Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes

Definitions

• the present invention is related to optical non-invasive methods and instruments to detect the presence or measure the concentration of a wide range of analytes, such as glucose, in the tissue of a subject.
• the spectra of mid-infrared radiation emitted from the subject's body are altered corresponding to the presence, absence or concentration of the analyte within the subject's tissue, one aspect of the present invention, the instrument floods a surface of the subject's body, such as the skin or eye, any orifice, piercing tract or cavity such as the mouth, ear or nose, with light in the mid-infrared range and determines an analyte's presence, absence or concentration based on said analyte's distinctive mid- infrared radiation signature reflected back to the instrument.
• an instrument measures the level of mid-infrared radiation from a surface of the subject's body, including but not limited to mid-infrared radiation emitted from any body surface, such as the skin or the eye, any orifice, piercing tract, or cavity, such as the mouth, ear or nose, and determines a specific analyte's presence or concentration based on said analyte's distinctive mid-infrared radiation signature.
• the present invention is related to non-invasive methods to detect the presence or measure the concentration of a wide range of analytes, such as glucose, in the conjunctiva of a subject.
• the spectra of mid-infrared radiation emitted or reflected from the subject's conjunctiva are altered corresponding to the presence, absence or concentration of the analyte within the subject's conjunctiva.
• the conjunctiva of the subject's eye is utilized as a source of an optical signal to determine an analyte's presence, absence or concentration based on said analyte's distinctive spectral characteristics detected by an instrument capable of detecting the optical signal.
• 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 a surface of a subject's body.
• Diabetes remains one of the most serious and under-treated diseases facing the worldwide healthcare system. Diabetes is a chronic disease where the body fails to maintain normal levels of glucose in the bloodstream. It is now the fifth leading.cause of death from disease in the U.S. today and accounts for about 15% of the entire healthcare budget. People with diabetes are classified into two groups: Type 1 (formerly known as “juvenile onset” or “insulin dependent” diabetes, that are required to take insulin to maintain life) and Type 2 (formerly known as "adult onset” or “non-insulin dependent,” that may require insulin but may sometimes be treated by diet and oral hypoglycemic drugs). In both cases, without dedicated and regular blood glucose measurement, all patients face the possibility of the complications of diabetes that include cardiovascular disease, kidney failure, blindness, amputation of limbs and premature death.
• SMBG Blood Glucose
• a preferred embodiment of the present invention seeks to replace the currently used blood glucose measurement methods, devices and instruments, including invasive measures and the use of glucose test strips, with an optical non-invasive instrument.
• U.S. Patent No. 5,086,229 (the '229 patent) is directed to an instrument which generates near-infrared radiation within the spectrum of about 600 to about 1100 nanometers.
• a person places their finger in between the generated near-infrared radiation source and a detector, which correlates the blood-glucose concentration based on the detected near-infrared radiation.
• U.S. Patent No. 5,321,265 (the '265 patent) also measures blood-glucose level using both near-infrared radiation and the fingertip as a testing site.
• the detectors disclosed in the '265 patent further comprise silicon photocells and broad bandpass filters.
• U.S. Patent No. 5,361,758 (the '758 patent) is directed to an instrument which measures near-infrared radiation that is either transmitted through or is reflected from the finger or earlobe of a human.
• the transmitted or reflected light is separated by a grating or prism, and the near-infrared radiation is detected and correlated with blood-glucose concentration.
• This instrument of the '758 patent also comprises an additional timing and control program wherein the device takes measurements specifically in between heartbeats and can also adjust for temperature.
• U.S. Patent No. 5,910,109 (the '109 patent) is also directed to an instrument for measuring blood-glucose concentration using near-infrared radiation and the earlobe as the testing site.
• the instrument of the '109 patent comprises four light sources of a very specific near-infrared emission spectrum, and four detectors having specific near-infrared detection spectra corresponding to the wavelength of the light sources. The signals detected by the four distinct detectors are averaged, and these averages are analyzed to determine blood-glucose concentration according to the '109 patent.
• U.S. Patent No. 6,362,144 discloses using the fingertip as a testing site, however, the described instrument uses attenuated total reflection (ATR) infrared spectroscopy.
