodstream. Today, it is now the fifth leading cause of death from illness in the United States and accounts for approximately 15% of the overall health care budget. People with diabetes have two groups: type 1 (formally known as “young” or “insulin-dependent” diabetes that requires taking insulin to sustain life) and type 2 ( Formally, it may require insulin but is often classified as "adult" or "non-insulin dependent" which can be treated with diet and oral hypoglycemic drugs. In both cases, without dedicated and regular blood glucose measurements, all patients face potential diabetic complications including cardiovascular disease, kidney disease, blindness, amputation and premature death .

  The number of diabetes cases in the United States has soared 40% over the past decade. This high rate increase is believed to be due to genetic causes and lifestyle combinations that appear to be long-term trends, including obesity and poor diet. The American Diabetes Association (ADA) and others estimate that approximately 17 million Americans and more than 150 million people worldwide have diabetes, and up to 40% of these people are not currently Presumed to be a diagnosis. American Diabetes Association, "Facts & Figures."

  Diabetes must be “controlled” to delay the onset of complications of the disease. Thus, people with diabetes must measure their blood glucose level several times per day in an attempt to maintain their glucose level within the normal range (80-130 mg / dL) It is. These glucose measurements are used to determine the amount of insulin or alternative treatment required to bring glucose levels within target limits. Blood glucose self-monitoring (SMBG) is a continuous process that is repeated multiple times per day for the remainder of the patient's life.

  All FDA-approved invasive or “less invasive” glucose monitoring products currently on the market (blood is taken from the arm or other fingertips) glucose monitoring products allow blood collection to make a quantitative measurement of blood glucose I need. Continued and frequent measurement requests (1 to perhaps 10 times per day) present all diabetics with pain, skin trauma, inconvenience, and risk of infection, with appropriate insulin doses or other treatments. It is generally reluctant to make frequent important measurements necessary to make a choice.

  The disadvantages of these current products lead to poor patient compliance. Among type 1 diabetics, 39% measure their blood glucose less than once a day, and 21% do not monitor their glucose at all. Among type 2 diabetics who take insulin, only 26% monitor at least once per day and 47% do not monitor at all. Over 75% non-insulin type 2 diabetics, never monitor their glucose levels. Roper Star World Wide Survey. Of the 1,186 diabetic patients investigated, 91% were interested in non-invasive glucose monitoring [www. childrenwithdiabetes. com]. Thus, there is both tremendous interest and clinical need for non-invasive glucose sensors.

  Preferred embodiments of the present invention seek to replace currently used glucose measurement methods, devices and instruments, including invasive measurements and the use of glucose test strips with optical non-invasive instruments.

  Various methods have been developed for non-invasive glucose sensing using skin test sites such as fingers or ear lobes. These methods mainly employ instruments that measure blood glucose levels by generating and measuring only light in the near infrared illumination spectrum. For example, US Pat. No. 4,882,492 (the '492 patent) relates to a device that transmits near-infrared radiation through a sample to be tested on a human skin surface. In this' 492 patent, near-infrared radiation passing through this sample is split into two beams, where one beam is passed through a negative correlation filter and the second beam is a neutral density filter. Pass through. The differential light intensity measured through these filters of the two light beams is proportional to the glucose concentration according to the '492 patent.

  US Pat. No. 5,086,229 (the '229 patent) relates to an instrument that produces near-infrared radiation in the spectrum of about 600 to about 1100 nanometers. According to the '229 patent, a person places their finger between the generated near-infrared irradiation source and a detector, based on the detected near-infrared irradiation, Associate concentrations. Similarly, US Pat. No. 5,321,265 (the '265 patent) also measures blood glucose levels using both near infrared radiation and a fingertip as a test site. The detector disclosed in the '265 patent further comprises a silicon photocell and a broadband pass filter.

  US Pat. No. 5,361,758 (the '758 patent) relates to a device that measures near-infrared radiation that is either transmitted through or reflected from a human finger or earlobe. In the '758 patent, the transmitted or reflected light is separated by a diffraction grating or prism, and the near-infrared radiation is detected and correlated with blood glucose concentration. The instrument of the '758 patent also has additional timing and control programs, where the device can take measurements specifically during the heartbeat and also adjust to temperature.

  US Pat. No. 5,910,109 (the '109 patent) also relates to a device for measuring blood glucose concentration using near-infrared irradiation and an earlobe as a test site. The instrument of the '109 patent comprises four light sources with a very specific near infrared emission spectrum and four detectors with a specific near infrared detection spectrum corresponding to the wavelength of this light source. The signals detected by the four separate detectors are averaged and these averages are analyzed to determine blood glucose concentration according to the '109 patent.

  Techniques that use near-infrared radiation, where the near-infrared radiation is transmitted through or reflected from the skin test site, and are monitored to measure glucose in vivo are known to be inaccurate. The desired glucose concentration is in the blood or tissue fluid and not on the surface of the skin. Therefore, these methods must penetrate into the layers below the top layer of skin. There are many substances in the skin that can interfere with this near infrared glucose level. Furthermore, there is a wide range of variation in human skin, both between individuals and within a given individual. Furthermore, glucose simply lacks a “fingerprint” that can be satisfactorily identified in the near-infrared radiation spectrum. Because near-infrared radiation is not well absorbed by glucose and the level of tissue interference found in the skin, this technique is substantially less desirable for accurate measurement of blood glucose concentration.

  US Pat. No. 6,362,144 (the '144 patent) discloses using a fingertip as a test site. However, the instrument described therein uses attenuated total reflection (ATR) infrared spectrophotometry. According to the '144 patent, a selected skin surface, preferably a finger, is contacted with the ATR plate while ideally maintaining the pressure of contact. The skin is then irradiated with a mid-infrared beam, where the infrared radiation is detected and quantified to measure blood glucose levels. However, this technique is such that the surface of the skin tissue where the measurement is made is very dense in the wavelength region of interest, or like the eye, nose, mouth or other opening, cavity or perforated tube, It is not ideal if it is not easy to make direct contact with the ATR plate.

  The minimum depth of peripheral capillaries in epithelial tissue is typically about 40 microns. Here again there are physical features and numerous substances present in the skin that can interfere with the desired glucose-specific signal. While useful in the laboratory, both the near-infrared transmission method described above and the ATR method are not practical or may not be suitable for use in monitoring blood glucose levels in patients. I don't know.

