EP0626819A1 - Mesure non invasive de la glycemie - Google Patents

Mesure non invasive de la glycemie

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Publication number
EP0626819A1
EP0626819A1 EP94905335A EP94905335A EP0626819A1 EP 0626819 A1 EP0626819 A1 EP 0626819A1 EP 94905335 A EP94905335 A EP 94905335A EP 94905335 A EP94905335 A EP 94905335A EP 0626819 A1 EP0626819 A1 EP 0626819A1
Authority
EP
European Patent Office
Prior art keywords
optical
polarized
laser beam
fiber
glucose
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94905335A
Other languages
German (de)
English (en)
Other versions
EP0626819A4 (en
Inventor
Vladimir Kuperschmidt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunshine Medical Instruments Inc
Original Assignee
Sunshine Medical Instruments Inc
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 US08/007,568 external-priority patent/US5398681A/en
Priority claimed from US08/071,321 external-priority patent/US5448992A/en
Application filed by Sunshine Medical Instruments Inc filed Critical Sunshine Medical Instruments Inc
Publication of EP0626819A1 publication Critical patent/EP0626819A1/fr
Publication of EP0626819A4 publication Critical patent/EP0626819A4/en
Withdrawn legal-status Critical Current

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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
    • A61B5/14558—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 by polarisation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/21—Polarisation-affecting properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7203—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal
    • A61B5/7207—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal of noise induced by motion artifacts

Definitions

  • the present invention relates to measuring the concentration of glucose, more particularly to the non-invasive, phase-sensitive measurement of the glucose concentration in blood.
  • finger poke Another invasive technique, referred to as a "finger poke” or a “finger stick” uses an integrated, self-contained instrument that evaluates a much smaller blood sample (approximately 0.25 ml).
  • the small blood sample is obtained by puncturing a finger with a small lancet.
  • the sample is then placed on a chemically treated carrier and inserted into the instrument.
  • the finger poke devices normally provide the glucose concentration results in a few moments. However, they are still quite costly for private use, i.e., in the range of several thousand dollars.
  • Invasive techniques for glucose analysis are problematic and suffer from poor patient compliance. Many people who would benefit from knowing their glucose concentration are reluctant to have blood withdrawn by a finger poke or a hypodermic needle or have a generalized fear of invasive medical procedures. Still others suffer anxiety in connection with the sampling and worry about the discomfort (pain) and possibility of infection. Another problem is that frequent invasive glucose testing uses up convenient sample sites and complicates further testing until the used convenient sites heal.
  • Non-invasive methods for measuring blood constituents including glucose have been described. However, to date none of these techniques has resulted in a commercially useful instrument.
  • the non-invasive monitoring methods are roughly divided into measurements based on either the intensity of light being transmitted through or reflected from the tissue, or the phase shift of modulated light transmitted through the tissue (the "phase-sensitive" measurement) .
  • the known intensity sensing methods for measuring the level of a blood constituent, including glucose, are based on measuring a real absorption spectrum for blood perfused tissue at two or more different wavelengths, and subtracting therefrom the statistical absorption spectra for each of the various blood components, except for the one component being measured. It is assumed that after such subtraction, the remainder is a real spectrum of the constituent to be measured.
  • Rosenthal et al. U.S. Patent 5,086,229 refers to such a non-invasive, near-infrared quantitative analysis instrument for measuring blood glucose.
  • the instrument contains a plurality of near-infrared laser sources having different wavelengths of emission and one or a plurality of photodetectors.
  • a blood-containing part e.g., a finger
  • the light sources are illuminated and the wavelengths then transmitted through the blood-containing part are detected.
  • the real absorption spectrums obtained from the photodetector signals are compared with individual statistical absorption spectra of each constituent, which are stored in the memory of the instrument.
  • a glucose level is derived from the comparison.
  • the intensity measuring instruments suffer from the following disadvantages.
  • the subtraction technique is based on statistically derived absorption data for each individual constituent, the results obtained are of necessity statistical.
  • the differences between the actual glucose level in blood and the results of statistical measurements may be substantial and significant.
  • the absorption due to the glucose concentration is very small compared to other components such that statistical errors may be a greater component of the determined value than the actual glucose component.
  • the non-invasive phase sensitive measurement methods possess significantly higher sensitivity and a much higher signal-to-noise ratio than intensity-measurement methods.
  • the higher sensitivity is the consequence of the noise sources affecting the amplitude, but not the phase, of a signal.
  • an instrument compares a known reference signal, e.g., a sine wave, with a measurement signal that has been passed through the tissue.
  • the measurement signal will have a time delay (phase shift) relative to the reference signal because of various factors, e.g., a fluorescence time delay, etc. Concentrations of blood constituents then may be obtained from a measurement of the time delay (phase shift) .
  • Cote refers to passing linearly- polarized light through the anterior chamber of an excised human eye and determining the glucose level of the aqueous eye humor based on the phase shift between the reference signal and the measurement signal that was converted by the glucose.
  • a helium-neon laser beam coupled through a rotating linear polarizer along with two stationary linear polarizers and two detectors, is used to produce reference and signal outputs.
  • the polarizer was rotated by means of a synchronous electric motor.
  • the amplitudes of these outputs varied sinusoidally with a frequency twice that of the angular velocity of the rotating polarizer.