• ATR attenuated total reflection
• a selected skin surface preferably the finger
• the skin is then irradiated with a mid-infrared beam, wherein said infrared radiation is detected and quantified to measure blood-glucose levels.
• the minimal depth of peripheral capillaries in epithelial tissues is typically about 40 microns. Again, there are physical characteristics as well as a number of substances present in the skin that can interfere with the desired glucose-specific signal. While useful in the laboratory, both the near-infrared transmission methods, and the ATR method mentioned above are not practical, or may not be adequate for use in monitoring blood glucose concentration in patients.
• the measurement of optical absorption is possible whereas measurement of the optical rotation through the aqueous humor is not possible.
• the intensity of the diffusely reflected light may be analyzed to obtain useful information on the optical properties of the aqueous humor, including blood-glucose concentration.
• U.S. Patent No. 5,687,721 also discloses a method of measuring blood-glucose concentration by generating both a measurement and reference polarized light beam, and comparing said beams to determine the angle of rotation, which is attributable to the blood-glucose concentration.
• the preferable testing site disclosed, however, is the 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 a light source.
• U.S. Patent No. 5,788,632 discloses a non-invasive instrument for determining blood-glucose concentration by transmitting a first beam of light through a first polarizer and a first retarder, then directing the light through the sample to be measured, transmitting the light through a second polarizer or retarder, and lastly detecting the light from the second detector. The rotation of measured polarized light is correlated to the blood-glucose concentration of the sample measured according to the '632 patent.
• U.S. Patent No. 5,433,197 discloses a non-invasive instrument for determining blood-glucose concentration using a broad-band of near-infrared radiation which illuminates the eye in such a manner that the energy passes through the aqueous humor in the anterior chamber of the eye and is then reflected from the iris. The reflected energy then passes back through the aqueous humor and the cornea and is collected for spectral analysis.
• the electrical signals representative of the reflected energy are analyzed by univariate and/or multivariate signal processing techniques to correct for any errors in the glucose determination. Again, the accuracy of the instrument in the '197 patent is limited because glucose simply lacks a sufficiently distinguishable "fingerprint" in this near-infrared radiation spectrum.
• 5,666,956 discloses an instrument which measures electromagnetic radiation from the tympanic membrane and computes monochromatic emissivity using Plank's law by measuring the radiation intensity, spectral distribution, and blackbody temperature.
• the resultant monochromatic emissivity is variable depending on the spectral characteristics of the site measured, namely the blood-glucose concentration measured from the tympanic membrane. It should be noted, however, that the '956 patent equates skin surfaces of the body to a "gray-body” rather than a black-body with respect to its monochromatic emissivity.
• the accuracy of such skin surface-based methods utilizing natural black-body emitted radiation is not useful for analyte measurements, as compared to a method of subsurface analysis utilizing natural black-body radiation emitted from the tympanic membrane.
• the human body naturally emits from its surfaces infrared radiation whose spectrum, or radiation signature, is modified by the presence, absence or concentration of analytes in the body tissues.
• the eye is particularly well suited as a testing site to detect this infrared radiation.
• certain analytes such as glucose, exhibit a minimal time delay in glucose concentration changes between the eye and the blood, and the eye provides a body surface with few interferences.
• the present invention is related to non-invasive methods and instruments to detect the presence of an analyte, or the level of analyte concentrations, in the tissue of a subject either by flooding a body surface with infrared radiation and measuring the reflected infrared radiation or by using the subject's natural black-body radiation and analyzing the emitted radiation to determine the analyte concentration.
• the instruments and methods of the present invention do not require direct contact of the instrument with a surface of a subject's body in order to make the analyte measurements.
• a body surface that is particularly well suited for such measurements is the conjunctiva.
• the conjunctiva covers the exposed surface of the eye, with the exception of the cornea.
• the conjunctiva is a clear, thin layer of tissue that lies over the white part of the eye and also lines the inside of the eyelids.
• the conjunctiva helps keep the eyelids and eyeball moist, and has other functions important for the eye.
• the conjunctiva is highly vascularized, and the interstitial fluid contained within the conjunctiva has been found to provide an excellent site for the non-invasive measurement of blood or tissue analytes, including glucose.