  Methods have also been developed for non-invasive glucose sensing using the eye as the test site. For example, both US Pat. Nos. 3,958,560 (the '560 patent) and 4,014,321 (the' 321 patent) describe devices that utilize optical rotation of polarized light. In the '560 and' 321 patents, a light source and a photodetector are incorporated into a contact lens, which is placed on the surface of the eye so that the eye is either corneal or aqueous humor each source. Are scanned using two sources of polarized illumination that transmit with different absorption spectra. This optical rotation of radiation through the cornea correlates with the glucose concentration in the cornea according to the '560 and' 321 patents. While this method can be referred to as “non-invasive” because blood drawing is not required, it can still cause significant discomfort or distorted vision of the user. This is because it is necessary to place the sensor directly on the eye.

  US Pat. No. 5,009,230 (the '230 patent) uses a polarized beam of near-infrared radiation in the range of 940-1000 nm. In the '230 patent, the amount of rotation imparted by glucose present in the bloodstream of the eye on the polarized beam is measured to determine the glucose concentration. Here again, accuracy is limited. This is because glucose simply lacks a sufficiently distinguishable “fingerprint” in this near-infrared radiation spectrum.

  Both US Pat. No. 5,209,231 (the '231 patent) and International Publication No. WO 92/07511 (the' 511 application) are first split by a beam splitter into a reference beam and a detector beam, and then preferably The use of polarized light that passes through a specimen that is the aqueous humor of the eye is similarly described. The amount of phase shift compared between the transmitted reference beam and the detector beam is related to determine the glucose concentration in these '231 and' 511 applications. US Pat. No. 5,535,743 (the '743 patent) measures the diffusely reflected light provided by the iris surface to the aqueous humor of the eye. According to the '743 patent, this optical absorption measurement is possible, but optical rotation through the aqueous humor is not possible. However, in this' 743 patent, the intensity of diffusively reflected light can be analyzed to obtain useful information regarding the optical properties of ocular effusion, including blood glucose concentration.

  US Pat. No. 5,687,721 (the '721 patent) also generates both a measurement and reference polarization beam and compares these beams to determine the angle of rotation due to blood glucose concentration. A method for measuring blood glucose concentration is disclosed. However, the preferred test site disclosed is a finger or other suitable appendage according to the '721 patent. The '721 patent further discloses and requires the use of a monochromatic laser and / or semiconductor as the light source.

  U.S. Pat. No. 5,788,632 (the '632 patent) transmits a first beam of light through a first polarizer and a first retarder, and then the sample to be measured. To determine the blood glucose concentration by allowing it to pass through, transmitting this light through a second polarizer or retarder, and finally detecting this light from the second detector A non-invasive instrument is disclosed. The measured polarization rotation is related to the measured blood glucose concentration of the sample by the '632 patent.

  US Pat. No. 5,433,197 (the '197 patent) is a broadband near-infrared radiation that irradiates the eye in such a way that energy passes through the anterior chamber of the eye, aqueous humor, and then is reflected from the iris. A non-invasive instrument for determining blood glucose concentration using irradiation is disclosed. This reflected energy then returns through the aqueous humor and cornea and is collected for spectral analysis. According to the '197 patent, representatives of reflected energy electrical signals are analyzed by univariate and / or multivariate signal processing techniques to correct any errors in glucose determination. Here again, the accuracy of the instrument in the '197 patent is limited because glucose simply lacks a “fingerprint” that is sufficiently distinguishable in this near-infrared radiation spectrum.

  Disclosed are instruments and methods that use naturally emitted radiation to measure blood glucose levels using the human body as a test site, and in particular the tympanic membrane. U.S. Pat. Nos. 4,790,324; 4,797,840; 4,932,789; 5,024,533; 5,167,235; 169,235; and 5,178,464 describe various designs, stabilization and calibration techniques for a tympanic non-contact thermometer. In addition, US Pat. No. 5,666,956 (the '956 patent) uses a Plank law by measuring electromagnetic radiation from the eardrum and measuring irradiation intensity, spectral distribution, and black body temperature. An instrument for calculating emissivity is disclosed. According to the '956 patent, the resulting monochromatic emissivity can vary depending on the spectral characteristics of the site being measured, ie the blood glucose concentration measured from the tympanic membrane. The '956 patent, however, makes the body's skin surface equal to a “gray body” rather than a black body for its monochromatic emissivity. Thus, according to the '956 patent, the accuracy of such a skin-based method utilizing the radiation emitted by a natural black body is the subsurface using the natural black body radiation emitted from the eardrum. Not useful for analyte measurements when compared to analytical methods.

  The human body naturally emits infrared radiation from its surface, and its spectral or radiation distinguishing properties are modified by the presence, absence or concentration of the analyte in the body tissue. The eye is particularly well suited as a test site for detecting this infrared radiation. For example, certain analytes such as glucose show minimal time delay with changes in glucose concentration between the eye and blood, and the eye provides a body surface with little interference. Cameron et al. (3) 2 DIABETES TECHNOL. THER. 202-207 (2001). Thus, in the field of non-invasive analyte monitoring, accurate analyte concentrations such as blood glucose concentrations and other desired analyte concentrations in subjects that require this type of blood analyte measurement There is an unmet need for a suitable instrument for measuring, and a method of using it.

(Summary of the Invention)
To determine the analyte concentration by pouring infrared radiation onto the body surface and measuring this reflected infrared radiation or using the patient's natural blackbody radiation It relates to a non-invasive method and apparatus for detecting the presence of an analyte in a subject's tissue, or the level of analyte concentration, either by analyzing the emitted radiation. The instrument and method of the present invention does not require direct instrument contact with the surface of the patient's body to make the analyte measurement. A body surface that is particularly well suited for such measurements is the conjunctiva. This conjunctiva covers the exposed surface of the eye except for the cornea. The conjunctiva is a transparent thin tissue layer that lies on the white part of the eye and also lines the inside of the eyelid. This conjunctiva helps maintain eyelid and eyeball moisture and has other functions important for the eye. The conjunctiva is highly vascularized and the tissue fluid contained within the conjunctiva has been found to provide an excellent site for non-invasive measurement of blood or tissue analytes containing glucose. Non-invasive methods of the present invention include, but are not limited to, electromagnetic irradiation and any other optical signal measurement.

  In a preferred embodiment, the analyte that is actually measured or detected can be any compound or substance that has radiation distinguishing properties in the mid-infrared range. In addition to directly measuring the presence, absence or concentration of a particular analyte, the methods and instruments of the present invention are also not limited and may be affected by any metabolite or degradation product of the analyte, or the analyte of interest. Any compound that presents a surrogate marker for another analyte of interest, including any upstream or downstream pathway component or product, or correlates with the presence, absence, or concentration of another analyte of interest, or Can be used to detect the presence, absence or concentration of a substance. In this situation, the analyte actually measured is a surrogate marker for another analyte of interest. The methods and instruments of the present invention can also be utilized to detect the presence, absence or concentration of analytes in the air contacted with or exhaled by a patient. Such air analytes can also be any volatile compound or volatile material including, for example, without limitation, ketones, β-hydroxybutyric acid, or alcohols.