  • the phase difference of the outputs would be proportional to the rotation of the linear polarization vector passing through the anterior chamber of the eye.
  • Cote apparatus uses a synchronous motor which generates mechanical vibrations which cannot exceed, e.g., 200 Hz. Therefore, the frequency of rotation of the motor falls into the frequency range (1 Hz to 600 Hz) of mechanical vibrations produced by different sources, interferes with those mechanical vibrations, and produces high measurement noise.
  • the Cote technique can be implemented only under laboratory conditions where mechanical vibrations can be isolated, and is unsuitable for application in the form of a portable instrument for personal use.
  • Another problem with the Cote measurement system is that it is based on passing the light through the human eye. It is thus inconvenient for practical self-administration of the test. More important, however, is that the eye is subject to involuntary high-frequency movements (such as microsaccadic movements) which fall into the same frequency range as the rotating frequency of the driving motor of the system and have amplitudes of 1 to 3 min of arc. Should the apparatus be used in vivo, such involuntary eye movements would lead to interference with the measurement signals and would markedly increase the measurement noise.
  • an object of the invention to overcome the disadvantages of existing non-invasive instruments and to provide improved methods and apparatus for the non-invasive phase-sensitive measurement of blood constituents such as glucose, based on phase-sensitive measurements.
  • the invention concerns apparatus and methods for the non-invasive measurement of the concentration of a constituent in blood based on precision, phase sensitive and high signal to noise measurements.
  • One aspect of the invention is directed to methods and apparatus for producing a phase-modulated laser beam via a polarizing frequency shifter, measuring a phase difference introduced, e.g., by a finger or a ear lobule of a subject, measuring phase difference between a reference signal and a probe signal, and processing the obtained data which are then presented as blood glucose concentration.
  • One such method is for the non-invasive precision phase sensitive measurement of the glucose level in the blood and includes the steps of: passing a beam emitted by an infrared laser beam source through a polarizing frequency shifter that is driven by a piezoelectric transducer and produces a polarized-modulated beam having a direction of polarization rotating in the plane of polarization with a frequency of rotation falling into a frequency range beyond that of mechanical vibrations; passing the polarized-modulated beam through an optical transducer which splits the polarized-modulated beam into a reference optical beam and a probe optical beam; passing the probe optical beam through a blood- carrying body part to form a passed probe optical beam, the above-mentioned optical transducer having a first sensor for measuring the reference optical beam and converting it into a reference electric signal having a phase corresponding to the polarized-modulated optical beam, and a second sensor for measuring the passed probe beam and converting it into a probe electric signal having a phase corresponding to the passed probe beam, the
  • the phase difference is preferably measured by subtracting the phase of reference electric signal from the phase of the scattering-free probe electric signal.
  • the blood-carrying body part may be any well perfused tissue in which blood vessels are distributed with high density such as an appendage, e.g., finger, earlobe, toe or bridge of the nose.
  • an appendage e.g., finger, earlobe, toe or bridge of the nose.
  • the laser beam is preferably transmitted through the nail-bed, which is especially concentrated with blood vessels.
  • One such apparatus includes a polarizing frequency shifter which is based on the use of bulk optics (crystal optics) . Although satisfactory, it is relatively expensive and cannot be easily produced in small dimensions because its polarizing frequency shifter cannot be manufactured in an integrated-optic implementation. Hence, the present invention also is directed to an improvement of the bulk optics methods and apparatus disclosed herein, namely, the non-invasive phase-sensitive measurement of blood glucose level which is small in size and can be produced in integrated-optic implementation.
  • another aspect of the invention is directed to a method and apparatus for the non-invasive precision phase sensitive measurement of the glucose level in the blood using integrated fiber optics.
  • One such method includes the steps of: passing a beam emitted by an infrared laser beam source through an optical phase modulator that is fiber-optic based and driven by a piezoceramic transducer and produces two polarized-modulated beams, each having a direction of polarization rotating in the plane of polarization with a frequency of rotation falling into a frequency range beyond that of mechanical vibrations, as a reference optical beam and a measurement optical beam; passing the measurement optical beam through a blood-carrying body part to form a passed measurement optical beam; measuring the reference optical beam and converting it into a electrical reference signal having a phase corresponding to the polarized-modulated optical beam; measuring the passed measurement optical beam and converting it into a electrical measurement signal having a phase corresponding to the passed measurement beam, preferably using a balanced receiver having means for dividing the passed measurement optical beam into a
  • One such apparatus includes: a laser beam source; an optical phase modulator including a polarizer, an optic-fiber system that has an input coupler that couples the polarized laser beam into two polarization preserving fiber-optic conductors, a phase shifter that strains one of the fiber-optic conductors to modulate the beam propagating therein, an output optical coupler that reco bines and coherently mixes the phase modulated beam and the unmodulated beam and then couples the combined beams into the outputs of the two fiber-optic conductors, a quarter-wave plate structure that converts the respective outputs of the two fiber ⁇ optic conductors into a polarized-modulated reference beam and a measurement beam; a glucose measuring head that has an aperture to receive a blood-carrying tissue and a balanced receiver which receives the measurement optical beam after it passes through the tissue and produces an electrical measurement signal corresponding to the phase shift due to optical interaction with glucose in the blood; and an electronic signal processing unit that converts the phase difference between the balanced receiver output and the reference beam into
  • the phase difference is preferably measured by subtracting the phase of reference electric signal from the phase of the scattering-free probe electric signal.