• Non-invasive methods of the present invention include, but are not limited to, electromagnetic radiation and any other optical signal measurement.
• the analyte that is actually measured or detected may be any compound or substance that has a radiation signature in the mid-infrared range.
• the methods and instrument of the present invention may also be used to detect the presence, absence or concentration of any compound or substance that represents a surrogate marker for or has a correlation to the presence, absence, or concentration of another analyte of interest, including but not limited to any metabolite or degradation product of an analyte, or an upstream or downstream pathway component or product that is affected by an analyte of interest.
• the analyte that is actually measured is a surrogate marker for another analyte of interest.
• the methods and instrument of the present invention may also be utilized to detect the presence, absence or concentration of analytes in air that has been contacted with or exhaled by a subject.
• airborne analytes may be, for example, any volatile compound or substance including but not limited to ketones, beta hydroxybutyrate, or alcohols.
• Another embodiment of the present invention relates to a method for measuring an analyte concentration in a tissue of a subject which may comprise exposing the eye of the subject to mid-infrared radiation, determining the reflected mid-infrared radiation spectrum and determining the analyte concentration in the tissue.
• the subject being tested may be a mammal, and preferably the subject is a human.
• the analyte concentration being measured may be any analyte having a detectable radiation signature.
• the analyte concentration being measured is glucose concentration.
• the analyte concentration may be measured for a wide variety of tissues of a subj ect' s body.
• the present invention relates to an instrument which measures the level of mid-infrared radiation from a surface of a subject's body and determines a specific analyte's concentration based on the analyte's distinctive mid- infrared radiation signature.
• the instrument in this embodiment may optionally further comprise a light source capable of generating mid-infrared radiation and a mid-infrared radiation detector.
• the instrument may also comprise a microprocessor and a display.
• the instrument comprises a light source which may be any suitable mid-infrared light source, including, but not limited to, broad band or narrow band light emitting diodes, a Nernst glower, a NiChrome wire, and a Globar.
• the instrument may also comprise a wavelength selector which may further comprise a filter of any suitable type, including but not limited to, an absorption filter, interference filter, monochro ator, linear variable filter, circular variable filter, and a prism,
• the instrument may also comprise a mid- infrared light detector, which may be any suitable type, including, but not limited to a thermocouple, a thermistor, a microbolometer, and a liquid nitrogen cooled MTC.
• the present invention relates to an instrument which floods a surface of a subject's body with light comprising light in the mid-infrared range and measures analyte concentrations based on a mid-infrared radiation signature of the analyte reflected back to the instrument.
• the instrument further comprises a light source capable of generating mid-infrared radiation having wavelengths in the range of about 2.5 microns to about 25.0 microns, a mid-infrared radiation detector capable of detecting mid-infrared radiation having wavelengths in the range of about 8.0 microns to about 11.0 microns, and optionally comprising a microprocessor, and a display, hi one embodiment, the instrument further comprises a light source which may be any suitable mid-infrared producing light source, including, but not limited to, broad band or narrow band light emitting diodes, a Nernst glower, a NiChrome wire, and a Globar.
• a light source capable of generating mid-infrared radiation having wavelengths in the range of about 2.5 microns to about 25.0 microns
• a mid-infrared radiation detector capable of detecting mid-infrared radiation having wavelengths in the range of about 8.0 microns to about 11.0 microns
• the instrument further comprises a light
• the instrument of this embodiment may optionally further comprise a selector which itself may further comprise a suitable wavelength filter, including, but not limited to, an absorption filter, interference filter, monochromator, linear variable filter, circular variable filter, and a prism.
• a suitable mid- infrared light detector including, but not limited to, a thermocouple, a thermistor, a microbolometer, and a liquid nitrogen cooled MTC.
• the instrument may comprise a display, such as an alphanumeric display, including, but not limited to, a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED), h another embodiment of the present invention, the instrument comprises an audio display which may be provided with an audio source comprising recorded audio clips, speech synthesizers and voice emulation algorithms to audibly report the analyte concentration.
