WO2001022061A1 - Mesure non invasive du niveau de sucre dans le sang - Google Patents

Mesure non invasive du niveau de sucre dans le sang Download PDF

Info

Publication number
WO2001022061A1
WO2001022061A1 PCT/US2000/001698 US0001698W WO0122061A1 WO 2001022061 A1 WO2001022061 A1 WO 2001022061A1 US 0001698 W US0001698 W US 0001698W WO 0122061 A1 WO0122061 A1 WO 0122061A1
Authority
WO
WIPO (PCT)
Prior art keywords
value
article
manufacture
pixels
eye
Prior art date
Application number
PCT/US2000/001698
Other languages
English (en)
Inventor
Walter K. Proniewicz
Dale E. Winther
Original Assignee
Proniewicz Walter K
Winther Dale E
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1999/021680 external-priority patent/WO2000016692A1/fr
Application filed by Proniewicz Walter K, Winther Dale E filed Critical Proniewicz Walter K
Priority to KR1020027003472A priority Critical patent/KR20020070964A/ko
Priority to EP00909963A priority patent/EP1216409A1/fr
Priority to CA002390520A priority patent/CA2390520A1/fr
Priority to JP2001525185A priority patent/JP2003524153A/ja
Priority to AU32135/00A priority patent/AU3213500A/en
Publication of WO2001022061A1 publication Critical patent/WO2001022061A1/fr

Links

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
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/14—Arrangements specially adapted for eye photography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0004—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by the type of physiological signal transmitted
    • A61B5/0013—Medical image data
    • 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
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
    • G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
    • G16H40/63—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices for local operation
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems

Definitions

  • This invention relates generally to apparatus and systems for making noninvasive tests, assessments, or determinations of substances that may be part of a human being or other biological entity and, more particularly, to software implemented apparatus and systems that noninvasively test, assess, or determine the concentration, or other features of molecular or other substances in organic matter or fluids, such as blood, existing in human beings and other biological entities.
  • the invasive procedure typically involves physically withdrawing blood from the finger tips or ear lobes by using suitable lancing devices or withdrawing blood from veins by using suitable hypodermic syringes. Once withdrawn, the blood sample is then deposited within a suitable device which determines the level of blood glucose with a certain level of accuracy and reliability.
  • a suitable device which determines the level of blood glucose with a certain level of accuracy and reliability.
  • such devices have taken the form of hand-held monitors that human diabetics use to self-test their level of glucose.
  • the human diabetic withdraws his or her blood by a lancing device and deposits the withdrawn blood on an indicator strip that is inserted into the monitor.
  • the deposited blood is then analyzed and furnishes a reading of the level of glucose in the blood of the human diabetic.
  • wave data is manipulated.
  • wave data reflected from a biological entity is received and the reflected wave data is correlated to a substance in the biological entity.
  • the wave data may comprise light waves, and the biological entity may comprise a human being or blood.
  • a substance may comprise, for example, a molecule or ionic substance.
  • the molecule may be, for example, a glucose molecule.
  • the wave data is used to form a matrix of pixels with the received wave data.
  • the matrix of pixels may be modified by techniques of masking, stretching, or removing hot spots.
  • the pixels may be integrated to obtain an integration value that is correlated to a glucose level.
  • the correlation process may use a lookup table, which may be calibrated to a particular biological entity.
  • an amplitude and phase angle may be calculated for the reflected wave data and used to identify a glucose level in the biological entity.
  • the reflected wave data may be used to determine glaucoma pressure.
  • the glucose level may be displayed on a monitor attached to the computer.
  • the computer may be a portable, self-contained unit that comprises a data processing system and a wave reflection capture system.
  • the computer may be attached to a network of other computers, wherein the reflected wave data is received by the computer and forwarded to another computer in the network for processing.
  • a technique for noninvasively measuring glucose concentration is provided.
  • light waves reflected from an eye as pixels are received.
  • the pixels are integrated to form an integrated value.
  • the integrated value is correlated to a glucose level.
  • the pixels may be processed to identify a center of the eye, to calculate an average brightness around the pupil of the eye, to equalize the iris of the eye using the brightness around the pupil as a baseline, to mask the pupil of the eye, and/or to remove hot spots.
  • a technique for noninvasively measuring glucose concentration is provided.
  • light waves reflected from a biological entity are received.
  • An amplitude and a phase angle are calculated for the reflected light waves.
  • a glucose level is identified in the biological entity.
  • the biological entity may comprise, for example, an eye, skin, blood, or a nail bed.
  • the received light waves form a matrix comprised of pixels.
  • the amplitude is calculated by summing all of the pixels.
  • the phase angle is calculated by summing the rows of pixels of the matrix to obtain an xGRU value, summing the columns of pixels of the matrix to obtain a yGRU value, and calculating a ratio of the xGRU value and the yGRU value.
  • a true amplitude is calculated by subtracting a phase angle from a summation of pixels formed by the light waves.
  • the matrix of pixels may be processed to mask a portion of the matrix or by applying a filter to the reflected light waves. Furthermore, automatic level control is performed to modify the value of the pixels to obtain an average desired value. Automatic fine tuning is also performed.
  • FIG. 1 is a hardware environment used to implement an embodiment of the invention
  • FIG. 2 is a schematic illustration of the hardware environment of an embodiment of the present invention, and more particularly, illustrates a typical distributed computer system
  • FIG. 3 is a schematic diagram, in plan, of a CCD camera assembly used in one embodiment of the invention, and contemplated for adaptation into a commercial unit;
  • FIG. 4 is a block diagram showing the image input data stream derived from optoelectronic measurements of an eye, using the FIG. 3 camera assembly in a centralized illumination arrangement;
  • FIG. 5 is an isometric view of a representative illumination geometry, one of several variations, illustrating a diffuse-illumination approach
  • FIG. 6 is a perspective view of an optical bench, particularly including a foam ocular and a forehead rest;
  • FIG. 7 is a more detailed view shown in FIG. 6;
  • FIG. 8 is a perspective view of an early eye-tracking system
  • FIG. 9 is a perspective view of an early bezel for mounting at the front of the camera lens and for aiming a small light source toward the eye;
  • FIG. 10 is an enlarged view of the FIG. 9 bezel, shown with light source and eye, in longitudinal elevation generally along the system centerline;
  • FIG. 11 is an illustration of part of a representative control panel, seen on a computer screen while the system is imaging a subject eye and showing false light images;
  • FIG. 12 are representative histograms that are another part of the same control panel display, particularly showing histograms representing results of different processing stages within the program;
  • FIG. 13 is a display of a control panel associated with an average program and having controls used to correlate typical values with an actual concentration of patient blood glucose in conventional units;
  • FIG. 14 is a diagrammatic showing of focal-distance measurements that can be used to determine glaucoma pressure automatically with apparatus analogous to certain forms of the glucose-concentration measuring systems described herein;
  • FIG. 15 is a flow diagram illustrating the steps performed by the noninvasive measurement system in one embodiment of the invention.
  • FIG. 16 illustrates a control panel for one embodiment of the invention
  • FIG. 17 displays another control panel for one embodiment of the invention
  • FIG. 18 illustrates various Phase/ Amplitude lookup tables that have been calibrated for different settings
  • FIG. 19 displays histograms for Image A and Image B; and FIGS. 20A-20C are a flow diagram illustrating the steps performed by the noninvasive measurement system in one embodiment of the invention.
  • the present invention includes a noninvasive measurement system, method, apparatus, and article of manufacture (which will be referred to below as noninvasive measurement system), which obtains waves in the electromagnetic spectrum as input.
  • the electromagnetic spectrum comprises a broad spectrum of wavelengths and frequencies, including visible light, infrared and ultraviolet radiation, audio transmissions, and x-rays.
  • focus will be on light waves (visible and infrared); however, it will be appreciated that the invention encompasses other types of waves that provide information appropriate to the processing described below.
  • the received waves are reflected off of a biological entity (e.g., human or other animal or a substance from the biological entity).
  • the waves may be reflected off of an eye, skin, a nail, or a blood sample.
  • the waves are received with a wave reflection capture system (e.g., a camera).
  • the noninvasive measurement system processes the received waves and correlates the reflected waves to a substance in the biological entity.
  • the reflected waves are used to determine the concentration of glucose (i.e., commonly called blood sugar) that is found in the blood of a human being.
  • the noninvasive measurement system has numerous advantages and applications.
  • the noninvasive measurement system may be used to diagnose patients to determine whether they have diabetes.
  • the noninvasive measurement system may also be used as a preventive step to monitor blood glucose levels in an individual who, for example, has a history of diabetes in the family.
  • the noninvasive measurement system may also be used to monitor diabetics who need their blood glucose levels checked multiple times a day or multiple times a week, etc.
  • the noninvasive measurement system may also be linked with an insulin releasing system so that, when the noninvasive measurement system recognizes that insulin is needed, it can signal the insulin releasing system to release insulin.
  • the noninvasive measurement system may be used to obtain glaucoma pressure.
  • the noninvasive measurement system may also be used to locate tumors and to locate and correct blood clots.
  • the noninvasive measurement system may be used to detect breast cancer by processing light that penetrates through flesh and is reflected.
  • the noninvasive measurement system may process x-rays or other high energy particles, instead of light waves, with application to various technologies using x-rays and other high energy particles (e.g., medical technologies). Moreover, the noninvasive measurement system may process ultraviolet rays to highlight or detect different types of minerals or other substances, such as ethanol present in the blood. The noninvasive measurement system can distinguish between substances based on their rotation (e.g., a glucose molecule rotates in a clock-wise direction as its density increases, while, a fructose molecule rotates in a counter-clockwise direction).
  • the noninvasive measurement system effectively eliminates need for piercing the body or otherwise obtaining blood samples, and so avoids the discomfort, fear and other detriments of using a conventional one touch glucose monitor.
  • the noninvasive measurement system can be manufactured as a small unit or monitor that can fit, for example, in the palm of a hand, thus allowing for use at home, or at an office or other business , or in cars, restaurants, etc.
  • wave input is provided to a computer, which performs the processing of the input and displays a result on a monitor attached to the computer.
  • FIG. 1 is hardware environment used to implement an embodiment of the invention.
  • the present invention is typically implemented using a computer 100, which generally includes one or more processors 102, random access memory (RAM) 104, data storage devices 106 (e.g., hard, floppy, and/or CD-ROM disk drives, etc.), data communications devices 108 (e.g., modems, network interfaces, etc.), display devices 110 (e.g., CRT, LCD display, etc.), and input devices 112 (e.g., camera, video recorder, mouse pointing device, and keyboard).
  • RAM random access memory
  • data storage devices 106 e.g., hard, floppy, and/or CD-ROM disk drives, etc.
  • data communications devices 108 e.g., modems, network interfaces, etc.
  • display devices 110 e.g., CRT, LCD display, etc.
  • attached to the computer 100 may be other devices, such as read only memory (ROM), a video card, bus interface, printers, etc.
  • ROM read only memory
  • video card a video card
  • bus interface a bus interface
  • printers a printer
  • the computer 100 operates under the control of an operating system (OS) 114.
  • the operating system 114 is booted into the memory 104 of the computer 100 for execution when the computer 100 is powered-on or reset.
  • the operating system 114 controls the execution of one or more computer programs 116, such as a noninvasive measurement system 118 and a counter 120, by the computer 100.
  • the present invention is generally implemented in these computer programs 116, which execute under the control of the operating system 114 and cause the computer 100 to perform the desired functions as described herein.
  • the counter 120 may be part of the noninvasive measurement system.
  • the operating system 114 and computer programs 116 are comprised of instructions which, when read and executed by the computer 100, causes the computer 100 to perform the steps necessary to implement and/or use the present invention.
  • the operating system 114 and/or computer programs 116 are tangibly embodied in and/or readable from a device, carrier, or media, such as memory 104, data storage devices 106, and/or data communications devices 108.
  • the computer programs 116 may be loaded from the memory 104, data storage devices 106, and/or data communications devices 108 into the memory 104 of the computer 100 for use during actual operations.
  • the present invention may be implemented as a method, apparatus, system, or article of manufacture using standard programming and/or engineering techniques to produce software, firmware, hardware, or any combination thereof.
  • article of manufacture (or alternatively, “computer program product”) as used herein is intended to encompass a computer program accessible from any computer-readable device, carrier, or media, including the internet.
  • FIG. 1 is not intended to limit the present invention. Indeed, those skilled in the art will recognize that other alternative hardware environments may be used without departing from the scope of the present invention.
  • the computer 100 may be a portable, self-contained unit that comprises a data processing system and a wave reflection capture system (e.g., a camera).
  • the computer 100 may be about the size of the palm of an average individual's hand.
  • the noninvasive measurement system 118 may be incorporated into different apparatus than those illustrated herein.
  • the counter 120 may comprise software that is structured to limit the use of the noninvasive measurement system over a specified period of time (e.g., one year) or for a specified number of uses (e.g., 1000 uses).
  • FIG. 2 is a schematic illustration of the hardware environment of an embodiment of the present invention, and more particularly, illustrates a typical distributed computer system using a network 200 to connect client computers 202 executing client applications to a server computer 204 executing software and other computer programs, and to connect the server system 204 to data sources 206.
  • a typical combination of resources may include client computers 202 that are personal computers or workstations, and a server computer 204 that is a personal computer, workstation, minicomputer, or mainframe. These systems are coupled to one another by various networks, including LANs, WANs, SNA networks, and the Internet.
  • Each client computer 202 and the server computer 204 additionally comprise an operating system and one or more computer programs.
  • a client computer 202 typically executes a client application and is coupled to a server computer 204 executing one or more server software.
  • the server software may include a noninvasive measurement system 210.
  • the server computer 204 also uses a data source interface and, possibly, other computer programs, for connecting to the data sources 206.
  • the client computer 202 is bi-directionally coupled with the server computer 204 over a line or via a wireless system.
  • the server computer 204 is bi-directionally coupled with data sources 206.
  • the data sources 206 may be geographically distributed.
  • the operating system and computer programs are comprised of instructions which, when read and executed by the client and server computers 202 and 204, cause the client and server computers 202 and 204 to perform the steps necessary to implement and or use the present invention.
  • the operating system and computer programs are tangibly embodied in and/or readable from a device, carrier, or media, such as memory, other data storage devices, and/or data communications devices.
  • the computer programs Under control of the operating system, the computer programs may be loaded from memory, other data storage devices and/or data communications devices into the memory of the computer for use during actual operations.
  • the present invention may be implemented as a method, apparatus, system, or article of manufacture using standard programming and/or engineering techniques to produce software, firmware, hardware, or any combination thereof.
  • article of manufacture (or alternatively, “computer program product”) as used herein is intended to encompass a computer program accessible from any computer-readable device, carrier, or media, including the internet.
  • part or all of the noninvasive measurement system may reside at the server computer.
  • An individual may transmit an image of, for example, their eye at the client computer to the server computer.
  • the noninvasive measurement system would process the image data and return a blood glucose level (i.e., commonly referred to as "blood sugar”) to the client computer, for use by the individual.
  • blood glucose level i.e., commonly referred to as "blood sugar
  • FIG. 2 is not intended to limit the present invention. Indeed, those skilled in the art will recognize that other alternative hardware environments may be used without departing from the scope of the present invention.
  • the noninvasive measurement system determines the concentration of glucose in blood, without the need for invasive procedures.
  • the noninvasive measurement system can determine glucose levels by analyzing light waves reflected from the eye.
  • a handheld illumination and imaging system is used to take blood glucose measurements.
  • the system advantageously operates by integrating the reflected light from the iris portion of the eye, rather than from the retina.
  • Numerous anterior blood vessels present a means of directly observing bloodstream content with exterior optical techniques. Glucose accumulations in this area produce a change in the intensity of reflected light. The more glucose present, the higher the level of reflected light. The concentration of glucose in this area can potentially change in seconds.
  • a CCD camera images the eyeball and the image is digitized. These data are processed to remove the pupil pixels. Only the iris pixels are used as representative of glucose levels as such, but as explained elsewhere the pupil pixels are used to develop baseline and illumination levels. The iris pixels are integrated (summed) to produce a single intensity number. This is sometimes called the "integrated data number" or IDN for short; it is interchangeably designated “GLU", for glucose value.
  • the IDN (or GLU) value can be calibrated by removing image scene and illumination discrepancies. It can be further calibrated to an individual patient to produce an extremely accurate IDN-to-blood-glucose (GL or glucose level) correlation. Repeatable scene geometry is also very desirable for accurate measurements.
  • the primary IDN calibration technique uses pupil reflection and geometry data. Changes in input light levels are detected by sensing pupil brightness.
  • the average reflected intensity level of the pupil is used as the dark-level baseline for IDN processing. Only intensities that are higher than that of the pupil are integrated into the IDN.
  • Imaging the eyeball refers to taking a picture of the eye.
  • the noninvasive measurement system transmits broad spectrum visible and near infrared light to the eye.
  • the transmitted light can come from different sources, such as tungsten light, light emitting diodes (LEDs), and white or colored light bulbs.
  • the noninvasive measurement system receives back a portion of the waves (i.e., some of the waves are absorbed). In one embodiment, the portion received back and used comprises' infrared waves.