  • the blood-carrying body part may be any well perfused tissue in which blood vessels are distributed with high density such as an appendage, e.g., finger, earlobe, toe or bridge of the nose.
  • an appendage e.g., finger, earlobe, toe or bridge of the nose.
  • the laser beam is preferably transmitted through the nail-bed, which is especially concentrated with blood vessels.
  • Fig. 1 is a block diagram of an apparatus in accordance with a preferred embodiment of the present invention.
  • Fig. 2 is a schematic structural view of the polarizing frequency shifter of Fig. 1 for measuring polarization rotation angle
  • Fig. 3 is a graph illustrating the rotating vector of polarization in the plane of travel
  • Figs. 4 is a schematic structural view of the optical transducer of Fig. 1;
  • Figs. 4A and 4B are partial structural views of Fig. 4 showing the calibration cell cartridge in different positions;
  • Fig. 5 is a block diagram of the balanced receiver of Fig. 4;
  • Fig. 6 is a schematic structural view of an embodiment of a built-in glucose measuring head of Fig. 1;
  • Fig. 6A is a schematic structural view of another embodiment of a remotely-located glucose measuring unit of Fig. 1;
  • Fig. 6B is a schematic structural view of another embodiment of a glucose measuring head of Fig. 1;
  • Fig. 7 is a block diagram of the electronic signal processing unit of Fig. 1;
  • Fig. 8 is a graph illustrating a calibration procedure
  • Fig. 9 is a schematic structural view of the polarizing frequency shifter in accordance with a second embodiment of the present invention.
  • Fig. 10 is a block diagram of the balanced receiver for operation in conjunction with polarizing frequency shifter of Fig. 9;
  • Fig. 11 is a block diagram of a third embodiment of the present invention utilizing direct frequency modulation of a laser diode
  • Fig. 12 is a schematic structural view of a polarizing frequency shifter of Fig. 11;
  • Fig. 13 is a block diagram of an apparatus in accordance with an alternate preferred embodiment of the present invention.
  • Fig. 14 is a schematic structural view of the optical phase modulator of Fig. 13;
  • Fig. 15 is a perspective view of a section of the phase shifter of Fig. 14;
  • Figs. 16a, 16b, and 16c are graphs illustrating the positions of axes of polarization with respect to an X-Y reference coordinate plane at three locations in the optical phase modulator of Fig. 14, namely at the optical polarizer output, in a first arm of the phase modulator, and in a second arm of the phase modulator, respectively;
  • Fig. 17 is a block diagram of the electronic signal processing unit of Fig. 13.
  • FIG. 1 A preferred embodiment of a non-invasive apparatus in accordance with the present invention is shown in Fig. 1.
  • the apparatus which is designated in general by reference numeral 20, including a light source 22, a polarized frequency shifter ("PFS") 24, an optical transducer unit 30, an electronic signal processing unit 34, and optionally, one or both of an audio transmitter 35 and a visual display device 36.
  • PFS polarized frequency shifter
  • Visual display device 36 may be a conventional liquid crystal display or a paper printer.
  • Audio transmitter 35 may be a speaker (or microphone transducer) that indicates audibly the measured value (and, optionally, some indication of the range of normal values) for visually-impaired individuals.
  • optical signals are shown by double lines and electrical signals are shown by single lines.
  • Light source 22 is preferably a laser source which produces a laser beam, more preferably a laser diode.
  • Laser source 22 has a power-supply unit (not shown) and a collimating lens 40 which produces a collimated optical beam B (1 to 3 mm) with low divergence.
  • the wavelength range is selected to correspond to a known wavelength range that includes a peak of the optical rotation characteristic of the component to be measured.
  • laser source 22 operates in the wavelength of 750 to 1000 nm, e.g., 850 nm (the near-infrared range) and preferably with a low-noise intensity and phase variation.
  • One such laser diode is available from Spectra Diode Labs, San Jose, California. It should be understood that other light sources and other wavelength ranges corresponding to other optical activity peaks for glucose (and similar peaks for other blood constituents) could be used.
  • PFS 24 receives collimated optical beam B and has a piezoelectric transducer ("PZT") 26, which is controlled by a piezoelectric controller 28.
  • Piezoelectric controller 28 is a conventional circuit that generates a modulating signal, e.g. , a sawtooth or triangular waveform at a selected frequency f, preferably responsive to a feedback control signal FS from electronic signal processing unit 34 (as described below) , and causes PZT 26 to vibrate accordingly.
  • PZT 26 is used to impart a phase modulation to a component of optical beam B and PFS 24 produces a linearly polarized-modulated optical beam Bl having a direction of polarization which rotates in the plane of polarization, which is perpendicular to the direction of its propagation with a frequency equal to one-half that of PZT 26.
  • Optical beam Bl is sent to optical transducer 30.
  • Optical transducer 30 receives optical beam Bl and produces a reference electric signal SR corresponding to the phase of optical beam Bl, a polarized electric signal SP corresponding to the phase of optical beam Bl after it has passed through blood-carrying tissue, which includes a phase shift introduced by glucose (described in detail below) , and an electric signal SL, having an amplitude proportional to the thickness of the measured blood-carrying tissue, e.g., a finger.