• a display such as an alphanumeric display, including, but not limited to, a liquid crystal display (LCD), a plasma display panel (PDP), and a field emission display (FED)
• the instrument comprises an audio display which may be provided with an audio source comprising recorded audio clips, speech synthesizers and voice emulation algorithms to audibly report the analyte concentration.
• the instrument of the present invention comprises a microprocessor and a memory which is operatively linked to the microprocessor.
• the instrument of this embodiment may also further comprise a communications interface adapted to transmit data from the instrument to a computer system, hi this embodiment, the communications interface selected may be any suitable interface, including, but not limited to, a serial, parallel, universal serial bus (USB), FireWire, Ethernet, fiber optic, co- axial, and twisted pair cables.
• USB universal serial bus
• the present invention relates to a computer system for downloading and storing measured analyte concentrations.
• This embodiment may further comprise a computer processor, a memory which is operatively linked to the computer processor, a communications interface adapted to receive and send data within the computer processor, and a computer program stored in the memory which executes in the computer processor.
• the computer processor of this embodiment further comprises a database, wherein data received by the processor may be stored on the memory as a database, and sorted into predetermined fields, and the database may be capable of graphical representations of the downloaded analyte concentrations.
• the graphical representations of this embodiment may include, but are not limited to, column, line, bar, pie, XY scatter, area, radar, and surface representations.
• the present invention relates to a computer interface which is further adapted to transmit data for analyte concentrations to a remote computer processor or user.
• a remote user may be physicians, research institutes, specialists, nurses, hospice service providers, insurance carriers, and health care providers.
• the present invention relates to a method or system for downloading and storing a subject's analyte concentrations which may comprise measuring the analyte concentration using a non-invasive instrument having a communications interface, connecting the non-invasive instrument through the communications interface to a computer system having a computer processor, a computer program which executes in the computer processor, and an analogous communications interface, and downloading the measured analyte concentrations from the non-invasive instrument to the computer system.
• the communications interface of this embodiment further comprises a communications interface adapted to transmit data from the instrument to a computer system.
• the communications interface may include, for example, serial, parallel, universal serial bus (USB), FireWire, Ethernet, fiber optic, co-axial, and twisted pair cables.
• FIG. 1 Panels A and B: Provides a graphical illustration of the human eye in Panel A showing the conjunctiva.
• Panel B shows the high degree of vascularization in the conjunctiva, with veins (V) and arterioles (A).
• Figure 2 Provides a chart that depicts the mid-infrared radiation spectral fingerprint for glucose.
• Figure 3 Provides a graphical illustration of one embodiment of the present invention, wherein analyte concentration is measured from the mid- infrared radiation reflected back from the eye.
• Figure 4 Provides a graphical illustration of one embodiment of the present invention, wherein analyte concentration is measured from the mid- infrared radiation naturally emitted from the eye.
• Figure 5 Provides a flowchart of one embodiment of the present invention, comprising a method wherein a remote access user can receive a subject's measured analyte concentrations which have been downloaded and stored in a computer system.
• Figure 6 Provides a graph of multiple dose response measurements using detection of varying concentrations of aqueous glucose solutions using polyethylene membranes as the measurement surface.
• Figure 7 Shows a plot of the glucose concentration versus mid- infrared absorption using polyethylene membranes as the measurement surface
• Figure 8 Shows a plot of the results obtained from mid-infrared measurements of glucose concentration using rabbit eye as the surface from which the measurements were made.
• Figure 9 Shows a plot of human data obtained from the surface of the patient's eye measured using mid-infrared absorption to determine blood glucose concentration of the patient.
• Figure 10 Shows a plot of the data obtained from a human diabetic patient in a glucose tracking study demonstrating a correlation of glucose concentration with mid-infrared absorption measured from the human eye surface.
• Analyte As used herein describes any particular substance to be measured. Analyte may also include any substance in the tissue of a subject, or is present in air that was in contact with or exhaled by a subject, which demonstrates and infrared radiation signature.
• analytes include, but are not limited to, metabolic compounds or substances, carbohydrates such as sugars including glucose, ⁇ proteins, peptides, or amino acids, fats or fatty acids, triglycerides, polysaccharides, alcohols including ethanol, toxins, hormones, vitamins, bacteria-related substances, fungus-related substances, virus-related substances, parasite-related substances, pharmaceutical or non-pharmaceutical compounds, substances, pro-drugs or drugs, and any precursor, metabolite, degradation product or surrogate marker of any of the foregoing.