  Another embodiment of the invention relates to a method for measuring an analyte concentration in a tissue of a subject, the method comprising exposing a patient's eye to mid-infrared radiation, and reflecting the reflected mid-infrared radiation spectrum. Determining, and determining an analyte concentration in the tissue. In this embodiment, the subject to be tested can be a mammal, and preferably the subject is a human. Further, the analyte concentration measured can be any analyte having a detectable radiation signature. In one embodiment, the analyte concentration measured is a glucose concentration. In another embodiment, the analyte concentration can be measured for a wide variety of tissues in the subject's body.

  In another embodiment, the present invention provides an instrument that measures the level of mid-infrared radiation from the surface of a subject's body and determines the concentration of a particular analyte based on the characteristic mid-infrared radiation signature of the analyte. About. The instrument in this embodiment may further comprise a light source capable of generating mid-infrared radiation and a mid-infrared radiation detector, if desired. In another embodiment, the instrument can also include a microprocessor and a display. In one embodiment, the instrument can be any suitable mid-infrared light source including, but not limited to, diodes that emit broadband light or narrow-band light, Nernst lamps, nichrome wires, and Glover lamps. In another embodiment, the instrument may also include a wavelength selector that may further comprise any suitable type of filter including, but not limited to, absorption filters, interference filters, monochromators, linear variable filters, annular variable filters, and prisms. Can be provided. In another embodiment, the instrument can also comprise a mid-infrared photodetector that can be of any suitable type including, but not limited to, thermocouples, thermistors, microbolometers, and liquid nitrogen cooled MTC.

  In another embodiment, the invention pours light, including light in the mid-infrared range, onto the surface of the subject's body and reflects the analyte concentration based on the mid-infrared signature of the analyte reflected back to the instrument. It relates to a measuring instrument. In this embodiment, the instrument is a light source capable of producing mid-infrared radiation having a wavelength in the range of about 2.5 microns to about 25.0 microns, in the range of about 8.0 microns to about 11.0 microns. It further comprises a mid-infrared radiation detector capable of detecting mid-infrared radiation having a wavelength, and optionally comprises a microprocessor and a display. In one embodiment, the instrument includes a light source that can be any suitable mid-infrared light source including, but not limited to, diodes that emit broadband light or light in a narrow frequency band, Nernst lamps, Nichrome wires, and Glover lamps. Further prepare. In addition, the instrument of this embodiment may further include suitable wavelength filters, including but not limited to absorption filters, interference filters, monochromators, linear variable filters, annular variable filters, and prisms, as necessary. A selector may be further provided. In one embodiment, the instrument may also include a suitable mid-infrared photodetector including, but not limited to, a thermocouple, thermistor, microbolometer, and liquid nitrogen cooled MTC.

  In another embodiment of the present invention, the appliance may comprise a display such as, but not limited to, an alphanumeric display including a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED). In another embodiment of the present invention, the instrument comprises an acoustic display that may comprise an acoustic source including recorded acoustic clips, a speech synthesizer and a speech emulation algorithm and reports the analyte concentration to be heard.

  In another embodiment, the instrument of the present invention comprises a microprocessor and a memory operably connected to the microprocessor. The instrument of this embodiment may also further comprise a communication interface adapted to communicate data from the instrument to the computer system. In this embodiment, the selected communication interface is any suitable interface including, but not limited to, serial, parallel, USB (Universal Serial Bus), firewire, Ethernet, optical fiber, coaxial cable, and twisted pair cable. possible.

  In another embodiment, the invention relates to a computer system for downloading and storing measured analyte concentrations. This embodiment is further implemented within a computer processor, a memory operably coupled to the computer processor, a communication interface adapted to receive and transmit data within the computer processor, and the computer processor. A computer program stored in the memory may be provided. The computer processor of this embodiment further comprises a database, wherein data received by the processor can be stored in memory as a database and stored in a predetermined field, and the database is downloaded. It can be a presentation of a graph of the analyte concentration. Presentation of graphs in this embodiment can include, but is not limited to, column, line, bar, pie, XY scanner, area, radar, and surface presentation.

  In another embodiment, the present invention relates to a computer interface that is further adapted to communicate data about analyte concentration to a remote computer processor or user. In this embodiment, the remote user may be a doctor, laboratory, expert, nurse, hospice service provider, insurer, and healthcare provider.

  In a further embodiment, the invention relates to a method or system for downloading and storing a subject's analyte concentration, comprising measuring an analyte using a non-invasive instrument having a communication interface, Connecting the invasive instrument through the communication interface to a computer processor, a computer program implemented on the computer processor, and a computer system having a similar communication interface, and the analyte concentration measured from the non-invasive instrument. Downloading to the computer system may be included. The communication interface of this embodiment further comprises a communication interface adapted to transfer data from the instrument to the computer system. In this embodiment, the communication interface may include, for example, serial, parallel, universal serial bus (USB), firewire, Ethernet, optical fiber, coaxial cable, and twisted pair cable.

  Other objects, features and advantages of the present invention will become apparent from the following detailed description. This detailed description and specific examples, while indicating specific embodiments of the invention, are provided by way of illustration only. Accordingly, the present invention also includes various changes and modifications within the spirit and scope of the present invention that will become apparent to those skilled in the art from this detailed description.

(Detailed description of the invention)
It is to be understood that the invention is not limited to the particular methods, protocols, instruments, systems, and the like described herein, as these can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Must be noted. Thus, for example, reference to a “mid-infrared filter” is a reference to one or more filters, and includes its permeates known to those skilled in the art.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. . Although preferred methods, devices, and materials are described, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

(Definition)
Analyte: As used herein, describes any particular substance to be measured. Analytes can also include any substance present in the subject's tissue or in the air in contact with or exhaled by the subject that exhibits infrared radiation signature. Examples of analytes include, but are not limited to, metabolic compounds or substances, carbohydrates such as sugars including glucose, proteins, peptides or amino acids, lipids or fatty acids, triglycerides, polysaccharides, alcohols including ethanol, toxins, hormones, vitamins, Bacteria-related substances, fungal-related substances, virus-related substances, parasite-related substances, pharmaceutical or non-pharmaceutical compounds, substances, prodrugs or drugs, and any precursors, metabolites, any degradation products or surrogates of the preceding Contains a marker. Analytes can also include any material that is foreign to or is not normally present in the subject's body.

  Conjunctiva: As used herein, describes the membrane tissue that covers the exposed surface of the eye and the inner surface of the eyelid.