  • the portion received back and used comprises' infrared waves.
  • the noninvasive measurement system comprises an apparatus that holds a light source directly in front of the camera lens.
  • the light source is made to shine onto the eye from the geometric center of the camera lens. This results in even illumination of the eye, eliminating reflections and hot spots.
  • the light source becomes a visual centering target for the patient
  • the light source becomes a peak amplitude point for finding the image center.
  • the noninvasive measurement system takes a picture of the eye. This results in the light waves that are reflected from the eye passing through a lens system.
  • the lens focuses the waves on the surface of a CCD detector.
  • the waves strike with different amounts of energy and different angles. This leads to a picture that is represented by pixels of the CCD detector.
  • an 8-bit CCD detector each pixel value falls in the range of 0-255, with each value in the range corresponding to a different shade of gray.
  • a CCD is a charge coupled device whose semiconductors are connected so that the output of one is the input to another.
  • a CCD camera is based on electronic chips called CCD sensors.
  • a CCD chip is an array of light-sensitive capacitors. The capacitors are charged by the electrons generated by the light. Each light element that reaches the CCD array displaces some electrons that are providing a current source. The current sources are localized in small delimited areas called pixels. The pixels form a CCD matrix.
  • the surface layer of this chip contains a grid, and each cell of the grid is a silicon diode which builds an electrical charge proportional to intensity and time light falls on it.
  • a discharging circuit is connected to all cells. Behind these cells is a matching grid of pixels (i.e., a CCD matrix). Each cell stores an analog voltage rather than an off-on (binary) value.
  • the storage capacity of a pixel is also referred to as a well, and the electric charge storage capacity of a typical pixel can be several hundred thousand electrons.
  • the charges are converted to voltages through an analog to digital (A D) converter.
  • a D converter the electric charge of a pixel is converted to an 8-bit number ranging from 0-255.
  • the 8-bit number is referred to as a pixel data number.
  • the pixel data number represents the converted amplitude of each pixel.
  • the noninvasive measurement system uses a black & white CCD television (TV) camera and a personal computer. A fully portable version of the noninvasive measurement system that fits in the palm of one's hand is presently possible.
  • a CCD camera uses 8 digits to represent the amount of light energy that hits the CCD surface. Because 8 digits are used to represent the amount of light energy, it can express brightness in 256 (0-255) levels.
  • a filter is used.
  • a band pass filter is placed in front of the camera lens and behind the light. This filters light to eliminate most of the visible spectrum.
  • the light waves are cut off just before or after a particular wavelength value.
  • a digital camera is used. With a digital camera, 312 bits are used to represent the amount of light energy that hits the CCD surface. The 312 bits are used to represent the amount of light energy ranges from 0 to 4096 (rather than 0 to 255). This leads to better resolution of the light energy.
  • the next processing step is to find the center of the pupil.
  • the noninvasive measurement system centers the pupil on the image.
  • the image of the picture is transmitted by the camera to a computer having a monitor.
  • the noninvasive measurement system Prior to "snapping" a picture for use in calculating a blood glucose value (i.e., concentration), the noninvasive measurement system enables the eye to be adjusted relative to the camera lens to physically place the eyeball in the center of the picture.
  • the pixels of the CCD matrix are stored in an array, sequentially, by row order. The center of the array identifies the center pixel of the picture. That is, the noninvasive measurement system finds the energy center.
  • the noninvasive measurement system Having found the center of the pupil, the noninvasive measurement system also performs the following processes: zeroes-out the area within the light source, to eliminate the light source from the pupil image, determines the eye registration within the camera frame and calculates the useful image area, grows a pupil mask from the light source centerpoint and use it to cover the pupil area in the image, and captures the area under the aligned pupil mask for the dark-level calibration. These are discussed in more detail below.
  • the noninvasive measurement system calculates the average brightness around the pupil center.
  • the noninvasive measurement system treats the pupil as a black dot. After finding the center of the pupil, the noninvasive measurement system takes 150 pixels horizontally and vertically from the center of the pupil and calculates an average brightness (i.e., this is the sum of the values of the pixels divided by the number of pixels summed). This average is the average brightness of the center of the pupil. This will be used as a baseline value for further calculations.
  • the noninvasive measurement system masks out the pupil region of the eye.
  • the noninvasive measurement system masks a central area, sufficient to cover a pupil. Different people have different size pupils.
  • the area to be masked was a "sufficiently large” amount that would cover the pupil of most individuals. For one embodiment, this "sufficiently large” value was experimentally found to be about 90,000 square pixels.
  • the noninvasive measurement system forms a sufficiently large box around the pupil and sets the pixels in this box to zero.
  • the pupil is then a dark level reference.
  • the masking process results in excluding the pupil from further processing.
  • the noninvasive measurement system defines a number of pixels in an iris that are to be processed.
  • the noninvasive measurement system processes approximately the same number of pixels for an iris across different individuals. If changes in pupil diameter between individuals and pupil centering are not held constant, the total number of iris pixels available for integration will change. To control these effects, a software pupil mask is employed. This zeroes-out a fixed region around the pupil.
  • the software pupil mask is larger than the largest pupil diameter and covers pupil- centering errors. Some iris pixels may be zeroed in the process, but all image frames are treated in the same way.
  • the pupil mask is preferably always the same size, and therefore all image frames contain the same number of iris pixels. The geometric distortions due to pupil variations are eliminated.
  • the mask size may be determined based on an individual's own pupil size.
  • the noninvasive measurement system also applies image contrast equalization, also referred to as stretch.
  • image contrast equalization also referred to as stretch.
  • This causes pixels to fill the complete dynamic range of pixel data.
  • the pupil baseline data is applied to this process, permitting only the pixels that are brighter than the pupil to be remapped.
  • Stretch takes an 8-bit number (i.e., the pixel data number) representing pixel data and remaps the pixel data number to the full dynamic range of 0-255.
  • the pupil which has been masked, contains all zeroes.
  • the noninvasive measurement system may map the values 0-95 to 0-255, with 0-5 mapping to zero and 90-95 mapping to 255.
  • several values e.g., 12, 13, and 14
  • can be mapped to the same number e.g., 56. This resolves small variations in the scene in the eye (e.g., tearing).
  • a technique called auto-stretch is used, which is well-known in the image processing area. This compensates for small changes in illumination (e.g., the light source is drifting or if room light gets in as well as light transmitted by the noninvasive measurement system). This also deals with the problem in which light does not fall on an eye the same for sequential pictures. Consistency is needed for better accuracy of the results. By weeding out variables, such as changes in light, the noninvasive measurement system can detect that the changes in pixels represents a change in the level of glucose in the blood, rather than other changes.
  • the noninvasive measurement system may use a gamma stretch, which is a non-linear stretch.
  • the gamma stretch takes care of the effects of bright sunlight.
  • a gamma stretch amplifies more when there is darkness, and less when there is bright light.
  • Most cameras have gamma circuits.
  • the hardware gamma stretch was turned off
  • a controlled software gamma stretch is used to enhance specific regions of the return levels (e.g., the bottom or top level of the picture).
  • Hot spots are extraneous illuminations of light (e.g., outside light) or uneven illumination of the eye (e.g., light source is not over the center of the eye or there is a reflection of the light).
  • the illumination does not change. Therefore, the location of hot spots have been found by experimentation with light (e.g., can see light source reflected in the eye). This leads to customized masking based on a particular illumination system.
  • the noninvasive measurement system draws a box around the hot spot and zeroes the pixels in the box. The size of the box was experimentally found and differs based on the illumination system used.
  • the noninvasive measurement system performs hot-spot removal with software masks. Thus, peak signal amplitudes are removed before the integration process.
  • the noninvasive measurement system finds the light (seen as a hot spot in the center of the pupil) and performs a position alignment based on its location.
  • the noninvasive measurement system adds up the pixels that form the picture of the eye. Because the pupil has been masked (i.e., set to zeroes), the pixels that are added are those of the iris. The sum of the pixels is referred to as an "integrated data number" or IDN.
  • IDN integrated data number
  • GLU for glucose value.
  • IDN integrated data number
  • the noninvasive measurement system maps the IDN to a glucose level (GL) using an IDN-to-GL lookup table.
  • the look up table effectively provides a correlate of glucose concentrations. That is, it provides ranges of values that are conelated to different glucose concentrations.
  • the process of converting the IDN to a true glucose measurement requires a simple lookup operation to verify that the result is within a predetermined error band.
  • the correlation from IDN to milligrams per deciliter (mg/dl) can be seen in the following formula.
  • An program entitled “Average” determines a minimum and maximum IDN value by comparing IDN values for a series of images of the same eye, taken in succession. Similarly, the program determines the minimum and maximum GL values by comparing GL values for the same series of images. The program also determines the actual glucose level using the lookup table.
  • GL max highest possible glucose value (in mg/dl)
  • Inserting a milligram/deciliter value in GL yields its equivalent IDN value in IGN. Going from IDN to GL is accomplished by searching or hashing a lookup table.
  • the IDN lookup table is produced by averaging multiple calibrated IDN samples for known glucose values.
  • a fixed enor range is based on a plus-or-minus deviation percentage from the average IDN. This is preferably done for all available glucose numbers. Because it is difficult to obtain values for every glucose number, values between known samples can be interpolated to create a complete table. In one embodiment, a limited range of measurements were used to produce a small example conversion table, which is shown above.
  • a larger database of images and experimental data may be used to create an IDN-to-GL look-up table for a broader range of glucose measurements.
  • the IDN-to-GL lookup table has columns for a minimum and maximum range of the IDN number. Each minimum to maximum range maps to a GL number.
  • the IDN-to- GL table was calibrated by experimenting on an individual, Walter K. Proniewicz. Each experiment consisted of using a camera to obtain an image of an eye of the individual, calculating an IDN value, and obtaining a GL value for the individual using the noninvasive measurement system. Traditional (one-touch) glucose monitors were used to verify the validity of the glucose concentration found via the technique of this invention.
  • the IDN-to-GL lookup table was built by identifying, by this experimentation a GL value that conelated to ranges of the IDN value.
  • Additional system sensitivity and accuracy can be obtained by capturing multiple frames and summing their IDNs together. Changes due to small movements of the eye are thereby averaged out. Digitally summed IDN also increase effective integration time, resulting in a larger dynamic range.
  • the noninvasive measurement system displays the GL value on a display device connected to the computer, such as a computer monitor.
  • the combined result of the camera/computer arrangement is a numeric output that displays blood-glucose levels in units of milligrams/deciliter, on a computer screen or small LCD display.
  • a high-resolution black-and-white digital video camera assembly uses a charge-coupled detector (CCD) array as a sensor.
  • the camera includes a body 310 for housing the CCD array, a mounting section 311 with an attachment thread 329, a camera sync connector 312, and a video-out connector 313.
  • An extension tube 314 holds a 1 : 1.4 lens 315, making the focal length approximately 2V_ cm (one inch).
  • the purpose of the extension tube is to maximize the amount of data from the iris 432 (FIG. 4) of the eye 430 and limit, to zero, the amount of white of the eye.
  • a Snappy devise manufactured by Play Inc., is an image-capture card for a personal computer (PC). It captures a one-thirtieth-second frame from a moving image and stores it for future analysis.
  • a small light source 433 (FIG. 2) directs light 434 toward the center of an eye 430, and reflections 435 from the pupil 431 and iris 432 traverse the lens 315 to the CCD camera 310. Note that no optical dispersing or wavelength-selecting device is included.
  • the CCD camera 310 sees the reflected light 435 from the eye.
  • Raw video data 437 go to a digital interface 438, which responds with corresponding digital data 439 that proceed into a computer 440.
  • the computer may be a portable, self-contained unit that comprises a data processing system (e.g., computer 440 or a microprocessor) and a wave reflection capture system or a receiver that receives wave data (e.g., camera 310).
  • the central-illumination arrangement of Figs. 3 and 4 was the successor to numerous earlier efforts based instead on diffuse illumination of and data collection from the eye. In the first successful, repeatable one of those (FIG. 5), light from a forty- watt incandescent party bulb 543 was integrated by flat white paint on the walls of the room itself - essentially a large integrating-sphere concept.
  • the light was arranged to approach the eye 430 at a right angle to the optical axis 541 between the lens and the eye, to minimize formation of reflections and shadows.
  • the illumination was passed through a diffuser 542 - created from a plain white paper cylinder placed around the light source.
  • FIG. 6 An optical bench with a foam ocular 645 (FIG. 6) was built.
  • a headrest (FIG. 7) helps stabilize the eye.
  • the optical bench three feet long, was fashioned from two aluminum rails 647 (FIG. 6) - a rectangular one, lying horizontal, and a square bar turned on the diagonal so that one corner fits into conesponding notched grooves in the base 648 of the headrest and in the base of the camera support.
  • the bar allows movement only along the z-axis (i. e., longitudinally). This geometry also allows setting of distances between the headrest (i. e., the eye position) and the camera.
  • the support stand allows up-and-down (y-axis) adjustment by means of a vertical rod with an adjustment knob.
  • the two rails are kept parallel by being mounted on two eight-inch crossbars with three legs made from machinist jackscrews. One leg is attached to the center of the cross-bar; the other two legs are attached at opposite ends of the other crossbar, thereby allowing leveling in a classical manner.
  • the headrest is mounted to a sliding aluminum base 648, to support two one-foot- long threaded vertical rods 754 holding a curved aluminum forehead piece 646.
  • the whole mechanism is mounted on a centered vertical support rod 753.
  • a crossbar 752 supports a subject's chin on a soft pad (not shown), and the forehead rests against the forehead piece 646 to stabilize the head. Adjustment and locking are facilitated by an adjustment screw 752.
  • the CCD camera is also mounted on a support rod, set in a commercial support stand. The rod is attached to the camera, which is inside a tubular cardboard light shield 649 (made from a cardboard mailing tube). A trapdoor allows for adjustments to the camera with two camera-support screws through the tubular shield, centering the camera in the shield.
  • the tube is four inches in diameter and fourteen inches long.
  • the trapdoor is eight inches long and sections out half of the tube, starting one inch back from the front.
  • the camera lens face is flush with the end of the tube.
  • the interior of the tube is painted flat white.
  • Various other experimental setups included some geometries with two tubes - one for each eye, with an eye-tracker disc placed in front of the eye not being sampled. In one embodiment, a system with no ocular lens and in which the nondata eye is exposed is used.
  • a pair of slip-tube swing arms 869 fixed to the camera mounts - above and below the tubular shield 649 - held a vertical rod 861 on which a block 862 slides up and down 864, carrying a light-emitting diode (LED) 863.
  • the LED served as the light source for central illumination.
  • the slip tubes enabled horizontal adjustments 866, and the LED block vertical movement 864.
  • a video monitor is used to show real-time video of the eye being viewed for data collection.
  • the subject views his or her own eye on the monitor, and can rapidly correct for positioning of the eye, thus minimizing the amount of white of the eye showing - and allowing for detection of unwanted reflections.
  • Looking at a real-time video is faster and easier than doing eye-tracking using the mechanical tracking system.
  • Selected single frames were stored using a frame grabber or SnappyTM image- capture card. In this process, data collection took a long time because frames with high data enor - usually half of the frames taken - had to be discarded.
  • the LED was held centered by a diametral vane or web 972 (FIGS. 9 and 10) with a hollow central hub 973 for the LED, in an aluminum bezel 971.
  • the LED is held in front of the camera lens and aimed at the eye.
  • the back of the LED is covered with black tape 1081 to shield the lens (surface) 315 so that none of the direct LED light is picked up by the camera. Only the light reflected by the pupil 431 and iris 432 is seen by the camera.
  • This scheme also enables the subject to center the subject's own eye by looking directly into the LED - or a grain-of- wheat size incandescent bulb.
  • Bezels were made to accommodate two sizes of LED: a so-called “Tl” 3mm and a “T-P ⁇ ” (5 mm).
  • the larger LED masks the entire pupil - thereby negating the data that would be gathered for pupil calibration.
  • the data collected is nevertheless very useful in obtaining the conection factor to establish total system linearity.
  • the bezel portion that goes over the lens shade has a 1.39 inch inside diameter, with a 0.05 inch wall, 0.3 inch deep.
  • the web that holds the LED has a thickness of 0.04 inch (to minimize the masking of data from the iris to the CCD camera) and is 0.125 inch deep.