  • Optical transducer 30 also includes a glucose measuring head 32 which receives the blood-carrying tissue to be measured. Head 32 may be either securely attached to optical transducer 30 (shown in Fig.
  • Electronic signal processing unit 34 is connected to optical transducer 30, receives electric signals SR, SP, and SL and provides feedback signal FS.
  • Unit 34 processes signals SR and SP and produces a measurement phase difference signal S ⁇ .
  • the measurement signal phase difference ⁇ M is then taken together with signal SL and calibration data (which provides information regarding the effective thickness of the blood-carrying body) and converted into information about the glucose concentration.
  • the information may be displayed, e.g., in a decimal digital form on visual display 36, which is connected to electronic signal processing unit 34.
  • Feedback signal FS is used to provide a linear motion of piezoelectric transducer 24 with a fixed frequency f and to avoid hysteresis.
  • signal processing unit 34 also (or alternatively) may be connected to audio transmitter 35 having an audio output AO (see Fig. 6B) .
  • Audio transmitter 35 may repeat the glucose information in an audible form, e.g., by synthesized speech as is conventionally used in the telecommunications field.
  • a preferred structure of PFS 24 includes a polarized-beam splitter cube (hereafter referred to as "PBSC") 42 which has an optical beam input side 42a and an optical beam output side 42b.
  • PBSC 42 splits beam B, which can be unpolarized, into two optical beams BSP and
  • Optical beams BSP and BPP are polarized and have orthogonal (mutually perpendicular) directions of polarizations.
  • Optical beam BSP is a so-called S-polarized beam having a polarization direction which is perpendicular to the plane of incidence (i.e., to the plane of the drawing).
  • Optical beam BPP is a so-called P-polarized beam, having a polarization direction which is in the plane of incidence (i.e., in the plane of the drawing) .
  • a quarter-wave plate is a well known optical element that introduces a phase delay equal to a quarter of the wavelength and which is characterized by a fast axis and a slow axis.
  • Each quarter- wave plate 44 and 46 has an orientation of the direction of their fast axes so that they form a 45° angle with respect to the polarization direction of optical beams BPP and BSP.
  • plates 44 and 46 are illustrated separated from PBSC 42, in the actual construction of PFS 24 they may be cemented or bonded to the respective sides of PBSC 42.
  • Mirrors 48 and 50 are respectively located outwardly of, and spaced distances L48 and L50 from the center C of PBSC 42.
  • the difference between distances L48 and L50 is maintained at a value less than the coherent length of laser diode 22. In order to achieve a desired accuracy on the order of a few millidegrees, it is desirable that the above mentioned distance difference be less than 1.0 mm.
  • One of the mirrors e.g., mirror 50
  • PZT 26 is operated at selected frequency f that is sufficiently high to not be affected by mechanical vibration frequencies, which are typically less than 600 Hz, and sufficiently low to measure a phase shift on the order of ones of millidegrees (e.g., 3 millidegrees).
  • a suitable frequency range is 650 Hz to 15 kHz.
  • a preferred frequency range is selected from between 700 Hz and 5 kHz.
  • a quarter-wave plate 52 Located on optical beam output side 42B of PBSC 42, is a quarter-wave plate 52 which has its fast axis parallel to that of quarter-wave plate 44. Plate 52 is preferably secured to PBSC 42.
  • the S-polarized beam BSP reflects off mirror 48, passes back through center C and exits side 42B of PBSC 42.
  • the P-polarized optical beam BPP reflects off vibrating mirror 50 and becomes phase-modulated, and passes back to center C of PBSC 42 where it is reflected through side 42B and combined with the reflected optical beam BSP.
  • the combined or composite reflected optical beams BSP and BPP then pass through quarter-wave plate 52 to provide polarized-modulated optical beam Bl.
  • the output optical beam Bl of PFS 24 is a vector T which is defined by an angle ⁇ and an amplitude E 0 , as described below, and which is illustrated as beam ⁇ ?(t) in Fig. 3.
  • Fig. 3 illustrates an X-Y coordinate system and a vector ET of polarization which rotates in the plane XY with a frequency f/2.
  • Angle ⁇ is an angle of rotation of vector ⁇ ?, which varies with frequency f/2.
  • Angle ⁇ is determined by the following formula:
  • ⁇ 0 is a constant phase shift caused by the difference in the path lengths L48 and L50 between center C of PBSC 42 and respective mirrors 48 and 50
  • vector e (t) is a single vector of polarization
  • vectors e x and e ⁇ are single coordinate vectors which show the directions of the coordinate axes
  • E 0 is an amplitude of laser beam B.
  • the phase of the polarized- modulated optical beam Bl, and the phase shift introduced by the glucose concentration can be recovered by using the reference polarizer 58 (Fig. 4) and the measuring polarizer 68 in the balanced receiver 62 (Fig. 5) .
  • optical transducer 30 includes an optical beam splitter cube 54 which has an optical beam input side 54a, a reference optical beam output side 54r, and a measurement optical beam output side 54m. It preferably has a ratio of 50/50, i.e., it is a conventional optical element which splits an input optical beam, namely optical beam Bl, into two mutually- perpendicular components, namely optical beams BR and BP with a 50:50 ratio.