• Analyte may also include any substance which is foreign to or not normally present in the body of the subject.
• Conjunctiva As used herein describes the membranous tissue that covers the exposed surface of the eye and the inner surface of the eyelids.
• Far-Infrared Radiation As used herein refers to any radiation, either generated from any source or naturally emitted, having wavelengths of about 50.00 to about 1000.00 microns.
• Flooding As used herein refers to broadly applying relatively widely diffused or spread-out rays of light onto a surface.
• Focused As used herein means mostly parallel rays of light that are caused to converge on a specific predetermined point.
• Infrared Radiation refers to any radiation, either generated from any source or naturally emitted, having wavelengths of about 0.78 to about 1000.00 microns.
• Mid-Infrared Radiation refers to any radiation, either generated from any source or naturally emitted, having wavelengths of about 2.50 microns to about 50.00 microns.
• Mid-Infrared Radiation Detector refers to any detector or sensor capable of registering infrared radiation.
• suitable infrared radiation detectors include but are not limited to, a thermocouple, a thermistor, a microbolometer, and a liquid nitrogen cooled MTC.
• the combined detected infrared radiation may be correlated with wavelengths corresponding to analyte concentrations using means such as the Fourier transform to produce high resolution spectra.
• Near-Infrared Radiation refers to any radiation, either generated or naturally emitted, having wavelengths of about 0.78 to about 2.50 microns.
• Surface refers to any part of a subject's body that may be exposed to the external environment, including but not limited to, skin, the eye, ear, mouth, nose or any other orifice, body cavities, piercing tracts or other surface whether naturally occurring or artificial such as a surgically created surface.
• Tissue includes any tissue or component of a subject, including, but not limited to, skin, blood, body fluids, the eye, the tear layer of the eye, interstitial fluid, ocular fluid, bone, muscle, epithelium, fat, hair, fascia, organs, cartilage, tendons, ligaments, and any mucous membrane.
• mid-infrared radiation is flooded onto a body surface using a radiation source.
• This flooded mid-infrared radiation is reflected from the body surface to a detector.
• the reflected radiation is detected by a mid-infrared detection instrument placed before the body surface.
• the radiation signature of the reflected mid-infrared radiation is affected by the presence or concentration of analytes.
• This provides a non-invasive method employing an instrument of the present invention to measure analyte presence, absence or concentration, such as glucose, from any body surface, including the eye, of a subject ( Figure 3).
• human beings are natural emitters or radiators of energy in the mid-infrared radiation spectrum.
• the body acts as its own light (or heat) source, providing the mid-infrared radiation signature of the analytes present therein, hi this aspect, and with respect to the surfaces of a subject's body, light (or heat) from the body is emitted or radiated from a body surface, and is detected by a mid-infrared detection instrument.
• the mid-infrared radiation signature in the body's mid-infrared radiation emission is affected by the presence, absence or concentration of analytes, such as glucose, in the tissues of a subject.
• the natural mid-infrared radiation signature of glucose contained within the body's natural mid-infrared radiation signature provides the basis for a non-invasive glucose measurement method and instruments for making such measurements (Figure 3).
• decreasing or increasing the concentration of certain analytes may cause an increase in the body's natural emission of infrared radiation.
• Such an increase in the body's natural infrared radiation emission may provide a measurable signal that may be utilized to measure the presence, absence or concentration of an analyte.
• the glucose in the eye is located throughout the various components and compartments of the eye, including, but not limited to, epithelial cells, the aqueous humor, the vitreous humor, various layers of the cornea, iris, various layers of the sclera, conjunctiva, tears, the tear layer, and blood vessels. Therefore, the eye, including, but not limited to, the tear layer, is both an ideal and suitable body surface for non-invasive measurement of the presence, absence or concentration of analytes in the tissue of a subject.