  • a goal during data-taking is to illuminate the iris to the point, at least, l A full well on the total digital number (D/N) possible - or alternatively full well of the CCD camera.
  • D/N digital number
  • Empirical data-collection and -manipulation suggests that 1/4 full well may be a minimum needed to provide the amount of data necessary for all manipulation of calibration, subtraction and averaging for an experimental system.
  • the embodiments described above have employed a personal computer (PC) for data manipulation to get a glucose value
  • the invention contemplates, as a first step toward portability, making a hybrid integrated circuit to replace the PC. It also appears worthwhile to develop a "foolproof transmitter coded to transmit blood-glucose values directly to a diabetic's insulin pump, as well as calculation of utilization time and amount of insulin. Eventually continuous readings through a convenient means, such as for example eyeglass-mounted sensors, would bring the diabetic and others back to a more- normal life.
  • the glucose response has been observed over portions of the visible and near infrared portions of the light spectrum. Peak response appears to be in the yellow and yellow/green and near infrared portion of the spectrum for the algorithm described above.
  • a black-and-white CCD array is able to collect sufficient information for blood-glucose determination - reflected light level being distinctly conelated with glucose concentration.
  • GluconTM Two programs, "GluconTM” and “Average”, were written for implementation of the present invention and were instrumental in performing research and obtaining quantitative results from experimentation. Both programs were developed using a graphical programming language from National Instruments Corporation known as "GTM”, and also known as Lab ViewTM 5.0 - with the IMAQTM imaging tools. The description above, including the pseudo-code describes the processing of these programs.
  • the first program, Glucon extracts information from light waves. It embodies all necessary techniques for obtaining IDN or GLU values.
  • the second program, Average is used to conelate the IDN or GLU values obtained from an imaged eye with the actual concentration of patient blood glucose.
  • FIG. 11 illustrates a control panel 1100. While the noninvasive measurement system is imaging a subject eye with the camera, the noninvasive measurement system displays a control panel on the computer screen that includes various buttons and other controls along with two images (Image A 1102 and Image B 1104). Image A and Image B are two separate images of the same eye, taken at different times, that may be displayed together for comparison. However, the noninvasive measurement system can also display just one of the images. Image A and Image B are displayed by the noninvasive measuring system as false color intensity maps. These images, however, are in black and white format in the attached figures. The center of an image is the pupil and is masked (i.e., zeroed out, which corresponds to a black color).
  • the dark color is actually red and indicates that the concentration of blood glucose in the eye is high.
  • the GLU or IDN values in milligrams per deciliter (mg/dl) are calculated from the images.
  • Image A and Image B are provided for ease of understanding of the invention, but they are not required to practice the invention.
  • the control panel 1100 includes an X control that enables setting a filter factor.
  • the Filter control turns a filter on or off.
  • the Mean A control provides the mean of Image A.
  • the DEV A control displays the standard deviation for Image A.
  • the Mean B control displays the mean of Image B.
  • the DEV B control displays the standard deviation of Image B.
  • the GRU A control displays the GRU value for Image A, and the GRU B control displays the GRU value for Image B.
  • the BLK A &B controls display the number of dark pixels (0 DN) in the A&B images, respectively.
  • the LO control sets a minimum stretch limit.
  • the HI control sets a maximum stretch limit.
  • the THRESH control sets a threshold, so that when the EDN is being summed up, if the threshold is set, the summing begins at that level but does not include any pixels below that level.
  • the GLIM control indicates that the IDN summation will not include values above this.
  • the BIAS A control adds to the average level of brightness of the pupil for Image A.
  • the BIAS B control adds to the average level of brightness of the pupil for Image B.
  • the LEVEL A&B controls indicate the average brightness of the pupil for each image.
  • the PATH A and FILENAME A provide the path and filename used to locate the storage location of Image A.
  • the PATH B and FILENAME B provide the path and filename used to locate the storage location of Image B.
  • the GAMA control is a gamma stretch control.
  • the F MODE control select the different filter shape modes.
  • the XPOS control provides a readout of the X position of the mouse on an image
  • the YPOS control provides a readout of the Y position of the cursor on an image.
  • the DN control displays the data number of the pixel located under the cursor.
  • the DELTA control shows the difference between the line or row image segment sums between the A and B frame. These are the cumulative values of the pixels shown in the 2 waveform charts shown in figure 11.
  • the Switch marked SUM X/ SUM Y selects between row and columns in the image and these data are summed. The sums are compared and displayed by the DELTA control.
  • the CENT A&B controls indicate the X and Y position of the centroid of the respective image.
  • the A&B LINES control permits user manipulation of the SUM charts in figure 11.
  • the SUGAR A control displays the glucose level that correlates to Image A.
  • the ERROR A control is lit when an enor is detected. When the ERROR A control is lit, the SUGAR display is blanked out.
  • the NEG control is red when the second frame (i.e., Image B) has a smaller GRU that of the first frame (i.e., Image A). It is green when the second frame has a larger GRU than that of the first frame.
  • the STR control turns on a primary linear stretch.
  • the COL control allows selecting false color or black and white
  • the SUM X and SUM Y control enables showing the sum of X or the sum of Y in the graphs for the two images.
  • the A+B control indicates that two channels (i.e., two images) are being processed.
  • the BW control enables setting the background of the graph to be black or white.
  • the CLONE control enables cloning the second frame into the first frame. Then, if desired, a new frame can be brought into the second frame, to continue comparisons between different frames.
  • the 3D control indicates whether the images are to be show as pseudo 3D.
  • the PCUT control sets the pupil cutter to on or off.
  • the ICUT control sets the IRIS cutter (leaving only the pupil) to on or off
  • the CAL control is set to on for calibration of the pupil for a linear stretch.
  • the STOP control stops the program. At this time, the picture may be manipulated (e.g., moved horizontally or vertically and the mouse can be used to move the cursor about to identify individual pixel values).
  • the SNAP control invokes a program to snap a picture of the screen and store it as a bitmap.
  • the SAVE button directly saves the picture as a bitmap.
  • the SUGAR B control displays the glucose level that correlates to Image B.
  • the Error B control is lit when an enor is detected.
  • FIG. 12 are representative histograms that are another part of the same control panel display, particularly showing histograms representing results of different processing stages within the program.
  • Histogram Al 1200 represents Image A (from FIG. 11) initially.
  • Histogram A2 1202 represents Image A after data was normalized and stretched.
  • Histogram Bl 1204 represents Image B (from FIG. 11) initially.
  • Histogram B2 represents Image B after data was normalized and stretched.
  • FIG. 13 is a display of a control panel associated with an average program and having controls used to correlate typical values with an actual concentration of patient blood glucose in conventional units.
  • the Average program is used by the noninvasive measurement system to obtain calibrated IDN-to-GL data from the IDN values.
  • the COUNT control selects the number of image frames to be processed in the calibration average.
  • the AVNUM control is the average GRU obtained from the selected frames.
  • the AVPIX control is the average pixel brightness for all of the input images in the GRU average.
  • the PATH and FILENAME controls display the path and file name of the last image being processed.
  • the AVMIN control is the minimum average GRU from all of the processed images.
  • the AVMAX control is the maximum average GRU from all of the processed images.
  • the +DELTA control indicates the GRU enor delta from the average GRU in the positive direction.
  • the -DELTA control indicates the GRU enor delta from the average GRU in the negative direction.
  • the +PRCNT control indicates the maximum GRU enor percentage above the average.
  • the -PRCNT control indicates the minimum
  • the CAL control enables the pupil calibration to be applied to the Automatic Stretch algorithm.
  • the PCUT control sets the pupil cutter to on or off.
  • the GLIM control indicates that the IDN summation will not include values above this.
  • the LEVEL control indicates the average pupil brightness.
  • the noninvasive measurement system also uses the curvature of the iris to obtain glaucoma pressure at close focal length.
  • An eye machine can be used to automatically give a difference in comparative focal lengths of inner iris vs. outer iris as an indicator of pressure.
  • FIG. 14 illustrates the use of the noninvasive measurement system to identify glaucoma pressure.
  • the distance F ⁇ s ID represents the distance from the vertex plane of a CCD camera lens 315 to the inside diameter (ID) of the iris - in other words, to the circular transition between the iris 432 and the pupil 431.
  • F ms 0D represents the distance from the lens vertex plane to the outside diameter (OD) of the iris - i. e., to the circular transition between the iris 432 and the white 1400 of the eye 430.
  • the incremental distance 1402 which is to say the difference F ⁇ s ID - F ms 0D (or ratio) between the two distances, is related to pressure. Focal determinations thus yield a measure of intraocular pressure, a large distance conesponding to high pressure and a small distance to low pressure. Depth of field, for example 0.3 mm (0.012 inch), may form a limitation on this technique.
  • the noninvasive measurement system comprises apparatus and software for noninvasively measuring glucose concentration in blood.
  • software has been developed to optimize camera positioning and illumination consistencies.
  • FIG. 15 is a flow diagram illustrating the steps performed by the noninvasive measurement system in one embodiment of the invention.
  • the noninvasive measurement system images the eyeball.
  • the noninvasive measurement system finds the center of the pupil.
  • the noninvasive measurement system calculates the average brightness around the pupil.
  • the noninvasive measurement system masks out The pupil region of the eye.
  • the noninvasive measurement system equalizes the iris image using the pupil brightness as a level baseline.
  • the noninvasive measurement system removes hot spots, if any are present.
  • the noninvasive measurement system integrates all of the processed iris pixels.
  • the noninvasive measurement system searches a IDN-to-GL lookup table to find the closest IDN-to-GL match.
  • the noninvasive measurement system displays the imputed glucose number.
  • the noninvasive measurement system has several facets or aspects which are usable independently, although for greatest enjoyment of their benefits they are preferably used together and although some of them do have some elements in common.
  • the noninvasive measurement system measures blood-glucose concentration in a biological entity by measuring light reflectivity from the body.
  • the noninvasive measurement system includes a technique for directing light to such body (e.g., a light bulb).
  • the noninvasive measurement system includes a technique for receiving (e.g., with a camera) and processing (e.g., with a computer) light reflected from such body substantially without spectral analysis of the reflected light.
  • this facet of the invention entirely eliminates need for piercing the body or otherwise obtaining blood samples, and so avoids the discomfort, fear and other detriments discussed above. Furthermore this aspect of the invention is advantageous in that it requires no elaborate spectral modulation, or multiple detectors for different wavelength regions, or dispersive elements - such as required to perform spectral analysis.
  • the technique for directing light to an eye of the body and the technique for receiving and measuring include a technique for receiving and measuring light reflected from the eye.
  • the receiving and measuring a technique comprises a monochrome detector anay - and in this case still more preferably the monochrome detector anay comprises a black-and-white charge-coupled-detector (CCD) camera or detector.
  • the receiving and measuring a technique includes a digital processor for analyzing signals from the CCD camera.
  • such a processor is desirable for analyzing signals representative of quantities of the reflected light.
  • the digital processor be part of a personal computer, and the blood glucose level is reported on a monitor screen of the computer.
  • the noninvasive measurement system be a handheld portable unit, that the unit include a technique for reporting for indicating the blood glucose level, and that the digital processor be part of the handheld portable unit.
  • the reporting technique includes an LCD unit for visually indicating the blood glucose level.
  • the receiving and measuring technique includes a technique for detecting change in level of the reflected light, and relating said change to blood-glucose concentration. Still another is that the receiving and measuring technique include some technique for detecting change in level of the reflected light - and also some technique for reporting glucose concentration that varies substantially monotonically with reflected-light level. Another general preference is that the detecting technique include some technique for responding to reflected visible light and, in this case, particularly to light in the yellow, yellow-green and infrared portions of the spectrum.
  • the noninvasive measurement system includes a technique for eliminating response to some particular light band - e.g. the red or infrared, or both.
  • the technique for receiving and measuring substantially without spectral analysis preferably do take into account different signal responses in the red or infrared as opposed to the yellow/yellow green portion of the spectrum.
  • the noninvasive measurement system measures blood-glucose concentration in a biological entity by measuring light reflectivity from the body.
  • the noninvasive measurement system includes a self-contained case. It also includes a technique for directing light to the body. Also included is a technique for receiving and measuring light that is reflected from the body.
  • the entire invention is capable of reduction to be carried within a self-contained case
  • the many benefits of noninvasive measurement can be enjoyed in a unit that need not take the form of a machine only suited for use in a medical facility. Rather, the invention can be implemented in a machine suited for patients' use at home, or at an ordinary office or other business - or in cars, restaurants, etc.
  • the second major aspect of the invention provides significant advantageous features, nevertheless to better optimize enjoyment of its benefits preferably the invention is practiced in conjunction with certain additional features or characteristics.
  • the case is fully portable. Also in this instance preferably the case fits in the palm of a normal-size adult's hand.
  • the noninvasive measurement system measures blood-glucose concentration in a biological entity by measuring light reflectivity from an eye of the body.
  • the noninvasive measurement system includes a technique for directing light to an iris of such eye. It also includes a technique for receiving and measuring light reflected from such iris.
  • a programmed digital processor that analyzes the measured reflected radiation and computing blood glucose concentration therefrom - and in particular uses a reflection of the light source, from the eye, as a peak amplitude point for image alignment.
  • condition of the blood in the eye is generally particularly rapid in its response to or tracking of the condition of the blood in other critical parts of the body particularly the brain.
  • the receiving and measuring technique also includes a technique for receiving and measuring light from a pupil of the eye. This preference facilitates determination of a baseline dark level, or of an illumination level provided by the light directing technique, or both.
  • the noninvasive measurement system is a blood-glucose measuring technique.
  • the technique includes the step of imaging forward surfaces of a person's eye on an electronic camera. It also includes digitizing resultant image signals from the camera. Further the technique includes processing pixel signals representing the iris, separately from pixel signals representing other parts of the eye, to determine blood-glucose level.
  • the foregoing may represent a description or definition of the fourth aspect or facet of the invention in its broadest or most general form. Even as couched in these broad terms, however, it can be seen that this facet of the invention importantly advances the art.
  • analysis of conditions in the iris is advantageous in that the iris exhibits monotonic relationships (peculiar to different wavelength regions) between reflected light level and glucose concentration, enabling enjoyment of the previously mentioned benefits of measurement without spectral analysis.
  • the separation of iris and pupil signals for processing is amenable to straightforward implementation based upon geometry, leading to easy compensation for varying illumination level and the like as previously mentioned.
  • the fourth major aspect of the invention thus significantly advances the art, nevertheless to optimize enjoyment of its benefits preferably the invention is practiced in conjunction with certain additional features or characteristics.
  • the technique also includes the steps of processing pixel signals representing the pupil to obtain a baseline dark level or an illumination level, or both - and also applying the dark level or illumination level, or both, to refine the pixel signals representing the iris.
  • the processing step includes applying an average reflected intensity level of the pupil to represent the dark level baseline.
  • the iris-pixel signal processing comprises integrating all usable iris-pixel signals to produce a unitary intensity indication, in this case preferably the applying step includes integrating into the indication only intensities that are higher than that of the pupil.
  • Yet another basic preference is to include the step of substantially removing image scene and illumination variation. Still another preference is to include the step of calibrating readings for an individual patient.
  • the masking step also preferably includes applying a software pupil mask that substantially stabilizes the number of iris pixels available for use, and substantially stabilizes pupil centering within the iris image. Further if this is done preferably also the pupil mask is larger than the largest pupil diameter occurring in measurement conditions.