  • the one optical beam BR is passed through a reference channel including a neutral-density attenuator 56, a polarizer 58, and a photodetector 60.
  • Attenuator 56, polarizer 58, and photodetector 60 are arranged on an axis with optical beam BR, spaced sequentially from reference optical output side 54r, as illustrated in Fig. 4. In as much as optical beam BR is used to provide a reference phase measurement, its intensity may be attenuated by attenuator 56 to optimize recovery of the phase portion of the optical beam. The attenuation may be on the order of 40-80%.
  • Polarizer 58 is used to recover the reference signal phase information.
  • Photodetector 60 produces electrical signal SR having a phase modulation corresponding to the reference optical beam BR.
  • a cartridge 59 is placed between attenuator 56 and polarizer 58 for calibration purposes.
  • Cartridge 59 contains two reference cells 59a and 59b and a transparent window 61.
  • Cell 59a contains a first concentration Cj of a glucose solution and cell 59b contains a second concentration C 2 of a glucose solution.
  • Each cell has an equal optical pathlength (i.e., the length through which optical beam BR passes), e.g., 1.0 cm.
  • Window 61 has the same construction as cells 59a and 59b except that it is empty. Alternatively, window 61 may be an aperture.
  • cell 59a, transparent window 61, and cell 59b are linearly arranged on a sliding structure with window 61 located between cells 59a and 59b.
  • Cartridge 59 may be shifted from the "central" position, illustrated in Fig. 4, in the direction of either arrow Aj or arrow A 2 to the positions respectively shown in Figs. 4A and 4B. The movement may be manual or automatic under control of microcontroller 116.
  • cartridge 59 is in the central position and optical beam BR passes through window 61.
  • Fig. 4A cartridge 59 is shifted so that optical beam BR passes through cell 59a.
  • Fig. 4B cartridge 59 is shifted so that optical beam BR passes through cell 59b.
  • window 61 and cells 59a and 59b could be used, e.g., cells and window spaced about an axis so that cartridge 59 can be rotated from one position to the next.
  • probe optical beam BP is passed through glucose measuring head 32 to balance receiver 62, which are sequentially located on measurement optical output side 54m of beam splitter cube 54.
  • Probe optical beam BP is passed through the glucose measuring head 32 which may contain the object being measured, e.g., a blood carrying body part (tissue) such as a patient's finger F and produces a passed probe optical beam illustrated in Figs. 4 and 5 as beam BPl.
  • Optical beam BPl contains a polarized component which carries phase shift information related to the glucose concentration and a depolarized scatter component which does not carry such glucose related information. These components are collectively illustrated as optical beam BPl in Fig. 5.
  • the transmission of optical beam BP through blood-carrying body F changes the direction of polarization of optical beam BP.
  • This introduces a phase shift ⁇ M with respect to reference optical beam BR.
  • the transmission of optical beam BP through finger F is accompanied by the depolarization of part of optical beam BP, which is caused by the scattering of the optical beam in the finger.
  • the depolarized component of optical beam BPl has a time- constant average intensity and does not contain any information about the phase shift. Therefore, this component of the passed optical beam contributes only to the noise level of the signal.
  • less than 5% of optical beam BPl remains polarized after passage through the blood-carrying body. However, because only the polarized component of optical beam BPl produces an AC signal, that remaining 5% is sufficient data and may be used to recover the polarized signal.
  • Balanced receiver 62 functions to subtract out electronically the depolarized portion of the optical signal and to leave only the polarized component. It has as its output a probe electric signal SP corresponding to the polarized component of passed probe optical beam BPl.
  • Receiver 62 includes a beam-splitter plate 64 with a 50:50 splitting ratio.
  • Beam splitter plate 64 receives passed probe optical beam BPl and divides optical beam BPl into two equal components BP1-A and BP1-B. One of these components is converted into a polarized component.
  • located on the path of optical beam component BP1-A are a polarizer 68 and a photodetector 70.
  • the other component is used as a depolarized component.
  • located on the path of optical beam BP1-B is a photodetector 72.
  • Photodetectors 70 and 72 are preferably identical and matched and produce polarized component electric signal S-A and depolarized component electric signal S-B on their respective outputs.
  • Electrical signal S-A also is referred to as the polarized electric component.
  • Electric signal S-B also is referred to as the depolarized electric component.
  • Balanced receiver 62 also includes a difference amplifier 74, a low-pass filter 76, and a division amplifier 78.
  • Output electric signals S-A and S-B of photodetectors 70 and 72 are directed to the inputs of difference amplifier 74.
  • the output of difference amplifier 74 is connected to an input of division amplifier 78.
  • Low-pass filter 76 is located between photodetector 72 and division amplifier 78 and passes the DC signal components of signal S-B.
  • the other input to division amplifier 78 is the low pass filtered output of photodetector 72.
  • the signal SP output of division amplifier 78 is the ratio of its inputs and provides probe electric signal SP.
  • Unit 32 includes a housing 80 which has a central cavity 82, a spring-loaded axial stop element 84, a side opening 85, and a spring-loaded pressure element 88 having a compression spring 86. Housing 80 also has a second side opening 90 that is closed with a glass plate 92. Central cavity 82 serves to receive a finger F as a measuring object. Opening 90 serves for directing optical beam BP onto a nail bed NB of finger F. Axial stop element 84 serves to adjust the position of finger F so that optical beam BP intersects nail bed NB.