• Electromagnetic radiation is energy and hence when a molecule absorbs radiation it gains energy as it undergoes a quantum transition from one energy state
• the absorption of some amount of the radiation that is applied to a substance, or body surface containing substances, that absorbs radiation may result in a measurable decrease in the amount of radiation energy that actually passes through, or is affected by, the radiation absorbing substances.
• Such a decrease in the amount of radiation that passes through, or is affected by, the radiation absorbing substances may provide a measurable signal that may be utilized to measure the presence, absence or the concentration of an analyte.
• the human body emits electromagnetic radiation within the infrared radiation spectrum.
• the spectral characteristics of the infrared radiation emitted can be correlated with the properties of the emitting object, such as a subject's body surface. For example, glucose absorbs mid-infrared radiation at wavelengths between about 8.0 microns to about 11.0 microns. If mid-infrared radiation passes through or reflects from an object where glucose is present, a distinct radiation "fingerprint" or "signature” can be detected from the remaining light that is not absorbed, creating a radiation signature. The radiation signature created can both confirm the presence or absence of an analyte and indicate the concentration of an analyte.
• glucose is a radiation absorbing substance
• One embodiment of the present invention provides a method for non-invasively measuring the blood-analyte concentration in a subject comprising the steps of generating mid-infrared radiation which is flooded onto a body surface of the subject, detecting the reflected mid-infrared radiation, coreelating the spectral characteristics of the detected mid-infrared radiation with a radiation signature that corresponds to the analyte concentration, and analyzing the detected mid-infrared radiation signature to give an analyte concentration measurement.
• the method includes a filtering step before detection, by filtering the mid-infrared radiation reflected back from a body surface so that only wavelengths of about 8.00 microns to about 11.00 pass through the filter.
• the filtering step may be accomplished using absorption filters, interference filters, monochromators, linear or circular variable filters, prisms or any other functional equivalent known in the art.
• the detecting step may be accomplished using any mid-infrared radiation sensor such as a thermocouple, thermistor, microbolometer, liquid nitrogen cooled MTC, or any other functional equivalent known in the art.
• Correlating the spectral characteristics of the detected mid-infrared radiation may comprise the use of a microprocessor to correlate the detected mid-infrared radiation signature with a radiation signature of an analyte. If the analyte being measured is glucose, then the radiation signature generated may be within the wavelength range within about 8.0 to about 11.0 microns.
• the analyzing step further comprises a microprocessor using algorithms based on Plank's law to conelate the absorption spectrum with a glucose concentration, i another embodiment of the present invention, the analyzing step may comprise the use of a transform, such as, but not limited to, Kramers-Kronig transform or other classical transform known in the art, to transform the detected mid-infrared signal to the analyte spectra for conelation.
• a transform such as, but not limited to, Kramers-Kronig transform or other classical transform known in the art
• an instrument comprising a mid-infrared radiation detector and a display may be held up to a body surface of a subject.
• the infrared radiation from the body surface may optionally be filtered so that only wavelengths of about 8.0 microns to about 11.0 microns reach the mid-infrared radiation detector.
• the radiation signature of the mid-infrared radiation detected by the detector may then be conelated with a radiation signature that corresponds to a glucose concentration.
• the radiation signature may then be analyzed to give an accurate glucose concentration measurement.
• the measured glucose concentration may be displayed.
• an instrument comprising a mid- infrared radiation generator, a mid-infrared radiation detector and a display may be held up to a body surface of a subject.
• Mid-infrared radiation may be generated by the instrument and used for flooding or alternatively aiming a focused beam onto a body surface of a subject.
• the mid-infrared radiation generated may be broad band or narrow band radiation, and may also be filtered to allow only desired wavelengths of radiation to reach the body surface. Any analyte, such as glucose, present in any constituent of the body surface may absorb some of the generated radiation.
• the mid-infrared radiation that is not absorbed may be reflected back to the instrument.
• the reflected mid-infrared radiation may optionally be filtered so that only wavelengths of about 8.0 microns to about 11.0 microns reach the mid-infrared radiation detector.
• the radiation signature of the mid-infrared radiation detected by the detector may then be correlated with a radiation signature that corresponds to analyte, such as glucose, concentration.
• the radiation signature may be analyzed to give analyte, such as glucose, concentration.