  • Other general preferences relative to the technique of the invention include these steps, considered individually: masking out the pupil pixels from the iris region; diffusing source light to minimize hot spots; removing peak signal amplitudes, to minimize the effect of illumination hot spots; mapping illumination hot spots, to enable disregarding 5 hot-spot regions in said processing step; adjusting image contrast to substantially fill the complete dynamic range of pixel data words; looking up the measured level in a lookup table to obtain a conesponding numerical blood-glucose concentration indication in quantity of glucose per unit blood volume; and said digitizing step comprises distinguishing very low light-intensity changes.
  • Another preference, still as to the fourth aspect of the invention, is this sequence of steps: finding a center of the pupil of the eye; calculating average brightness around a pupil center; • masking out the pupil region of the eye; a equalizing the iris image using the pupil brightness as a level baseline; removing hot spots if present; integrating all of the processed iris pixels to obtain a numerical representation of brightness level of the iris; searching a lookup table to apply a previously developed calibration and thereby determine an imputed glucose concentration in quantity of glucose per unit volume; and displaying the imputed glucose concentration.
  • the noninvasive measurement system is a blood-glucose measuring technique for use with a small light source.
  • This technique includes the step of automatically finding a reflection, from a patient's pupil, of the light.
  • the technique also includes the step of automatically performing a position alignment based upon the location of the reflection of the light.
  • this mode of operation very easily resolves several otherwise knotty problems of alignment, which can otherwise threaten the integrity of the overall measurement process - since the process is sensitive to alignment and control of signal returns from the white of the eye as well as the pupil.
  • the fifth major aspect of the invention thus significantly advances the art, nevertheless to optimize enjoyment of its benefits preferably the invention is practiced in conjunction with certain additional features or characteristics.
  • the technique also includes zeroing-out the area within the light source, to form an image of forward surfaces of the eye without the light source.
  • the technique is for use with a centrally disposed light source, is the step of growing a pupil mask - starting from the light source as a centerpoint - to cover the pupil area in the image.
  • the technique also includes capturing brightness level in an area under the aligned pupil mask, for use in a dark-level calibration.
  • the noninvasive measurement system measures blood glucose concentration in a biological entity by measuring light reflectivity from an eye of the body.
  • This noninvasive measurement system includes a detector array. It also includes a small light source held directly in front of the detector anay, for directing light to the eye.
  • the noninvasive measurement system has a technique for receiving and measuring light reflected from the eye.
  • the noninvasive measurement system also includes a lens between the detector anay and the light source.
  • the noninvasive measurement system further includes a technique for using a reflection of the electromagnetic-radiation source, from the eye, as a peak amplitude point for finding the image center.
  • the light source serve as a visual centering target for the human being. In such a system, the human being looks substantially directly toward the light source to, in substance, automatically align or center (at least approximately) the pupil in the optical field.
  • the noninvasive measurement system measures blood glucose concentration in a biological entity, by measuring light reflectivity from blood of the body.
  • the noninvasive measurement system includes a technique for directing light to the blood. It also includes a technique for receiving and measuring light reflected from the blood substantially without spectral analysis of the reflected light.
  • a wave has an amplitude, which is its positive or negative displacement from an equilibrium point.
  • a glucose molecule rotates in a clockwise direction as its density increases. (On the other hand, a fructose molecule rotates in a counter-clockwise direction, and the noninvasive measurement system can distinguish between these molecules based on their rotation.)
  • This clock-wise rotation affects the polarization.
  • the invention takes into account that rotation affects polarization. The more glucose there is in the blood, the more light that is reflected.
  • a CCD is a charge coupled device whose semiconductors are connected so that the output of one is the input to another.
  • a CCD camera is based on electronic chips called CCD sensors. These components are sensitive to light and allow pictures to be stored in computers.
  • a CCD chip is an anay of light-sensitive regions called wells. The wells are charged by the electrons generated by the light. Each light element that reaches the CCD anay displaces some electrons that are providing a cunent source. The cunent sources are localized in small delimited areas called pixels. The pixels form a CCD matrix.
  • the surface layer of this chip contains a grid, and each cell of the grid is a silicon diode which builds an electrical charge proportional to intensity and time light falls on it.
  • a discharging circuit is connected to all cells. Behind these cells is a matching grid of pixels (i.e., a CCD matrix). Each cell stores an analog voltage rather than an off-on (binary) value.
  • the storage capacity of a pixel is also refened to as a well, and the electric charge storage capacity of a typical pixel can hundreds-of-thousands of electrons.
  • the charges are converted to voltages that can be interpreted by an analog to digital (A/D) converter.
  • A/D converter the electric charge of a pixel is converted to an 8- bit number ranging from 0-255.
  • the 8-bit number is refened to as a pixel data number.
  • the pixel data number represents the converted amplitude of each pixel.
  • the pixel data number may be "stretched". That is, if the pixel data number is 16, the numbers 0-16 may be mapped to 0-255, so that the stretched pixel data number is 255 (i.e., 16 may be mapped to 255).
  • mapping mechanisms may be used (e.g., mapping 0-31 to 0-255, with 16 mapping to 127).
  • the image of the eye is used to form a CCD anay, which is also refened to as a CCD matrix.
  • the CCD matrix represents each pixel with an entry in the matrix. Each entry has a value ranging from 0-255.
  • the phase angle is determined from a CCD matrix.
  • the rows of the CCD matrix are summed up, and then these values are totaled to form an XGRU value.
  • the columns of the CCD matrix are summed up, and then these values are totaled to form a YGRU value.
  • the ratio of the XGRU value and the YGRU value results in the phase angle. For example, if the light falls symmetrical, the XGRU value and the YGRU value are the same. However, for a substance, which is non-symmetrical, the
  • each pixel will be set to one of three states: 0, 1, 2.
  • a pixel can be of 0-255 states for an 8-bit system, and a pixel can have greater resolution with a larger bit system.
  • the noninvasive measurement system obtains row information YPA (summation of rows) and column information YPB (summation of columns) and calculates a true phase angle and a true GRU/true amplitude with the following:
  • the true phase angle is equal to approximately 10714285.
  • the true amplitude is equal to GRU - (YPA + YPB), which calculates the amplitude by removing the phase angle. Note that the true amplitude GRU is calculated by summing all of the pixels when the matrix is at 680X480, while YPA and YPB are calculated for a reduced size matrix of, for example, 380X380.
  • the noninvasive measurement system uses a Phase/ Amplitude lookup table. The
  • Phase/ Amplitude lookup table has columns for a frame cousin number (FRC), a glucose level (GL), an amplitude (AMPL), and a phase angle (PHASE).
  • the Phase/ Amplitude lookup table was created experimentally.
  • the Phase/Amplitude table was created by experimenting on an individual, Walter K. Proniewicz. Each experiment consisted of using a camera to obtain an image of an eye of the individual, calculating a GL value for the individual, and calculating a phase angle and amplitude.
  • Traditional (one- touch) glucose monitors were used to verify the validity of the glucose concentration found via the technique of this invention.
  • the Phase/Amplitude lookup table was built by identifying, by this experimentation, GL values that conelated to a phase angle and amplitude pair. Additionally, the noninvasive measurement system uses a Cousins table.
  • the cousins table has a column for a FRC number (frame cousin), a glucose level (MG/DL), an amplitude (AMPL), a phase angle (PHASE), and columns for eight cousins.
  • MG/DL glucose level
  • AMPL amplitude
  • PHASE phase angle
  • the cousins represent nodes that have similar phase angle and amplitude values.
  • the NODE TABLE DATA graph is a graph of phase angle versus amplitude. The top most line in the graph plots the ratio of phase angle to amplitude.
  • the cousin nodes in the Cousin table are nodes that are at approximately the same horizontal axis on the plot of the ratio. For example, for FRC 10, the cousins are FRC 25, FRC 28, FRC 23, FRC 29, and FRC 18. Each of these frame cousins has a similar phase angle to amplitude ratio.
  • One embodiment of the invention uses the phase angle and amplitude to identify a blood glucose level. This section provides an overview of the processing steps for this embodiment of the invention, along with pseudo-code. Only some of the processing steps will be discussed here to enable the reader to have a better understanding of these steps prior to providing the pseudo-code. Generally, when a Phase/Amplitude Lookup Table is used, the noninvasive measurement system performs the following steps:
  • the picture may be taken with a black and white video or electronic still frame camera.
  • a color camera or custom CCD may be used.
  • other detectors such as quantum well infrared arrays or mercad telluride a ⁇ ays or specialized radio receivers can be used.
  • a calibration mask is used. The calibration mask is placed between the eye and the lens of the camera. For example, one calibration mask may be a circular piece of glass.
  • each strip has different phase angle and amplitude value. For example, each strip may represent 5 mg/dl increments starting with 35 mg/d.
  • a strip may be the size, for example, of 50 pixels.
  • the number of strips used is the size of the strip divided by the number of pixels to be covered.
  • the comparison will assist in increasing the accuracy of calculating the glucose level.
  • the calculated phase angle and amplitude values may be compared to those of the strips.
  • the strips will give amplitude and phase angles for very low glucose values, thereby making extremely low glucose readings very accurate.
  • custom silicon a ⁇ ays e.g., a CCD
  • CCDs and custom silicon a ⁇ ays can be specially processed, modified, or enhanced to heighten their sensitivities to x-rays and other high energy particles.
  • the noninvasive measurement system may process x-rays or other high energy particles, instead of light waves.
  • CCDs and custom silicon a ⁇ ays can be specially processed, modified, or enhanced to be made sensitive to ultraviolet rays to highlight or detect different types of minerals.
  • the noninvasive measurement system may also be used to locate tumors and to locate and co ⁇ ect blood clots.
  • a photo-multiplier can be placed in front of a CCD to enhance its sensitivity. Then, a high intensity light that is synchronized to the integration time of the CCD is used to send light through an individual. The amount of light in that high intensity light source can penetrate flesh.
  • the noninvasive measurement system may be used to detect breast cancer.
  • the noninvasive measurement system may apply a spatial filter after taking the picture.
  • the spatial filter when used in the low-pass mode, reduces unwanted image features that tend to show-up as high frequency components. That is, the spatial filter takes out portions of an image that create "noise" from non-glucose information.
  • the filter parameters used operates on a 3X3 pixel area.
  • the filter will take a group of pixels (e.g., 9 pixels), average the values of the pixels, and set the values of each of the pixels in the group to that value. For example, if 2 of the 9 pixels are lit (i.e., set to one), and the remaining 7 pixels are not lit (i.e., set to zero), the average is zero, and all of the 9 pixels are set to zero.
  • tissue in the eye may show up as high frequency, so the low pass filter will remove these components from the image anay.
  • a high pass filter will exaggerate these components in the image anay.
  • the "hi-passed" data can be processed to uniquely identify an individual person. This can be used as an "iris fingerprint” to identify individuals by the unique characteristics of their iris. The individual eye images can thus be automatically conelated to specific patients.
  • the noninvasive measurement system may then perform automatic level control.
  • Automatic level control attempts to ensure that the average of all of the pixels is equivalent to the average of a calibrated average (i.e., an average that conelates to the calibrated data or desired average).
  • the value 35 was found by experimentation to be the best value.
  • the camera and A D converter returns the proper amplitudes for glucose detection around this average.
  • the number will be different for other cameras and converters. For example, if the data number is 35, then, the automatic level control will find the average of the pixels. If the average is lower than the average data number (e.g., 35), the automatic level control adds 1 to each pixel. If the average is higher than the data number (e.g., 35), the automatic level control subtracts 1 from each pixel. After the addition or subtraction process, the automatic level control finds a new average. If the new average is at or about 35, the automatic level control is complete. Otherwise, the automatic level control continues to add or subtract 1 to each pixel and calculating a new average until the new average is at or about 35.
  • the noninvasive measurement system calculates a true GRU or true amplitude.
  • the true GRU is the amplitude, with the phase angle portion removed.
  • the noninvasive measurement system calculates the true GRU as The GRU value - phase angle value. As will be discussed below, this amplitude is matched with the amplitude in the Phase/ Amplitude lookup table to obtain the closest amplitude.
  • phase angle i.e., the XGRU and YGRU ratio
  • the invention selects that phase angle and amplitude, and the conesponding GLU value, without performing automatic fine tuning. If there is no exact match, automatic fine tuning is performed. In another embodiment, because it is rare to find an exact match, automatic fine tuning is always performed, without the initial check. Automatic fine tuning involves tuning the Image matrix. The invention attempts to get a close match between the phase angle found with the Image matrix and the phase angles available for comparison in the Phase/Amplitude lookup table.
  • the invention attempts to fine tune the value to reach either 14017754 (i.e., node 13 in the Phase/Amplitude lookup table) or 14047686 (i.e., node 14 in the Phase/ Amplitude lookup table).
  • the automatic fine tuning uses a Ternary technique.
  • the Ternary technique if 1/4 is to be added to the image matrix, 1 is added to each fourth pixel. Then, a new phase angle is calculated. This phase angle is recorded. This is done for 18 passes, with an amount being added each of the 18 times (e.g., 0.1 may be added for the first pass, another 0.1 is added for the second pass, etc.).
  • an amount being added each of the 18 times e.g., 0.1 may be added for the first pass, another 0.1 is added for the second pass, etc.
  • a value is added to the pixels in the image matrix, then the phase angle is calculated, then a close match is sought in the Phase/ Amplitude lookup table. This results in a FRC value that conesponds to the selected entry in the Phase/Amplitude lookup table.
  • the FRC value is used as an index into the Cousins table. Then, a comparison is made between the phase angle calculated in the pass and the phase angle for each of the cousins and the selected FRC.
  • the FRC whose phase angle is closes to the calculated phase angle is saved in an array, along with phase angle enor (MNP) and amplitude enor (MNA). This anay results in 18 values conesponding to the 18 passes.
  • a mean phase angle is calculated from the 18 recorded values. This is then compared to the Phase/ Amplitude lookup table to find a matching phase angle, amplitude, and conesponding GLU. Also, the GLU value is used to index into the Cousins table.
  • the 18 passes are performed for each of four frame cousins (FRCs). The result is four final values, and one is selected from these four.
  • FRC 13 For each of the 18 steps, start with frame cousin (FRC) 13, which has a GLU value of 136. FRC 13 is used because the GLU value 136 is near the middle of the range. Also, FRC 13 has 8 cousins (the most cousins possible in the Cousins table). Then, a comparison is made between the phase angle and the phase angle in the Phase/ Amplitude lookup table for each cousin. During the process, one of the cousins is identified as being closest to 136 by the phase angle. This results in 18 values for each cousin within the FRC. Then, the FRC that is most often closest to the image phase angle is chosen. In one embodiment, there are four iterations, one starting with FRC 13, the next with FRC 14, the next with FRC 15, and the last starting with FRC 16.
  • the following pseudo-code reflects the processing performed by the noninvasive measurement system. Some of the steps occur when particular controls are set on a control panel. These controls will be discussed below.
  • pre-stretch set perform first linear stretch 6. create pupil mask in identified shape (i.e., "L" shape or rectangular shape)
  • corner tab cutter zero out boxes in corners to remove extraneous light, etc.
  • bitmap image format set change format to an x-y image format (i.e., an x-y anay), which removes the bitmap header, etc.
  • FIG. 16 illustrates a control panel 1600 for one embodiment of the invention.
  • the Phase/ Amplitude look up tables 1602 and 1604 have been calibrated for different options.
  • the Phase/Amplitude look up tables 1602 is a LOW NODES ALC HP, which means that it was calibrated for low brightness (LOW NODES), using a automatic level control (ALC), and a high pass filter (HP).
  • the Phase/Amplitude look up tables 1604 is LOW NODES, which means that it was calibrated for low brightness (LOW NODES).
  • the RESTORE L control enables restoring a Phase/ Amplitude look up table with a large base table.
  • a base table is a Phase/ Amplitude table, with large indicating it has the full range of glucose levels and small indicating it does not have the full range of glucose levels.
  • the RESTORE S control enables restoring a Phase/ Amplitude look up table with a small base table.
  • the AMPL TBL control displays an index, (e.g., 15), and a value conesponding to that index.
  • the PHASE TBL control displays an index and a value conesponding to that index.
  • the TAPA histogram 1606 displays the total energy of the incoming source.
  • the bar 1608 indicates the processing of the FRC values.
  • the MX DATA histogram 1610 has an x-axis that goes from 1-450 milligrams and displays a statistical distribution of findings of 1-18 steps.
  • the MXHD control displays the data of an anay that holds the 4 FRC values.
  • the PEAK control displays the peak value from the histogram 1610.