  Far-infrared irradiation: As used herein, any source having a wavelength of about 50.00 to about 1000.00 microns, either produced by any source or emitted naturally. Say.

  Pouring: As used herein, refers to broadly imparting a light beam of light that is relatively widely diffused or spread to the surface.

  Focused: As used herein, refers to a ray of mostly collimated light collected on a particular predetermined point.

  Infrared radiation: As used herein, refers to any radiation having a wavelength of about 0.78 to about 1000.00 microns, either generated from any source or emitted naturally. .

  Mid-infrared radiation: As used herein, any radiation having a wavelength of about 2.50 microns to about 50.00 microns, either generated from any source or emitted naturally. Say.

  Mid-infrared irradiation detector: As used herein, refers to any detector or sensor that can register infrared irradiation. Examples of suitable mid-infrared detectors include, but are not limited to, thermocouples, thermistors, microbolometers, and liquid nitrogen cooled MTCs. The infrared radiation detected together can be correlated with a wavelength corresponding to the analyte concentration using means such as a Fourier transform, producing a high resolution spectrum.

  Near-infrared radiation: As used herein, any radiation having a wavelength of about 0.78 microns to about 2.50 microns, either generated from any source or emitted naturally. Say.

  Surface: As used herein, without limitation, any skin, eye, ear, mouth, nose or any opening, either naturally occurring or artificial such as a surface created by surgery, Any portion of the patient's body that can be exposed to the external environment, including body cavities, perforated tubes or other surfaces.

  Tissue: As used herein, without limitation, skin, blood, body fluid, eye, tissue fluid, ophthalmic fluid, bone, muscle, epithelium, fat, hair, fascia, organ, cartilage, tendon, ligament, and any Any tissue or component of the subject, including any mucosa.

(Noninvasive glucose measurement)
In one aspect of the invention, mid-infrared radiation is poured onto the body surface using an illumination source. This poured irradiation is detected by a mid-infrared detector placed in front of the body surface. Here again, the radiation distinguishing properties of the reflected mid-infrared radiation are affected by the presence or concentration of the analyte. This provides a non-invasive method that employs the device of the present invention to measure the presence, absence or concentration of an analyte such as glucose from any body surface, including the subject's eye (FIG. 3). ).

  In another aspect of the invention, the human is a natural radiator or radiator of energy in the mid-infrared radiation spectrum. In one aspect of the present invention, the body itself acts as a light (heat) source, providing the mid-infrared illumination signature of the analyte present therein. In this aspect, and with respect to the surface of the subject's body, light (or heat) from the body is emitted or emitted from the body surface and detected by a mid-infrared illumination detection instrument. This mid-infrared irradiation distinguishing characteristic in the body's mid-infrared irradiation radiation is affected by the presence, absence or concentration of an analyte such as glucose in the subject's tissue. The natural mid-infrared radiation signature of glucose contained within the body's natural mid-infrared radiation signature provides the basis for non-invasive glucose measurements and instruments for making such measurements (FIG. 3). In addition, reducing or increasing the concentration of a particular analyte can cause an increase in the body's natural radiation of infrared radiation. Such an increase in the body's natural infrared radiation can provide a measurable signal that can be utilized to measure the presence, absence or concentration of the analyte.

  There is considerable evidence that fluctuations in blood glucose levels correlate well with glucose levels in the aqueous humor of the eye. (Steps, 1 (2) DIABETES TECHNOL. THER., 129-133 (1999)). In fact, it has been estimated that the time delay between blood glucose active and aqueous glucose concentration is about 5 minutes on average. (Cameron et al., 3 (2) DIABETES TECHNOL. THER., 201-207 (2001)). Aqueous humor is a watery liquid between the lens and cornea that bathes the cornea, lens and iris and provides nutrients (FIG. 1). Glucose in the eye is not limited and includes various components and compartments including epithelial cells, aqueous humor, vitreous humor, various layers of cornea, iris, various layers of sclera, conjunctiva, tears, tear layer, and blood vessels Is located throughout. Thus, without limitation, the eye containing this tear layer is both an ideal and appropriate body surface for non-invasive measurement of the presence, absence or concentration of an analyte in a subject's tissue.

(Measure mid-infrared radiation)
When electromagnetic radiation passes through a substance, it can either be absorbed or transmitted depending on its frequency and the structure of the molecule it encounters. Electromagnetic radiation is energy, so when a molecule absorbs radiation it gains energy because it undergoes a quantum transition from one energy state (E _initial ) to another energy state (E _final ). The frequency of the absorbed radiation is related to the energy of the transition due to Planck's law: E _final -E _initial = E = hn = hc / l. Thus, if there is a transition associated with the frequency of incident radiation due to the Planck constant, then this radiation can be absorbed. Conversely, if this frequency does not satisfy the Planck equation, then this illumination is transmitted. A plot of the specific measurement of the frequency of incident radiation versus the% of the radiation absorbed by the sample is the radiation signature of the compound. Some absorption of radiation applied to a body surface that contains a substance or substance that absorbs radiation can cause a measurable decrease in the amount of radiation that actually passes or is affected by the radiation-absorbing substance. Such a decrease in the amount of radiation that is passed through or affected by the radiation absorbing material may provide a measurable signal that can be utilized to measure the presence, absence or concentration of the analyte.

  The human body emits electromagnetic radiation within the infrared radiation spectrum. The spectral characteristics of the emitted infrared radiation can be related to the nature of this emitting object, such as the body surface of the subject. For example, glucose absorbs mid-infrared radiation at wavelengths between about 8.0 microns and about 11.0 microns. If mid-infrared radiation passes through or is reflected from an object in which glucose is present, a separate illumination “fingerprint” or “signature” can be detected from the remaining light that is not absorbed, and the illumination Generate discriminating characteristics. This generated radiation signature can both confirm the presence or absence of the analyte and indicate the concentration of the analyte. Furthermore, since glucose is a radiation absorbing material, there can be a measurable decrease in the amount of irradiation energy that passes or reflects through a glucose containing material, such as the body surface of a subject, including the subject's eye. This measurable decrease in the amount of irradiation energy can be utilized to measure the presence, absence or concentration of glucose in a subject.