• the measured analyte, such as glucose, concentration may be displayed by the instrument.
• Infrared radiation may be generated by the instrument of the present invention. Such infrared radiation may be generated by a narrow band wavelength generator or a broad band wavelength generator.
• an instrument may comprise a mid-infrared radiation generator.
• the instrument comprises a light source with one or more filters to restrict the wavelengths of the light reaching the body surface.
• the mid-infrared generator may further comprise a heating element.
• the heating element of this embodiment may be a Nernst glower (zirconium oxide/yttrium oxides), a NiChrome wire (nickel-chromium wire), and a Globar (silicon-carbon rod), narrow band or broad band light emitting diodes, or any other functional equivalent known in the art.
• Mid-infrared radiation has wavelengths in the range of about 2.5 microns to about 50.0 microns. Analytes typically have a characteristic "fingerprint” or "signature" with respect to its mid-infrared radiation spectrum that results from the analyte's affect on the mid-infrared radiation, such as absorption.
• Glucose in particular has a distinct spectral "fingerprint” or "signature” in the mid-infrared radiation spectrum, at wavelengths between about 8.0 microns to about 11.0 microns.
• This radiation signature of glucose may be readily generated for a wide variety of glucose concentrations utilizing a wide variety of body surfaces for taking radiation signature data.
• an instrument may comprise a mid-infrared radiation filter, for filtering out all mid- infrared radiation not within a range of wavelengths from about 8.0 to about 11.0 microns, h other embodiments the filter is selected to filter out all mid-infrared radiation other than other than the wavelengths that provide the radiation signature of the desired analyte, such as glucose.
• the instrument of the present invention may also comprise a mid-infrared radiation detector for detecting mid-infrared radiation.
• the mid-infrared radiation detector can measure the naturally emitted or reflected mid-infrared radiation in any form, including in the form of heat energy. Detecting the naturally emitted or reflected mid-infrared radiation may be accomplished using thermocouples, thermistors, microbolometers, liquid nitrogen cooled MTC, or any other functional equivalent known in the art. Both thermocouples and thermistors are well known in the art and are commercially available.
• thermocouples are commonly used temperature sensors because they are relatively inexpensive, interchangeable, have standard connectors and can measure a wide range of temperatures, hi addition,
• Thermometrics product portfolio comprises a wide range of thermistors (thermally sensitive resistors) which have, according to type, a negative (NTC), or positive (PTC) resistance/temperature coefficient.
• NTC negative
• PTC positive
• the instrument of the present invention may also comprise a microprocessor.
• the microprocessor of this embodiment correlates the detected mid-infrared radiation with a radiation signature whose spectral characteristics provide information to the microprocessor about the analyte concentration being measured.
• the microprocessor of this embodiment analyzes the resultant radiation signature using algorithms based on Plank's law to translate the radiation signature into an accurate analyte concentration measurement in the sample being measured.
• a broad band light source may be modulated by an interferometer, such as in Fourier transform spectroscopy, or by an electro-optical or moving mask, as in Hadamard transform spectroscopy, to encode wavelength information in the time domain.
• a discrete wavelength band may be selected and scanned in center wavelength using, for example, an acousto-optical tuned filter.
• the instrument of the present invention having a radiation source comprises one or more mid- infrared radiation sources, which provide radiation at many wavelengths, and also comprises one or more mid-infrared radiation detector.
• the instrument may further comprise one or more filter or wavelength selector to remove, distinguish or select radiation of a desired wavelength, before or after detection by the detector.
• the instrument may also comprise an alphanumeric display for displaying the measured blood-glucose concentration.
• the alphanumeric display of this embodiment may comprise a visual display and an audio display.
• the visual display may 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 audio display capable of transmitting alphanumeric data and converting this alphanumeric data to an audio display, may be provided with an audio source comprising recorded audio clips, speech synthesizers and voice emulation algorithms or any other functional equivalent known in the art.
• an instrument for non-invasively measuring blood-glucose concentration further comprises a microprocessor and a memory which is operatively linked to the microprocessor for storing the blood glucose measurements.
• the instrument of this embodiment further comprises a communications interface adapted to transmit data from the instrument to a computer system.