  • the RESD control displays the four glucose levels that conespond to the four FRC values selected with the auto fine tuning.
  • the RES control displays the glucose level of the last FRC processed.
  • the AVD control displays the average mg/dl value for each of the 4 FRC steps.
  • the AVX control displays the average amplitude.
  • the MNX control displays the minimum amplitude.
  • the MAX control displays the maximum amplitude.
  • the 2CYL/1CYL control enables switching between 1 or 2 cycles.
  • the PAUSE control enables pausing the processing.
  • the PHASE AT MATCH control displays the phase angle selected by the matching.
  • the enor controls T1-T5 are lit upon the occunence of certain enor conditions.
  • the Tl control is lit when the phase code is too low.
  • the T2 control is lit when AVX and MNX are the same (i.e., these are the average and minimum amplitudes).
  • the T3 control is lit when MX and MN are the same (i.e., these are the minimum and maximum glucose levels that are found).
  • the T4 control is lit when MXAMP and MNAMP are the same.
  • the T5 Control is lit when the phase code is out of bounds.
  • the PTWEEK control is a phase tweek that enables forcing the phase angle value to a particular value.
  • the ATWEEK control is an amplitude tweek that enables forcing the amplitude value to a particular value.
  • the FILTER1 control enables setting no filter, a low pass filter, or a high pass filter.
  • the FILTER2 control enables setting no filter, a low pass filter, or a high pass filter.
  • the FULL/PART control selects the portion of the Phase/Amplitude table to be used in the look-up process. FULL permits a look-up from FRC 0-37 and PART permits a look-up from FRC 10-18.
  • the XPOS control provides a readout of the X position of the mouse on an image
  • the YPOS control provides a readout of the Y position of the cursor on an image.
  • the DN control displays the data number of the pixel located under the cursor.
  • the DELTA control shows the difference between the line or row image segment sums between the A and B frame.
  • the PUPL/NORM control is not used.
  • the A-B/NORM control subtracts two images (e.g., Frame A - Frame B).
  • the SIG Control is an edge detection filter, which is a version of a high-pass filter.
  • the FLIP/PHASE control enables inverting a phase angle.
  • the ITER control displays an iteration of the 18 passes.
  • the PHASE A and PHASE B controls are ratios for two images, Image A and Image B, respectively.
  • the SUGAR control displays a glucose level.
  • the ERROR A control is lit when an enor occurs. When the ERROR A control is lit, the SUGAR display is blanked out.
  • the A LINES graph 1612 displays either the summation of the X values or the summation of the Y values from the CCD matrix, depending on which is selected with the SMX/SMY control, for Image A.
  • the NEG control is lit red when the second frame (e.g., for Image B) has a smaller GRU than the GRU of the first frame (e.g., for Image A).
  • the STR control turns on a primary linear stretch.
  • the COL control shows false color or black/white for the images that are displayed.
  • the BAL control balances based on the geography of a pupil if there are few iris pixels to work with (e.g., pupil too big).
  • the A B control enables working with two channels (i.e., two images) at once.
  • the B/W control enables, for all charts, either a black background or a white background.
  • the CLN Control enables cloning the Image B file name to the Image A file name to speed up manual processing. This avoids manually typing the information.
  • the ALC control sets automatic level control.
  • the INP control displays the input image, rather than a processed image.
  • the 3D control is used to select a 3D display format for false light intensity maps.
  • the PS control is a prestretch (before any other processing occurs).
  • the PCUT control sets a pupil cutter.
  • the C AL control is on for calibration of a pupil for a linear stretch.
  • the TABS control sets 4 corner tab masks.
  • the LPAT control enables selecting a square or L-shaped mask for the pupil.
  • the BOX control is used to box in part of an image.
  • the AMP/PHS control is used to select either amplitude or phase angle for indexing into the Phase/Amplitude table when a best possible match is being sought.
  • the STOP control stops the program.
  • the SNAP control invokes another program to snap a picture of the screen and store it as a bitmap.
  • the SAVE control directly saves the image displayed as a bitmap.
  • the NODES DBL control can change the HI/LOW control, which selects a high brightness or low brightness Phase/ Amplitude lookup table, to select two other tables.
  • the DLTA control causes comparisons to be made where the final result is selected based on the same comparison polarity. If the incoming phase angle is higher than the nearest table entry and the amplitude is lower than it's table entry, the comparison will be rejected.
  • the POL control is for polarity. In particular, during comparison of values in the Phase/ mplitude lookup table, if Bl is set, the answer can be above or below the actual value, and if MON is set, the value is the lower value found.
  • the B LINES graph 1614 displays either the summation of the X values or the summation of the Y values from the image matrix, depending on which is selected with The SMX/SMY control, for Image B.
  • the PATH A and FILENAME A provide the path and filename used to locate the storage location of Image A.
  • the PATH B and FILENAME B provide the path and filename used to locate the storage location of Image B.
  • the GAMA control is a gamma stretch control.
  • the F MODE control enables manipulating the filter scope mode.
  • the B-A control is the phase angle difference between the A and B image channels.
  • the T-A control shows the difference between the incoming phase angle and the table phase angle as indexed by the cunent amplitude match.
  • the PPSN control show the best FRC match based on the best phase angle match found during a cousin table scan.
  • the APSN control shows the best FRC match based on the best amplitude match found during a cousin table scan.
  • the AMPL control shows the difference between the incoming amplitude and the table amplitude as indexed by the cunent amplitude match.
  • the MNP control displays the phase angle enor.
  • the MNA control displays the amplitude enor.
  • the TGRUA control displays the true GRU for Image A.
  • the TGRUB control displays the true GRU for Image B.
  • the T B-A control displays the difference in true GRU between the A and B image channels.
  • the MXAMP control displays the maximum amplitude
  • the MNAMP control displays the minimum amplitude.
  • the MX control shows the maximum GLU value.
  • the MN control shows the minimum GLU value.
  • the UFM control displays the average before a filter is applied.
  • the ERD control is set, will set the ERROR A control if any enor indicator T1-T5 are on.
  • the PUFMl control displays the average before ALC is applied.
  • the AV control displays the average of MX and MN.
  • the CSN control indicates whether the CSN table (i.e., the cousins table) should be used or the primary FRC value should be used for comparisons.
  • the 10X control indicates how much should be added to the CCD anay in each of the 18 passes.
  • the AUTO TUNE control allows for selecting either pre-matrix (i.e., a sweep of amplitude before decoding phase angle and amplitude) or post-matrix (i.e., a sweep of amplitude after decoding phase angle and amplitude).
  • the MNPD control holds the MNP values.
  • the MNAD control holds the MNA values.
  • the IMAGE control enables using the input picture exactly as it is or normalizing the picture to be 480X680.
  • the LINE/FRAME control enables capturing a line or a frame.
  • the YPA control displays the XGRU.
  • the YPB control displays the YGRU.
  • the SEQ control enables selection of the number of FRC values to process with 18 passes, and this can range from 0-37.
  • the FRC control enables selection of the FRC value to start with.
  • the FINE GAIN control is manual fine tuning, which forces an offset with a Ternary gain.
  • the PUPIL BIAS control is a pupil size compensator.
  • the WINDOW LO and WINDOW HI controls enable selection of a low and high value, respectively, between 0-255; the result of this is that specific pixels in the range are selected for processing.
  • the LOS control sets a low limit on a secondary stretch
  • the HIS control sets a high limit on a secondary stretch
  • the LOP control sets a low limit on a primary stretch
  • the HIP control sets a high limit on the primary stretch.
  • the OFFSET A control puts a numerical offset to the entire Image A
  • the OFFSET B control puts a numerical offset to the entire Image B.
  • the BIAS A control enables adding to the computed pupil average of Image A.
  • the BIAS B control enables adding to the pupil average of Image B.
  • the ROT control is used to rotate the image.
  • the MEAN A control displays the mean of Image A, while the DEV A control displays the standard deviation.
  • the MEAN B control displays the mean of Image B, while the DEV B control displays the standard deviation.
  • the GRU A control displays the GRU of Image A, while the GRU B control displays the GRU for Image B.
  • the B-A control the raw GRU difference between image A and image B.
  • the PUPIL A control displays the brightness (before average) of the pupil of Image A.
  • the PUPIL B control displays the brightness (before average) of the pupil of Image B.
  • the threshold control indicates at what value the GRU should be summed to.
  • the GLIM control indicates at what value the system should not sum after.
  • the LEVEL A control is average pupil brightness of image A
  • the LEVEL B control is the average pupil brightness of image B.
  • FIG. 17 displays another control panel 1700 for one embodiment of the invention.
  • This control panel displays a cousins table 1702.
  • the cousins table has a column for a FRC number (frame cousin), a glucose level (MG/DL), an amplitude (AMPL), a phase angle (PHASE), and columns for eight cousins.
  • the cousins were derived using the NODE TABLE DATA graph 1704.
  • the NODE TABLE DATA graph is a graph of phase angle versus amplitude.
  • the top line 1706 in the graph plots the ratio of phase angle to amplitude.
  • the middle line 1708 plots amplitude, and the bottom line 1710 plots phase angle.
  • the cousin nodes in the Cousin table 1702 are nodes that are at approximately the same horizontal axis on the plot of the ratio.
  • FIG. 18 is illustrates various Phase/Amplitude lookup tables that have been calibrated for different settings.
  • LOW NODES refers to low brightness and ALC indicates that automatic level control was used.
  • HIGH NODES indicates that there was high brightness.
  • the BASE refers to a base line table that was calibrated with either a SMALL range of values or a LARGE (or all) range of values.
  • DOUBLE FILTER indicates that two filters were set.
  • COUSINS indicates that the cousins table was used.
  • FIG. 19 displays histograms for Image A and Image B.
  • the Al histogram 1900 reflects Image A after a low pass filter has been applied.
  • the A2 histogram 1902 reflects Image A before the low pass filter.
  • the A3 histogram 1904 reflects Image A after a gamma stretch (If enabled).
  • the Bl histogram 1906 reflects Image B after a low pass filter has been applied.
  • the B2 histogram 1908 reflects Image B before the low pass filter.
  • the B3 histogram 1910 reflects Image B after a gamma stretch (If enabled).
  • FIGS. 20A-20C are a flow diagram illustrating the steps performed by the noninvasive measurement system in one embodiment of the invention.
  • the noninvasive measurement system images the eyeball, with center brightness.
  • the noninvasive measurement system adjusts the geometry of the image to 640X480 pixels to match a screen size of a personal computer (PC).
  • PC personal computer
  • programmable level bias is set (in the range of 0-255)
  • the noninvasive measurement system performs level bias on the image.
  • gamma stretch if gamma stretch is set, the noninvasive measurement system performs gamma stretch (i.e., a to produce a non-linear stretch).
  • the gamma stretch is normally not set for eye measurements, and is set for skin measurements.
  • the noninvasive measurement system performs a first linear stretch.
  • the noninvasive measurement system creates a pupil mask in a specified shape.
  • a user may select either a "L" shape or a square shape. In other embodiments, an oval or circular shape may be provided, but it may require additional processing resources.
  • corner tab cutter zero out boxes in corners to remove extraneous light, etc.
  • the noninvasive measurement system uses either a programmable low or high pass filter, whichever is selected.
  • centering the noninvasive measurement system finds the center.
  • the noninvasive measurement system uses a programmable low or high pass filter, whichever is selected.
  • stretch set the noninvasive measurement system controls stretch from input from the control panel.
  • image rotator the noninvasive measurement system rotates the image (i.e., this can be used instead of Ternary technique).
  • the noninvasive measurement system performs automatic level control.
  • the noninvasive measurement system performs manual fine tuning (i.e., Ternary technique for biasing image).
  • the noninvasive measurement system performs automatic fine tuning (i.e., Ternary weights are added in here).
  • bitmap image format the noninvasive measurement system changes format to an x-y image format (i.e., an x-y anay), which removes the bitmap header, etc.
  • the noninvasive measurement system calculates GRU (i.e., by summing up all x rows and y columns in the image anay).
  • the noninvasive measurement system converts the image from 680X480 to 480X480 pixels.
  • using 380 pixels i.e., the noninvasive measurement system avoids using edges as it affects data, by offsetting 50 pixels in from edge in each axis, leaving a black margin at edge
  • the noninvasive measurement system sums up the x rows and y columns and divides the largest by the smallest to get a value that is greater than one.
  • the noninvasive measurement system obtains row information YPA (summation of rows) and column information YPB (summation of columns) by calculating the following:
  • the noninvasive measurement system performs automatic fine tuning, with 18 passes for each of 4 FRC values.
  • the noninvasive measurement system selects best true phase angle and true amplitude match.
  • the noninvasive measurement system displays results.
  • the embodiment of the invention described in section D may be modified without exceeding the scope of the invention.
  • the technique of the invention may be practiced in a networked environment, as described with respect to FIG. 2.
  • the noninvasive measurement system can also measure glucose concentrations from skin (e.g., wrist or stomach), blood (e.g., a drop of blood on a tissue), or nail beds. For each of these cases, the noninvasive measurement system generally uses the technique described in Section D, in which a phase angle and amplitude are conelated to a glucose level. When working with the skin, a lower light level is used (i.e., the eye absorbs more light). In particular, experimentation was successfully performed by using the noninvasive measurement device to transmit light waves onto a portion of the wrist. The wrist contains numerous blood vessels, which may contain glucose molecules that reflect the light waves.
  • a CCD camera was used to receive the reflected light waves from the wrist and to form a matrix of pixels that represented the received light waves.
  • the noninvasive measurement system applied a gamma 1 stretch to the matrix of pixels. This refers to a logarithmic re-mapping technique that gives more contrast for lower level pixels (small pixel values) and less contrast for higher level pixels (large pixel values), resulting in better resolution in the lower end.
  • the noninvasive measurement system then processed the
  • the noninvasive measurement system found a glucose level. It is to be understood that this process can be modified without exceeding the scope of the invention.
  • the controls of FIG. 16 may be set so that a pupil cutter is also applied prior to calculating the phase angle and amplitude.
  • experimentation was successfully performed by using the noninvasive measurement device to take a picture of a portion of the stomach.
  • experimentation was successfully performed by using the noninvasive measurement device to transmit light waves onto a portion of the stomach.
  • the stomach contains numerous blood vessels, which may contain glucose molecules that reflect the light waves.
  • a CCD camera was used to receive the reflected light waves from the stomach and to form a matrix of pixels that represented the received light waves.
  • a gamma 3 stretch was applied. This refers to a gamma stretch with a more gradual effect and that gives more contrast for lower level pixels (small pixel values) and less contrast for higher level pixels (large pixel values), resulting in better resolution in the lower end.
  • the noninvasive measurement system then processed the "stretched" matrix of pixels to obtain a phase angle and amplitude. From the phase angle and amplitude, the noninvasive measurement system found a glucose level. It is to be understood that this process can be modified without exceeding the scope of the invention.
  • the controls of FIG. 16 may be set so that a pupil cutter is also applied prior to calculating the phase angle and amplitude.
  • the blood drop was either on a tissue or on a test strip that had been used to run a test on a conventional (one touch) glucose monitor. With the test strips, the blood drop spread from a center point and retreated at an edge, so there were two layers of blood at the perimeter. With test strips, better values were derived from testing the perimeter.
  • the blood drop was tested as the skin was, in less light.
  • experimentation was successfully performed by using the noninvasive measurement device to transmit light waves onto the blood, which may contain glucose molecules that reflect the light waves.
  • a CCD camera was used to receive the reflected light waves from the blood drop and to form a matrix of pixels that represented the received light waves.
  • the noninvasive measurement system then processed the matrix of pixels to obtain a phase angle and amplitude. From the phase angle and amplitude, the noninvasive measurement system found a glucose level. It is to be understood that this process can be modified without exceeding the scope of the invention.
  • the controls of FIG. 16 may be set so that a pupil cutter is applied prior to calculating the phase angle and amplitude.
  • noninvasive measurement device may also be used on other portions of a body (e.g., on a leg).
  • noninvasive measurement system may also be used on other portions of a body (e.g., on a leg).
  • discussion has used human experimentation, the techniques of the invention are applicable to other biological entities.
  • any type of computer such as a mainframe, minicomputer, or personal computer, or computer configuration, such as a timesharing mainframe, local area network, or standalone personal computer, could be used with the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • Physics & Mathematics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Primary Health Care (AREA)
  • Optics & Photonics (AREA)
  • Epidemiology (AREA)
  • Databases & Information Systems (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Business, Economics & Management (AREA)
  • Data Mining & Analysis (AREA)
  • Business, Economics & Management (AREA)
  • Physiology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Ophthalmology & Optometry (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Computer Networks & Wireless Communication (AREA)
  • Emergency Medicine (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