  One embodiment of the present invention provides a method for non-invasively measuring blood analyte concentration in a subject and generating mid-infrared radiation that is poured onto the subject's body surface; Detecting the reflected mid-infrared radiation, associating the spectral characteristics of the detected mid-infrared radiation with the radiation identification characteristic corresponding to the analyte concentration, and analyzing and analyzing the detected mid-infrared radiation identification characteristic Providing an object concentration measurement. In another embodiment, the method comprises detecting by filtering mid-infrared radiation reflected back from the body surface so that only wavelengths from about 8.00 microns to about 11.00 microns pass through the filter. Including a step of filtering prior to. In this embodiment, the filtering step is accomplished using an absorption filter, interference filter, monochromator, linear variable filter and annular variable filter, prism or any other functional equivalent known in the art. obtain. The detection step can be accomplished using any mid-infrared irradiation sensor such as a thermocouple, thermistor, microbolometer, liquid nitrogen cooled MTC, or any other functional permeate known in the art. Associating the spectral characteristics of the detected mid-infrared radiation may include using a microprocessor to correlate the detected mid-infrared radiation identification characteristics with the irradiation identification characteristics of the analyte. If the analyte being measured is glucose, then the generated radiation signature can be in the range of about 8.0 to about 11.0 microns. The analysis step may further comprise a microprocessor using an algorithm based on Planck's law to associate the absorbed spectrum with the glucose concentration. In another embodiment of the invention, the analyzing step is not limited to the Kramers-Kronig transform or known in the art to convert the detected mid-infrared signal into an analyte spectrum for correlation. It may include the use of transformations such as other classical transformations.

  In another embodiment of the invention where glucose is in the analyte of interest, an instrument and display comprising a mid-infrared illumination detector can be supported on the subject's body surface. This mid-infrared radiation from the body surface can be filtered so that only wavelengths from about 8.0 microns to about 11.0 microns reach the mid-infrared radiation detector, if desired. The irradiation identification characteristic of the mid-infrared irradiation detected by this detector is then associated with the irradiation identification characteristic corresponding to the glucose concentration. This irradiation signature can then be analyzed to give an accurate glucose concentration measurement. The measured glucose concentration can be displayed.

  In another embodiment of the invention, an instrument comprising a mid-infrared radiation generator, a mid-infrared radiation detector and a display may be supported on the patient's body surface. Mid-infrared radiation can be used to pour or direct the beam generated by the instrument and collected on the subject's body surface. The generated mid-infrared radiation can be broadband or narrow frequency radiation and can also be filtered to reach only the desired radiation wavelength to the body surface. Any analyte such as glucose present in any component of the body surface can absorb some of the generated radiation. Mid-infrared radiation that is not absorbed can be reflected back to the instrument. This reflected mid-infrared radiation can be filtered if necessary so that only wavelengths from about 8.0 microns to about 11.0 microns reach the mid-infrared radiation detector. The irradiation identification characteristic of the mid-infrared irradiation detected by this detector can then be associated with an irradiation identification characteristic corresponding to the concentration of the analyte such as glucose. This irradiation signature can be analyzed to obtain the concentration of an analyte such as glucose. The measured concentration of an analyte such as glucose can be displayed by the instrument.

  Infrared radiation can be generated by the instrument of the present invention. Such infrared radiation can be generated by a broadband wavelength generator or a narrow frequency band wavelength generator. In one embodiment of the invention, the instrument may comprise a mid-infrared radiation generator. In another embodiment of the invention, the instrument comprises a light source with one or more filters to limit the wavelength of light reaching the body surface. The mid-infrared generator may further comprise a heating element. The heating elements of this embodiment include Nernst soot (zirconium oxide / yttrium oxide), nichrome wire (nickel-chromium wire), and glover (silicon-carbon rod), broadband light emitting diodes or narrow frequency band light emitting diodes, or the art And any other functional permeate known in the art. Mid-infrared radiation has a wavelength in the range of about 2.5 microns to about 50.0 microns. An analyte typically has a characteristic “fingerprint” or “discriminating characteristic” with respect to its mid-infrared radiation spectrum resulting from the influence of the analyte on mid-infrared radiation, such as absorption. In particular, glucose has a well-defined “fingerprint” or “discriminating characteristic” during mid-infrared irradiation at wavelengths from about 8.0 microns to about 11.0 microns. This irradiation signature of glucose can be easily generated for a wide variety of glucose concentrations, utilizing a wide variety of body surfaces to obtain radiation signature data. In one embodiment of the invention, the instrument may comprise a mid-infrared radiation filter to filter all mid-infrared radiation that is not within the wavelength range of about 8.0 to about 11.0 microns. . In other embodiments, the filter is selected to filter out all mid-infrared radiation except the wavelength that provides the radiation distinguishing properties of the desired analyte, such as glucose. Filtering mid-infrared radiation can be accomplished using absorption filters, interference filters, monochromators, linear variable filters, annular variable filters, prisms or any other functional permeate known in the art.

  The instrument of the present invention may also comprise a mid-infrared radiation detector for detecting mid-infrared radiation. This mid-infrared radiation detector can measure naturally emitted or reflected mid-infrared radiation in any form, including in the form of thermal energy. Detecting this naturally emitted or reflected mid-infrared radiation uses a thermocouple, thermistor, microbolometer, liquid nitrogen cooled MTC, or any other functional permeate known in the art. Can be achieved. Both thermocouples and thermistors are well known in the art and are commercially available. For example, thermocouples are commonly used sensors because they are relatively inexpensive, interchangeable, have standard connectors, and can measure a wide range of temperatures. . Furthermore, the thermometer product portfolio includes a wide range of thermistors (heat sensitive resistors), which have a resistance / temperature coefficient of negative (NTC) or positive (PTC) depending on the type.

  The device of the present invention may also comprise a microprocessor. The microprocessor in this embodiment correlates the detected mid-infrared radiation with an illumination signature that provides information to the microprocessor about the analyte concentration whose spectral characteristics are measured. The microprocessor in this embodiment analyzes the radiation signature obtained using an algorithm based on Planck's law and converts this signature to an accurate analyte concentration measurement in the sample being measured.

  A broadband light source can be modified by an interferometer such as Fourier transform spectroscopy, or by an electro-optic or moving mask such as Hadamard transform spectroscopy, and encoding wavelength information in the time domain Will be readily apparent to those skilled in the art. A separate wavelength band can be selected and scanned at the central wavelength using, for example, an acousto-optic tuning filter. The instrument of the present invention having an illumination source comprises one or more mid-infrared illumination sources, which provide illumination at a number of wavelengths and also comprise one or more mid-infrared illumination detectors. The instrument may further comprise one or more filters or wavelength selectors to remove, identify or select the desired wavelength of radiation before and after detection by the detector.

(Clinical application)
Diabetics and subjects at risk of diabetes maintain their blood glucose level within an acceptable range and make accurate blood glucose level records for both personal and medical records In an attempt to do so, it may be required to regularly measure blood glucose levels. In one aspect of the invention, the instrument may also include an alphanumeric display to display the measured glucose concentration. The alphanumeric display of this embodiment may comprise a visual display and an acoustic display. The visual display can be a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED) or any other functional equivalent known in the art. An acoustic display capable of transmitting alphanumeric data and converting the alphanumeric data into an acoustic display is a recorded acoustic clip, speech synthesizer and speech emulation algorithm or any other functional equivalent known in the art. It can be a thing.