  • Pressure element 88 is intended for the fixation of finger F during measurement and for increasing the amount of blood in the measured portion of finger F.
  • An increase in the amount of blood in the measured portion of finger F reduces the scattering of the light transmitted through finger F and increases the signal-to-noise ratio of the measurement.
  • housing 80 On the side of finger F opposite to nail bed NB of finger F, housing 80 has a recess 94 accommodating balance receiver 62.
  • Beam-splitter plate 64 of balance receiver 62 is located on the side of finger F opposite to nail bed NB, i.e., on the side of digital pulp DP of finger F. Beam ⁇ splitter plate 64 is protected by a glass plate 96.
  • Recess 94 also contains a sensor 98 which determines the thickness of finger F in the portion being measured and which generates the above-mentioned signal SL.
  • Sensor 90 may be a capacity-type or a resistor-type sensor capable of determining variations in the capacity or in the resistance between the conditions as they are in the absence of finger F and once finger F has been inserted.
  • Fig. 6A another embodiment of glucose measuring head 32A is shown. This embodiment is located remotely from optical transducer 30 and is connected to it through a polarization-preserving fiber-optical link 100. In this case, a ferrule 102 is inserted into side opening 90 and supports a GRIN rod microlens ("GRIN lens”) 104.
  • GRIN lens GRIN rod microlens
  • GRIN lens 104 is a gradient index lens which has an index of refraction which varies in a predetermined relationship with the thickness of the lens. It is intended to produce an output optical beam BP in a collimated form at the output of optical fiber 100. This is used because optical beam BP loses its collimation properties when it is transmitted through optical fiber 100. Polarization preserving optical fibers and GRIN lenses are commercially available products.
  • the remaining parts of unit 32A are the same as those of unit 32 shown in Fig. 6. Referring to Fig. 6B, an embodiment of glucose measuring head 32B for using a patient's earlobe E as the blood-carrying body is shown.
  • glucose measuring head 32B is attached to a head appliance 106 such as an arc-shaped head holder or band or a head band or of the same type as are used in conventional head sets including earphones for supporting microphones on the head of a wearer.
  • Head appliance 106 supports a speaker/microphone 35 for reproducing audio information about the glucose concentration, which is provided by suitable circuitry (not shown) associated with signal processing unit 34.
  • speaker/microphone 35 is supported at one end of head appliance 106.
  • Head appliance 106 also supports a U-shaped clip 101 which, in turn, supports glucose measuring head 32b and which can be attached to earlobe E of the patient.
  • GRIN rod lens 104b with an optical fiber link 100b while the other side of clip 101 holds a balance receiver 62 with a thickness sensor (not shown) .
  • GRIN rod lens 104b, balance receiver 62, and the sensor of the embodiment of Fig. 6B may be the same as those of Fig. 6a. Referring to Fig.
  • electronic signal processing unit 34 includes a phase-sensitive homodyne receiver 114, which receives the reference electric signal SR and the probe electric signal SP and produces on its output an electric signal S ⁇ which is proportional to a blood glucose concentration, a microcontroller 116, which processes signal S ⁇ in order to convert it into a glucose-concentration signal S G , and an analog-digital (A/D) converter 118 which receives, e.g., signal S G and converts it into digital information C G .
  • A/D converter 118 is passed to display 36 for displaying the obtained information about the concentration of glucose in the blood.
  • Phase-sensitive homodyne receiver 114 is a device which determines the phase difference between signals SR and SP. It may operate based on either a lock-in amplifier technique or a time-interval counter operating in a phase mode, in accordance with conventional techniques.
  • One useful phase- sensitive homodyne receiver, with a resolution of 0.001° in phase difference, is available from Stanford Research Systems, Inc. , Sunnyvale, CA.
  • Electronic signal processing unit 34 also contains a memory unit 115 which is connected to microcontroller 116 and which may store data required for custom calibration of apparatus 20, patient's measurement data, etc.
  • a memory unit 115 which is connected to microcontroller 116 and which may store data required for custom calibration of apparatus 20, patient's measurement data, etc.
  • each measurement procedure preferably begins with calibration of apparatus 20.
  • a reference calibration procedure is carried out by first passing optical beam BR through transparent window 61 (Fig. 4) and then sequentially through cells 59a and 59b.
  • the calibration procedure using cells 59a and 59b can be omitted.
  • frequent calibration is desired for continued accuracy.
  • cells 59a and 59b are sequentially shifted (in any order) into the positions shown in Figs. 4A and 4B in which they alternatively interfere with the optical path of optical beam BR.
  • the calibration procedure is the same as measuring the glucose concentration in object F, except that no tissue is inserted in measuring head 32, the meanings of signals SR and SP are reversed, and signal SL is not used because the sample cell path length is known, i.e., 1 cm.
  • the details of the propagation of the optical beams and processing of the obtained information is discussed below with reference to the measurement of glucose in blood carrying body' part F.
  • Both cells 59a and 59b contain glucose solution samples of different known glucose concentrations Cj and C 2 .