Cette invention se rapporte à un système de mesure non invasive qui offre une technique de manipulation de données d'ondes. Plus particulièrement, les données d'ondes réfléchies par une entité biologique sont reçues et une fois réfléchies elles sont mises en corrélation avec une substance contenue dans l'entité biologique. Les données d'ondes peuvent comporter des ondes lumineuses et l'entité biologique peut être un organisme humain ou du sang. En outre, la substance mise en corrélation peut être notamment une molécule ou une substance ionique. Cette molécule peut être notamment une molécule de glucose. Les données d'ondes sont en outre utilisées pour former une matrice de pixels avec les données d'ondes reçues. La matrice de pixel peut être modifiée par des techniques de masquage, d'étirement ou d'élimination des points chauds. Les pixels peuvent ensuite être intégrés pour produire une valeur d'intégration qui est mise en corrélation avec un niveau de glucose. Le processus de corrélation peut utiliser une table de consultation, laquelle peut être étalonnée sur une entité biologique particulière. Une amplitude et un angle de phase peuvent en outre être calculés pour les données d'ondes réfléchies et servir à identifier un niveau de glucose dans l'entité biologique. Les données d'ondes réfléchies peuvent en outre servir à déterminer la pression d'un glaucome. Le niveau de glucose peut être affiché sur un écran de contrôle relié à l'ordinateur. L'ordinateur peut être une unité autonome portative, qui contient un processeur de données et un système de capture de la réflexion des ondes. D'autre part, l'ordinateur peut être relié à un réseau d'ordinateurs, où les données d'ondes réfléchies sont reçues par l'ordinateur et acheminées vers un autre ordinateur du réseau pour leur traitement.
PCT/US2000/001698 1999-09-17 2000-01-21 Mesure non invasive du niveau de sucre dans le sang WO2001022061A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1020027003472A KR20020070964A (ko) 1999-09-17 2000-01-21 혈당 수준의 비 관혈적 측정법
EP00909963A EP1216409A1 (fr) 1999-09-17 2000-01-21 Mesure non invasive du niveau de sucre dans le sang
CA002390520A CA2390520A1 (fr) 1999-09-17 2000-01-21 Mesure non invasive du niveau de sucre dans le sang
JP2001525185A JP2003524153A (ja) 1999-09-17 2000-01-21 血糖レベルの非侵入的測定
AU32135/00A AU3213500A (en) 1999-09-17 2000-01-21 Noninvasive measurement of blood sugar level