  Blood glucose self-monitoring (SMBG) is a continuous process that is repeated multiple times per day for the remainder of the life of a diabetic patient. Accurate recording of these measurements is critical for diagnostic purposes. An easy storage and access system for this data is also contemplated by the present invention. In one aspect of the invention, an instrument for noninvasively measuring blood glucose concentration further comprises a microprocessor and a memory operably connected to the microprocessor for storing blood glucose measurements. Can be prepared. The instrument of this embodiment further comprises a communication interface adapted to communicate data from the instrument to the computer system. In this embodiment, the selected communication interface can be, for example, serial, parallel, universal serial bus (USB), firewire, Ethernet, optical fiber, coaxial cable, and twisted pair cable or any other known in the art Functional equivalents of

  In addition to storing instrumental blood glucose measurement data, the present invention includes a computer system for downloading and storing these measurement data to facilitate storage and access of this information. The invention further includes a computer processor, a memory operably connected to the computer processor, a communication interface adapted to receive or send data within the computer processor, and the memory executed within the computer processor. Contemplates computer programs stored in The computer program of this embodiment may further comprise a database, where the data received by the database may be stored in a predetermined field, and the database may contain the downloaded analyte concentration. A graph can be displayed. The graphical display of this embodiment can include, but is not limited to, columns, lines, bars, pies, XY scanners, regions, radar, and surface presentation.

  The computer system contemplated by the present invention should be accessible to remote access users for use as a diagnostic, research or other medical related tool via a similar communication interface. Physicians can, for example, log on to this computer system via their similar communication interface and upload the patient's blood glucose readings for any amount of time. This information may provide physicians with accurate records for use as patient monitoring or diagnostic tools such as, for example, adjusting the level of drug therapy or recommending dietary changes. Other contemplated remote access users may include research facilities, clinical trial centers, professionals, nurses, hospice service providers, insurers, and any other healthcare provider.

  The present invention has shown that glucose can be measured non-invasively using mid-infrared signals from the body surface. Studies were conducted in various systems, in vitro studies using glucose concentrations on membrane samples, in vivo rabbit studies with varying blood glucose concentrations, and human studies with diabetic human volunteers with varying blood glucose concentrations . These studies used different types of infrared detector heads to take infrared measurements.

  The inventors of the present invention are unable to penetrate mid-infrared radiation (in the 8-12 micron wavelength range) through the cornea (which is about 500 microns thick) and into the aqueous humor. I found out. The inventors of the present invention also found that the mid-infrared irradiation penetrated the conjunctiva and that the glucose readings obtained from this conjunctiva using mid-infrared irradiation were blood glucose using a standard SMBG test strip. We found that it provided a dose-dependent curve that correlated very well with the measurement.

  All studies, including human studies, clearly demonstrated a dose-dependent response to glucose concentration using mid-infrared radiation measurement techniques.

  The following examples are provided to illustrate and illustrate the present invention. Accordingly, they should not be construed as limiting the scope of the invention. Those skilled in the art will appreciate that many other embodiments are also within the scope of the present invention. This is because it is described in the specification and claims.

(Example 1)
Experimental in vitro model to test instrument accuracy and accuracy (use of instrument)
The instrument used for mid-infrared irradiation measurement was a SOC portable FTIR. This SOC portable FTIR is based on an interferometer and was originally designed for the US Army to detect battlefield gases. This instrument was modified to allow measurements on rabbit and human eyes. These modifications allow for the installation of a filter that allows only energy in the region to be measured at 7-13 microns, and also the faceplate that allows easier placement of this device for rabbit and human eyes. Modifications were included.

(In vitro study)
Studies have been conducted to show that solutions containing varying concentrations of glucose can provide a mid-infrared dose response. A hydrophilic polyethylene membrane from Millipore Corporation was saturated with 2000 mg / dL and a lower concentration glucose solution. A series of curves generated in this experiment is shown in FIG. For this plot, the following equation was used: Absorption = −ln (sample spectrum / gold reference spectrum). When the glucose concentration was plotted against absorption at 9.75 microns, the plot shown in FIG. 6 was observed. These studies confirmed that glucose concentration can be measured in an aqueous environment in the mid-infrared wavelength range.

(Example 2)
(Experimental rabbit model)
(Ketamine anesthetized rabbit study)
As described in the scientific literature (Cameron et al., DIABETES TECH. THER., (1999) 1 (2): 135-143), rabbits anesthetized with ketamine are rapidly released due to the release of glucose from the liver. And experience a significant increase in blood glucose concentration. We confirmed this in a series of experiments and observed that rabbit blood glucose could change from about 125 mg / dL to about 325 mg / dL in 60 minutes as measured with an LXN ExpressView blood glucose meter. did. These experiments require a preliminary use of gas anesthesia (Isoflorane) prior to the use of ketamine. The rabbit was fixed after anesthesia so that the eyeball was available for measurement with SOC portable FTIR. Once the animal became unconscious, a drop of blood was drawn from the vein and tested on a blood glucose test strip using an LXN ExpressView blood glucose meter. Such samples were taken every 15 minutes throughout the study. The gas must be interrupted in order for this ketamine effect to manifest itself enough. Drying from the eye can be prevented by suturing the eyelids and using sutures to open the eye for measurement, and then closing them to moisten the eyeball after measuring them.

  Data from a rabbit study measuring glucose concentration from the sclera resulted in a regression coefficient (R-square) of 0.86, as shown in FIG.

(Example 3)
(Human clinical research)
Several studies have been conducted with non-diabetic and diabetic human volunteers. Prior to conducting these studies, it was confirmed that the infrared radiation used did not impose a health hazard.

  Several experiments with diabetic volunteers were conducted. Subjects were asked to adjust food intake and insulin administration to have the subject's glucose levels moving from about 100 to 300 mg / dL over a 3-4 hour time frame. During the study, every 10-15 minutes, patients took double fingerstick glucose measurements and were scanned with SOC 400 approximately every 15 minutes. Prior to collecting an infrared scan, the instrument operator attempted to align the SOC 400 with the subject's eye and collect the strongest signal reflected away from the eye.

(Human research using SOC diffusion detector)
Glucose tracking studies were performed using a diffusion detector for SOC400 (all previous experiments were performed using a reflectance detector). Glucose tracking studies were performed on diabetic volunteers and the results shown in FIG. 9 show that glucose concentration changes were clearly detected and measured using the instrument and method of the present invention.