  • cells 59a and 59b alternatively may contain or comprise some optically active material (in any state) , other than two different solutions of glucose, which have the same effects on the polarized-modulated laser beam as do the glucose solutions at two different known concentrations, but have a longer useful life than solutions of glucose.
  • phase shift ⁇ M between probe electric signal SP and reference electric signal SR will depend on many factors, including effective pathlength L EFF for beam BP.
  • Effective length L EFF is only that part of the optical path of beam BP which is passed only through the blood-filled portion of the measurement object and differs from actual thickness of the finger. Therefore, in order to obtain the glucose-concentration information from the results of measurement, it is necessary to subtract all extraneous data.
  • Phase shift ⁇ M may be generally expressed by the following formula (1) :
  • ⁇ SUB is a phase shift introduced by other blood components which also are optically active, i.e., subject to optical rotation at the wavelength of light used
  • ⁇ GL is a known optical parameter which, for a given wavelength, may be obtained from spectroscopy data.
  • This parameter and effective path-length L EFF may be obtained based on two (or more) measurements taken at different glucose concentrations for which the glucose concentrations are obtained by a conventional invasive procedure (e.g.> a finger poke measurement, laboratory analysis, or other biochemical analysis method, preferably on the basis of finger poke measurements) .
  • the concentration of glucose is measured at least twice: for example, once on an empty stomach and once an hour after administration of a concentrated solution of dextrose (or any other substance which raises the blood glucose level) .
  • These calibrating measurements need be performed only once for each person, prior to using the apparatus for the first time, as part of a start-up calibration procedure.
  • the results of such two calibrating measurements may be expressed by the following formulae (2.1) and (2.2) :
  • ⁇ M CGL ( ⁇ MZ " ⁇ MI ) + ⁇ SUB + ⁇ 0 (4 )
  • Fig. 8 shows the normalized curve D and curve K.
  • the ordinate represents ( ⁇ M - ⁇ 0 ) /L EFF .
  • memory unit 115 contains a suitable algorithm, which can be derived from experimentally acquired data, for processing the above- mentioned data by known methods of correlation analysis so as to minimize the above-mentioned deviations.
  • One of the variables of such algorithm may be an actual thickness of the finger. It is understood that the above formulae are parts of the algorithm and that all calculations are performed automatically in microcontroller 116.
  • apparatus 20 of the invention for measuring the blood-glucose concentration will be now described for the case of glucose measuring head 32 for a finger F built into the apparatus (i.e., for non-remote version of Figs. 4 and 6) .
  • laser diode 22 When apparatus 20 is switched on, laser diode 22 generates a laser beam B which is directed through collimating lens 40 to PFS 24.
  • PFS 24 produces a polarization modulation of optical beam B via mirror 50 and PZT 26 which is driven by piezoelectric controller 28.
  • the resulting polarized-modulated optical beam Bl is sent to optical transducer 30.
  • Optical transducer 30 splits optical beam Bl into a polarized-modulated reference optical beam BR and a polarized-modulated probe optical beam BP.
  • Reference optical beam BR is passed through optical attenuator 56, window 61, polarizer 58, and converted by photodetector 60 into reference electric signal SR.
  • Probe optical beam BP is sent to glucose measuring head 32.
  • the transmitted optical beam BPl passes through protective plate 96 to a beam-splitting plate 64 of balanced receiver 62.
  • optical beam BPl is split into two optical beams BP1-A and BP1-B.
  • Component BP1-A is directed through polarizer 68 to photodetector 70.
  • Photodetector 70 produces an electrical signal S-A corresponding to the polarized component of optical beam BP1-A, which is input to difference amplifier 74.
  • component BP1-B is directly passed to photodetector 72.
  • Photodetector 72 produces an electric signal S-B corresponding to the non-polarized component of optical beam BP1-B, which is also input to difference amplifier 74.
  • Difference amplifier 74 then provides an output that is the difference between the electrical signals S-A and S-B corresponding to depolarized and polarized components of optical beams BP1-A and BP1-B.
  • the output signal of difference amplifier 74 thus carries information only about the polarized component BP1-A. However, the amplitude of this difference signal still contains noise associated with light scattering. To further reduce this noise component, the amplitude of the output signal from difference amplifier 74 is divided, in division amplifier 78, by the amplitude of the signal from photodetector 72 which contains the same scattering noise.
  • the output of photodetector 72 is passed through low-pass filter 76 for removing frequencies above 10 to 100 Hz and the filtered signal is provided as the denominator to the division amplifier 78.
  • the resulting probe electric signal SP thus carries information about polarized component BP1-A, but the amplitude of signal SP is free of the noise influence.
  • Reference electric signal SR and probe electric signal SP are then passed to phase-sensitive homodyne receiver 114.
  • An output of homodyne receiver 114 is provided as a feedback signal FS to piezoelectric controller 28.
  • Receiver 114 extracts a phase-difference signal S ⁇ , which is sent to the input of microcontroller 116.
  • microcontroller 116 receives length measurement signal SL from sensor 98 and calibration data from memory unit 115.
  • microcontroller 116 produces a signal S G proportional to the concentration of glucose.
  • Signal S G is converted by A/D converter 118 into a digital glucose-concentration information C G which can be shown on display 36 and/or indicated on display 35.