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PCT/US1999/021680 WO2000016692A1 (fr) 1998-09-18 1999-09-17 Mesure non invasive de la glycemie fondee sur des observations optoelectroniques de l'oeil
USPCT/US99/21680 1999-09-17
US4433800A 2000-01-21 2000-01-21
US09/044,338 2000-01-21

Publications (1)

Publication Number Publication Date
WO2001022061A1 true WO2001022061A1 (fr) 2001-03-29

Family

ID=26721420

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/001698 WO2001022061A1 (fr) 1999-09-17 2000-01-21 Mesure non invasive du niveau de sucre dans le sang

Country Status (4)

Country Link
EP (1) EP1216409A1 (fr)
AU (1) AU3213500A (fr)
CA (1) CA2390520A1 (fr)
WO (1) WO2001022061A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052204A1 (fr) * 2002-12-06 2004-06-24 Kwan-Ho Kim Systeme de controle de la glycemie
US6853854B1 (en) 1998-09-18 2005-02-08 Q Step Technologies, Llc Noninvasive measurement system
JP2006525084A (ja) * 2003-05-02 2006-11-09 オクリア， インコーポレイテッド 非侵襲的分析物測定のための方法およびデバイス
FR2894806A1 (fr) * 2005-12-19 2007-06-22 Spincontrol Sarl Systeme et procede d'imagerie et/ou de mesure reproductibles sur un sujet maintenu par un dispositif de contention
US8090424B2 (en) 2005-01-10 2012-01-03 Sti Medical Systems, Llc Method and apparatus for glucose level detection
DE102013010611A1 (de) * 2013-06-25 2015-01-08 Sms Swiss Medical Sensor Ag Messvorrichtung und Messverfahren zum Messen von Rohdaten zur Bestimmung eines Blutparameters, insbesondere zur nichtinvasiven Bestimmung der D-Glucose-Konzentration
US9442065B2 (en) 2014-09-29 2016-09-13 Zyomed Corp. Systems and methods for synthesis of zyotons for use in collision computing for noninvasive blood glucose and other measurements
US9554738B1 (en) 2016-03-30 2017-01-31 Zyomed Corp. Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4200362A (en) * 1972-09-25 1980-04-29 Retina Foundation Ophthalmoscope with uniform illumination
US4249825A (en) * 1979-05-14 1981-02-10 The Trustees Of Boston University Method and apparatus suitable for ocular blood flow analysis
US4491730A (en) * 1980-08-14 1985-01-01 Panametrics, Inc. Method and apparatus for feedback stabilized photometric detection in fluids
WO1992000513A1 (fr) * 1990-06-27 1992-01-09 Futrex, Inc. Mesure non invasive de glycemie
WO1993007801A1 (fr) * 1991-10-17 1993-04-29 Scientific Generics Limited Procede et appareil de determination non-invasive d'analytes sanguins
US5424843A (en) * 1992-12-23 1995-06-13 The Regents Of The University Of California Apparatus and method for qualitative and quantitative measurements of optical properties of turbid media using frequency-domain photon migration
EP0722692A1 (fr) * 1995-01-20 1996-07-24 Hughes Aircraft Company Méthode noninvasive et appareil pour déterminer des composants chimiques du corps
EP0807812A1 (fr) * 1996-05-16 1997-11-19 Fuji Photo Film Co., Ltd. Procédé et dispositif pour mesurer la concentration de glucose
DE19741198A1 (de) * 1996-12-06 1998-06-18 Siemens Ag Gerät zur nichtinvasiven Messung von Vitalparametern
US5855205A (en) * 1994-06-30 1999-01-05 U.S. Philips Corporation Device for and method of carrying out optical measurements in turbid media
WO2000016692A1 (fr) * 1998-09-18 2000-03-30 Proniewicz Walter K Mesure non invasive de la glycemie fondee sur des observations optoelectroniques de l'oeil

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4200362A (en) * 1972-09-25 1980-04-29 Retina Foundation Ophthalmoscope with uniform illumination
US4249825A (en) * 1979-05-14 1981-02-10 The Trustees Of Boston University Method and apparatus suitable for ocular blood flow analysis
US4491730A (en) * 1980-08-14 1985-01-01 Panametrics, Inc. Method and apparatus for feedback stabilized photometric detection in fluids
WO1992000513A1 (fr) * 1990-06-27 1992-01-09 Futrex, Inc. Mesure non invasive de glycemie
WO1993007801A1 (fr) * 1991-10-17 1993-04-29 Scientific Generics Limited Procede et appareil de determination non-invasive d'analytes sanguins
US5424843A (en) * 1992-12-23 1995-06-13 The Regents Of The University Of California Apparatus and method for qualitative and quantitative measurements of optical properties of turbid media using frequency-domain photon migration
US5855205A (en) * 1994-06-30 1999-01-05 U.S. Philips Corporation Device for and method of carrying out optical measurements in turbid media
EP0722692A1 (fr) * 1995-01-20 1996-07-24 Hughes Aircraft Company Méthode noninvasive et appareil pour déterminer des composants chimiques du corps
EP0807812A1 (fr) * 1996-05-16 1997-11-19 Fuji Photo Film Co., Ltd. Procédé et dispositif pour mesurer la concentration de glucose
DE19741198A1 (de) * 1996-12-06 1998-06-18 Siemens Ag Gerät zur nichtinvasiven Messung von Vitalparametern
WO2000016692A1 (fr) * 1998-09-18 2000-03-30 Proniewicz Walter K Mesure non invasive de la glycemie fondee sur des observations optoelectroniques de l'oeil

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6853854B1 (en) 1998-09-18 2005-02-08 Q Step Technologies, Llc Noninvasive measurement system
WO2004052204A1 (fr) * 2002-12-06 2004-06-24 Kwan-Ho Kim Systeme de controle de la glycemie
JP2006525084A (ja) * 2003-05-02 2006-11-09 オクリア， インコーポレイテッド 非侵襲的分析物測定のための方法およびデバイス
US8090424B2 (en) 2005-01-10 2012-01-03 Sti Medical Systems, Llc Method and apparatus for glucose level detection
FR2894806A1 (fr) * 2005-12-19 2007-06-22 Spincontrol Sarl Systeme et procede d'imagerie et/ou de mesure reproductibles sur un sujet maintenu par un dispositif de contention
DE102013010611A1 (de) * 2013-06-25 2015-01-08 Sms Swiss Medical Sensor Ag Messvorrichtung und Messverfahren zum Messen von Rohdaten zur Bestimmung eines Blutparameters, insbesondere zur nichtinvasiven Bestimmung der D-Glucose-Konzentration
US9442065B2 (en) 2014-09-29 2016-09-13 Zyomed Corp. Systems and methods for synthesis of zyotons for use in collision computing for noninvasive blood glucose and other measurements
US9448164B2 (en) 2014-09-29 2016-09-20 Zyomed Corp. Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
US9448165B2 (en) 2014-09-29 2016-09-20 Zyomed Corp. Systems and methods for control of illumination or radiation collection for blood glucose and other analyte detection and measurement using collision computing
US9453794B2 (en) 2014-09-29 2016-09-27 Zyomed Corp. Systems and methods for blood glucose and other analyte detection and measurement using collision computing
US9459201B2 (en) 2014-09-29 2016-10-04 Zyomed Corp. Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
US9459203B2 (en) 2014-09-29 2016-10-04 Zyomed, Corp. Systems and methods for generating and using projector curve sets for universal calibration for noninvasive blood glucose and other measurements
US9459202B2 (en) 2014-09-29 2016-10-04 Zyomed Corp. Systems and methods for collision computing for detection and noninvasive measurement of blood glucose and other substances and events
US9610018B2 (en) 2014-09-29 2017-04-04 Zyomed Corp. Systems and methods for measurement of heart rate and other heart-related characteristics from photoplethysmographic (PPG) signals using collision computing
US9554738B1 (en) 2016-03-30 2017-01-31 Zyomed Corp. Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing

Also Published As

Publication number Publication date
AU3213500A (en) 2001-04-24
EP1216409A1 (fr) 2002-06-26
CA2390520A1 (fr) 2001-03-29

Similar Documents

Publication Publication Date Title
US6853854B1 (en) Noninvasive measurement system
US7869848B2 (en) Noninvasive measurement system
KR100314296B1 (ko) 대상물의농도및광학적특성의비-분광광도측정장치및방법
US7167736B2 (en) Non-invasive measurement system and method for measuring the concentration of an optically-active substance
JP3701031B2 (ja) 非侵襲血液検査装置
EP1494577B1 (fr) Analyse spectroscopique d'un tissu permettant de deceler le diabete
US6775565B1 (en) Imaging apparatus for displaying concentration ratios
US20030032064A1 (en) Correction of spectra for subject diversity
WO2004112601A1 (fr) Mesure non effractive du glucose sanguin
WO1996014567A1 (fr) Analyse optique rapide non invasive par traitement spectral a large bande passante
HU216847B (hu) Eljárás és berendezés vérösszetétel-paraméterek gyors noninvazív meghatározására
JP2010284552A (ja) 血糖レベルの非侵入的測定
JP2022009387A (ja) 涙液層厚み測定装置及び方法
WO2001022061A1 (fr) Mesure non invasive du niveau de sucre dans le sang
US6801316B2 (en) Measurement of an analyte concentration in a scattering medium
CN108261202B (zh) 一种测量血糖的系统及其使用方法
US8144960B2 (en) Method for measuring the concentration of a substance using advanced image processing techniques
JP2003524153A (ja) 血糖レベルの非侵入的測定
KR20020070964A (ko) 혈당 수준의 비 관혈적 측정법
CN113180622B (zh) 生物信息测量方法、装置、设备、存储介质及程序产品
CN116898430A (zh) 一种多波段近红外发光拍摄装置及数据采集方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1020027003472

Country of ref document: KR

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 525185

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 2000909963

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2390520

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 2000909963

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020027003472

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1020027003472

Country of ref document: KR

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)