(Example 4)
(How remote access can accept measured analyte concentration of a subject downloaded and stored in a computer system)
One aspect of the invention relates to a method for downloading and storing a measured analyte concentration in a subject (FIG. 5). Subjects first measure the analyte concentration from a body surface such as their eyes (100) so that the reflected mid-infrared radiation (150) is transmitted using a non-invasive instrument (200). Measured. The non-invasive instrument (200) further comprises a communication interface (250) that can connect (300) the non-invasive instrument (200) to the computer system (400) through the communication interface (250). The communication interface (250) is particularly adapted to communicate data from the instrument to the computer system (400). The computer system (400) includes a computer processor, a computer program implemented in the computer processor, and a similar communication interface (450). The analyte concentration measured from the non-invasive instrument (200) is downloaded to the computer system (400) via the communication interface (250). A remote access user (500) having a computer system with a similar communication interface (450) can retrieve the measured analyte concentration downloaded from the computer system (400). The communication interface (250, 450) may include, for example, serial, parallel, universal serial bus (USB), firewire, Ethernet, optical fiber, coaxial cable, and twisted pair cable. This information is used, for example, to provide data, alerts, advice or assistance to the patient or physician and to track the patient's progress throughout the course of the disease.

FIG. 1 (panel A) shows the conjunctiva and provides an illustration of the human eye in panel A. FIG. 1 (panel B) shows a high degree of angiogenesis in the conjunctiva, along with blood vessels (V) and small arteries (A). FIG. 2 provides a chart depicting the mid-infrared irradiation spectrum for glucose. FIG. 3 provides an illustration of one embodiment of the present invention, where the analyte concentration is measured from mid-infrared radiation reflected back from the eye. FIG. 4 provides an illustration of one embodiment of the present invention, where the analyte concentration is measured from mid-infrared radiation naturally emitted from the eye. FIG. 5 provides a flowchart of one embodiment of the present invention where a remote access user can accept a measured analyte concentration of a subject downloaded and stored in a computer system. Including methods. FIG. 6 provides a graph of a multiple dose response measurement using detection of varying concentrations of aqueous glucose solution using a polyethylene membrane as the measurement surface. FIG. 7 shows a plot of glucose concentration versus mid-infrared absorption using a polyethylene membrane as the measurement surface. FIG. 8 shows a plot of results obtained from mid-infrared measurements of glucose concentration using the rabbit eye from which measurements were taken as the surface. FIG. 9 shows a plot of human data obtained from the surface of the patient's eye, measured using mid-infrared absorption to determine the patient's blood glucose concentration. FIG. 5 shows a plot of data obtained from a human diabetic patient in a glucose tracking study showing the correlation of glucose concentration with mid-infrared absorption measured from the surface of the human eye.

Claims (57)