• the communications interface selected may include, for example, serial, parallel, universal serial bus (USB), Fire Wire, Ethernet, fiber optic, co-axial, and twisted pair cables or any other functional equivalent known in the art.
• the present invention includes a computer system for downloading and storing these measurement data to facilitate storage and access to this information.
• the present invention further contemplates a computer processor, a memory which is operatively linked to the computer processor, a communications interface adapted to receive and send data within the computer processor, and a computer program stored in the memory which executes in the computer processor.
• the computer program of this embodiment further comprises a database, wherein data received by the database may be sorted into predetermined fields, and the database may be capable of graphical representations of the downloaded analyte concentrations.
• the graphical representations of this embodiment may include, but are not limited to, column, line, bar, pie, XY scatter, area, radar, and surface representations.
• the computer system contemplated by the present invention should be accessible to a remote access user via an analogous communications interface for use as a diagnostic, research, or other medically related tool.
• Physicians could logon to the computer system via their analogous communications interface and upload a patient's blood-glucose measurements over any period of time. This information could provide a physician with an accurate record to use as a patient monitoring or diagnostic tool such as, for example, adjusting medication levels or recommending dietary changes.
• Other remote access users contemplated may include research institutes, clinical trial centers, specialists, nurses, hospice service providers, insurance carriers, and any other health care provider.
• the present invention has demonstrated that glucose can be non-invasively measured using a mid-infrared signal from a body surface. Studies have been performed in a variety of systems, in vitro studies using glucose solutions on membrane samples, in vivo rabbit studies with varying blood glucose concentrations, and human studies with a diabetic human volunteer with varying blood glucose concentrations. These studies have used different types of infrared detector heads for taking the infrared measurements.
• mid-infrared radiation in the 8 to 12 micron wavelength range
• the inventors of the present invention have also found that mid-infrared radiation did penetrate the conjunctiva, and that glucose measurements obtained using mid-infrared radiation from the conjunctiva provided a dose response curve that conelated very well to blood glucose measurements using standard SMBG testing strips.
• the instrument used for the Mid-infrared measurements was the SOC 400 portable FTIR.
• the SOC 400 portable FTIR is based on an interferometer and was originally designed for the US Army to detect battlefield gases.
• This instrument has been modified to allow measurements on rabbit and human eyes. These modifications have included the installation of a filter to allow only energy in the 7 to 13 micron region to be measured and also the modification of the faceplate to permit easier placement of the instrument for rabbit and human studies.
• a glucose tracking study was performed using the diffuse detector for the SOC 400 (all previous experiments were performed using the Specular detector).
• a glucose tracking study was performed with a diabetic volunteer and the results shown in Figure 9 demonstrate that the glucose concentration changes were clearly detected and measured using an instrument and method of the present invention.
• One aspect of the present invention relates to a method of downloading and storing a subject's measured analyte concentrations (Figure 5).
• a subject first measures the analyte concentration from a body surface such as their eye (100), whereby reflected mid- infrared radiation (150) is measured using a non-invasive instrument (200).
• the non- invasive instrument (200) further comprises a communications interface (250) which is capable of connecting (300) the non-invasive instrument (200) through the communications interface (250) to a computer system (400).
• the communications interface (250) is specifically adapted to transmit data from the instrument to the computer system (400).
• the computer system (400) comprises a computer processor, a computer program which executes in the computer processor, and an analogous communications interface (450).
• the measured analyte concentrations from the non-invasive instrument (200) are downloaded via the communications interface (250) to the computer system (400).
• a remote access user (500), having a computer system with an analogous communications interface (450) is capable of retrieving the downloaded measured analyte concentrations from the computer system (400).
• the communications interfaces (250, 450) may include, for example, serial, parallel, universal serial bus (USB), FireWire, Ethernet, fiber optic, co-axial, and twisted pair cables. This information is used, for example, to provide data, warnings, advice or assistance to the patient or physician, and to track a patient's progress throughout the course of the disease.

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• 2004
  • 2004-04-27 WO PCT/US2004/012893 patent/WO2004099824A2/en active Application Filing
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  • 2004-04-27 EP EP04760590A patent/EP1622507A2/de not_active Withdrawn

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