a. Using the subject's natural mid-infrared radiation, or exposing the subject's body surface to mid-infrared radiation;
b. Detecting mid-infrared radiation emitted or reflected from the body surface; and c. Determining a radiation distinguishing characteristic of the reflected mid-infrared radiation to determine an analyte concentration in the tissue of the subject. 2. The method of claim 1, wherein the method is non-invasive and the subject is a human. The analyte is a metabolite or metabolite, carbohydrate, sugar, glucose, protein, peptide, amino acid, fat, fatty acid, triglyceride, polysaccharide, alcohol, ethanol, toxin, hormone, vitamin, bacterial related substance, fungal related substance, virus Claim 1 or 2 selected from the group consisting of related substances, parasite related substances, pharmaceutical compounds, non-pharmaceutical compounds, prodrugs, drugs and any precursors, metabolites, degradation products and surrogate markers The method described. 4. The method according to any one of claims 1 to 3, wherein the analyte is glucose. The tissue is selected from the group consisting of skin, blood, body fluid, eye, tissue fluid, eye fluid, bone, muscle, epithelium, fat, hair, fascia, organ, cartilage, tendon, ligament, and mucous membrane. The method in any one of 1-4. 6. A method according to any preceding claim, wherein the mid-infrared irradiation of step a) is in a wavelength range ranging from about 2.5 microns to about 25.0 microns. The method according to claim 1, wherein the detecting step further includes selecting and detecting the mid-infrared irradiation. 8. A method according to any preceding claim, wherein the step of selecting the emitted or reflected mid-infrared radiation further comprises filtering the reflected mid-infrared radiation. The method according to claim 1, wherein the detecting step and the determining step further include using a microprocessor. 10. The method of any of claims 1-9, wherein the emitted or reflected mid-infrared radiation comprises a wavelength between about 2.5 microns and about 25.0 microns. 11. The method of any of claims 1-10, wherein the emitted or reflected mid-infrared radiation comprises a wavelength between about 2.5 microns and about 11.0 microns. a. Detecting naturally occurring mid-infrared radiation emanating from a subject using a non-invasive instrument comprising a mid-infrared detector;
b. Comparing the mid-infrared irradiation identification characteristic to the mid-infrared irradiation identification characteristic corresponding to the analyte concentration; and c. Analyzing the irradiation signature of the mid-infrared radiation from the subject to determine the concentration of the analyte in the tissue of the subject. The analyte is a metabolite or metabolite, carbohydrate, sugar, glucose, protein, peptide, amino acid, fat, fatty acid, triglyceride, polysaccharide, alcohol, ethanol, toxin, hormone, vitamin, bacterial related substance, fungal related substance, virus 13. The substance of claim 12, selected from the group consisting of related substances, parasite related substances, pharmaceutical compounds, non-pharmaceutical compounds, prodrugs, drugs, and any precursors, metabolites, degradation products and surrogate markers. Method. 14. A method according to claim 12 or 13, wherein the analyte is glucose. The tissue is selected from the group consisting of skin, blood, body fluid, eye, tissue fluid, eye fluid, bone, muscle, epithelium, fat, hair, fascia, organ, cartilage, tendon, ligament, and mucous membrane. The method in any one of 12-14. The method according to claim 12, wherein the tissue is blood. 17. The method of any of claims 12-16, wherein the naturally occurring mid-infrared radiation comprises infrared radiation having a wavelength between about 2.5 microns and about 25.0 microns. The method according to any of claims 12 to 17, wherein the detecting step further comprises selecting and detecting the desired wavelength of the naturally occurring mid-infrared ray. The method according to claim 12, wherein the comparing step and the analyzing step further include using a microprocessor. a. An irradiation source capable of producing mid-infrared radiation;
b. A mid-infrared radiation wavelength detector for detecting the generated mid-infrared radiation reflected from the surface of the patient's body; and c. An instrument comprising an alphanumeric or acoustic display of analyte concentration in the subject's tissue. A microprocessor for analyzing the wavelength to correlate the detected mid-infrared radiation having a wavelength corresponding to the analyte concentration to the analyte concentration and calculating the analyte concentration in the tissue; 21. The instrument of claim 20, comprising. The instrument of claim 20 or 21, wherein the mid-infrared radiation detector is selected from the group consisting of a thermocouple, a thermistor, a microbolometer, and a liquid nitrogen cooled MTC. The instrument according to any one of claims 20 to 22, wherein the mid-infrared radiation wavelength detector further comprises a mid-infrared radiation selector. 24. The instrument of claim 23, wherein the selector is selected from the group consisting of absorption filters, interference filters, monochromators, linear and annular variable filters, and prisms. 25. A device according to any of claims 20 to 24, wherein the display is an alphanumeric display selected from the group consisting of a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED). 26. An instrument according to any one of claims 20 to 25, wherein the display is an acoustic display comprising a speaker. 27. The instrument of claim 26, wherein the acoustic display comprises an acoustic source selected from the group consisting of recorded acoustic clips, speech synthesizers, and speech emulation algorithms. 28. An instrument according to any one of claims 20 to 27, wherein the instrument further comprises an infrared spectrometer. 29. The instrument of any of claims 20-28, wherein the microprocessor further comprises a memory operably coupled to the microprocessor. The instrument further comprises a communication interface, wherein the interface is selected from the group consisting of serial, parallel, USB (Universal Serial Bus), firewire, Ethernet, optical fiber, coaxial cable, and twisted pair cable. 30. A device according to any one of claims 20 to 29. a. A source of mid-infrared radiation within a range of about 2.5 to about 25.0 microns; and b. An instrument comprising a mid-infrared radiation detector for detecting said mid-infrared radiation transmitted through a subject in a wavelength range between about 8.0 and about 11.0 microns. A microprocessor for correlating the transmitted mid-infrared radiation with an irradiation identification characteristic corresponding to the analyte concentration and for analyzing the irradiation identification characteristic to calculate an analyte concentration in the tissue of the subject; 32. The instrument of claim 31, further comprising. 33. The instrument of claim 31 or 32, wherein the mid-infrared irradiation detector is selected from the group consisting of a thermocouple, thermistor, microbolometer, and liquid nitrogen cooled MTC. The instrument according to any of claims 31 to 33, wherein the mid-infrared radiation wavelength detector further comprises a mid-infrared radiation selector. 35. The instrument of claim 34, wherein the selector further comprises a filter selected from the group consisting of an absorption filter, an interference filter, a monochromator, a linear variable filter and an annular variable filter, and a prism. 36. The apparatus of any of claims 31-35, further comprising a display selected from the group consisting of a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED). 38. The instrument of claim 36, wherein the display is an acoustic display comprising speakers. 38. The instrument of claim 37, wherein the acoustic display comprises an acoustic source selected from the group consisting of recorded acoustic clips, speech synthesizers, and speech emulation algorithms. 39. The instrument according to any of claims 31 to 38, wherein the instrument further comprises an infrared spectrometer. 40. The instrument of any of claims 31-39, wherein the microprocessor further comprises a memory operably coupled to the microprocessor. 41. The instrument of any of claims 31-40, wherein the instrument further comprises a communication interface adapted to communicate data from the instrument to a computer system. The interface is selected from the group consisting of standard input / output, serial cable, parallel cable, USB (Universal Serial Bus), fire wire, network card, optical fiber, wireless, coaxial cable, and twisted pair cable. 41. Apparatus according to 41. A computer system for downloading and storing data collected from an instrument according to claim 20 or 31 comprising:
a. Computer processor;
b. A memory operably coupled to the computer processor;
c. A communication interface adapted to receive and transmit data within the computer processor; and d. A computer system comprising a computer program stored in the memory that is implemented in the computer processor. A method for downloading and storing a measured analyte concentration of a subject comprising:
a. 32. Measuring the analyte concentration using a non-invasive instrument according to claim 20 or 31 having a communication interface;
b. Connecting the non-invasive instrument through the communication interface to a computer system having a computer processor, a computer program implemented in the computer processor, and a similar communication interface; and c. Downloading the measured analyte concentration from the non-invasive instrument to the computer system. a. Exposing at least a portion of the conjunctival surface of the subject to electromagnetic radiation;
b. Detecting electromagnetic radiation reflected from the conjunctiva; and c. Determining a radiation distinguishing characteristic of the reflected electromagnetic radiation to determine an analyte concentration in the tissue of the subject. 46. The method of claim 45, wherein the method is non-invasive and the subject is a human. The analyte is a metabolite or metabolite, carbohydrate, sugar, glucose, protein, peptide, amino acid, fat, fatty acid, triglyceride, polysaccharide, alcohol, ethanol, toxin, hormone, vitamin, bacterial related substance, fungal related substance, virus 47. In claim 45 or 46, selected from the group consisting of related substances, parasite related substances, pharmaceutical compounds, non-pharmaceutical compounds, prodrugs, drugs, and any precursors, metabolites, degradation products and surrogate markers The method described. 48. A method according to any of claims 45 to 47, wherein the analyte is glucose. 49. A method according to any of claims 45 to 48, wherein the electromagnetic radiation is mid-infrared radiation. 50. The method of claim 49, wherein the mid-infrared radiation is in the wavelength range of about 2.5 microns to about 25.0 microns. 51. A method according to any of claims 45 to 50, wherein the detecting step further comprises selecting at least one wavelength within the reflected electromagnetic radiation. 52. The method of claim 51, wherein selecting the reflected electromagnetic radiation includes filtering the reflected electromagnetic radiation. 53. A method according to any of claims 45 to 52, wherein the determining step further comprises using a microprocessor. 54. The method of any of claims 45-53, wherein the reflected electromagnetic radiation comprises infrared radiation having a wavelength range between about 2.5 microns and about 25.0 microns. 55. The method of claim 54, wherein the reflected electromagnetic radiation is in a wavelength range between about 2.5 microns and about 11.0 microns. A computer system for downloading and storing data collected according to claim 45 comprising:
a. Computer processor;
b. A memory operably coupled to the computer processor;
c. A communication interface adapted to receive and transmit data within the computer processor; and d. A computer system comprising a computer program stored in the memory that is implemented in the computer processor. A method for downloading and storing a measured analyte concentration of a subject comprising:
a. 46. Measuring the analyte concentration using the non-invasive instrument of claim 45 having a communication interface;
b. Connecting the non-invasive instrument through the communication interface to a computer system having a computer processor, a computer program implemented in the computer processor, and a similar communication interface; and c. Downloading the measured analyte concentration from the non-invasive instrument to the computer system.

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