  • the apparatus uses averaging techniques for the measurements to extract the best signal to noise information and may require up to a minute to produce a glucose concentration measurement. Averaging will average out variations in blood volume due to pulsatile blood flow, motion artifact and other movements.
  • Apparatus 20 made in accordance with the embodiment of the remotely located glucose measuring head shown in Fig. 6A operates in the same manner as the apparatus of the embodiment of Fig. 6 except that optical beam BP is transmitted to finger F or another blood-carrying part, via optical-fiber link 100 and GRIN lens 104.
  • head appliance 106 is put on the patient's head as in the case of a conventional headphone so that transducer 108 is located near one ear of the wearer while the lobule E of the other ear of the patient is clamped by clip 101. In this manner, ear lobule E is located on the optical path of optical beam BP between fiber-optical link 100b and balanced receiver 62b. All other parts operate on the same principle as similar parts of the previous embodiment.
  • apparatus 20 may have small dimensions of about 40 cm x 15 cm x 20 cm, or less. This allows the use of the apparatus as a home and portable monitoring device. Use of customizable ASIC devices and/or customized integrated circuits will permit reducing the size further.
  • a rechargeable battery (or replaceable battery) may be used to operate the system electronics to permit portable use.
  • Figs. 1 through 8 relate to a method and apparatus based on the measurement of a polarization rotation angle of light transmitted through in vivo tissue.
  • the above described method and apparatus are based in part on an assumption that dependence of an angle of rotation on a wavelength has a maximum and that in a preferred embodiment of the apparatus the operative wavelength corresponds to this particular maximum.
  • any optically active medium e.g., glucose
  • the above medium may either change the angle polarization of the linear component of the polarized incident light, or (if the incident light contains left and right circular polarized components) it may absorb the left and right circular polarized components differently.
  • the latter one is known as "circular dichroism".
  • FIG. 1 Another aspect of the present invention concerns an apparatus for determining blood-glucose concentration by measuring circular dichroism.
  • the apparatus is the same as the one described above with reference to Figs. 1 through 8.
  • the main difference between both embodiments is in the structure of the polarizing frequency shifters. Therefore, in the following description of the apparatus based on measurement of circular dichroism, only those components and elements which are different will be described in detail.
  • the portions of the second embodiment having parts identical with the first embodiment will be designated by the same reference numerals with an addition of 100.
  • Polarizing frequency shifter of Fig. 9 is' identical to polarizing frequency shifter 42 of Fig. 2, with the exception that shifter 142 does not have output quarter-wave plate 52.
  • Fig. 10 shows a block diagram of a photoreceiver 162 of Fig. 4 which is suitable for the embodiment of the shifter of Fig. 9.
  • the parts identical with those of Fig. 5 will be designated by the same reference numerals, but with an addition of 100.
  • Receiver 162 includes a photodiode 170 which receives probe optical beam BPl and converts it into a mixture of DC and AC electrical signals.
  • An output of photodiode 170 is connected to a division amplifier 178 via a low-pass filter 174 and a high-pass filter 171 which are connected in parallel to each other.
  • An output of division amplifier 178 is an AC signal S out which may be represented by the following a formula:
  • ⁇ RCD and ⁇ LCD are absorption coefficients for right and left circular polarized lights
  • ⁇ 0 is an absorption coefficient for a non-polarized light
  • laser diode 22 When apparatus 20 is switched on, laser diode 22 generates a laser beam B which is directed through collimating lens 40 to PFS 124 (Fig. 9) .
  • PFS 124 produces a polarization modulation of optical beam B via mirror 150 and PZT 126 which is driven by piezoelectric controller 28.
  • the resulting polarized-modulated optical beam Bl constitutes a 50%:50% mixture of left and right circular polarized beams, which may be expressed as follows:
  • E B1 E RCP ( 1 - ie 12 ft+1 °) + E LCP ( 1 + ie 12 ft+1 °)
  • E RCP is the amplitude of the right circular polarized component of beam Bl
  • E LCP is the amplitude of the left circular polarized component of beam Bl
  • E B ⁇ is the amplitude of beam Bl
  • ⁇ 0 and f are the same as defined in the first embodiment.
  • Optical transducer 30 splits optical beam Bl into a polarized-modulated reference optical beam BR and a polarized-modulated probe optical beam BP.
  • Reference optical beam BR is passed through optical attenuator 56, window 61, polarizer 58, and converted by photodetector 60 into reference electric signal SR.
  • Probe optical beam BP is sent to glucose measuring head 32.
  • the patient For measuring the blood glucose level, the patient inserts his/her finger F into opening 82 against spring-loaded stop element 84 and adjusts the position of finger F so that nail bed NB is aligned with the position of side opening 90.
  • spring-loaded pressure element 88 applies pressure to finger F behind the measurement portion, whereby the amount of blood in the finger flesh to be measured increases to increase the sensitivity of measurements.
  • Probe optical beam BP thus passes through the blood of finger F and becomes passed probe optical beam BPl.
  • Transmission of probe optical beam BP through finger F changes the direction of polarization of the resulting optical beam BPl because glucose is an optically active material for the wavelength of probe optical beam BP.
  • an absorption difference occurs between the left and right circular polarized components of the incident light.
  • the absorption difference is on the order of (2 to 5)xl0 "5 .
  • the transmitted optical beam BPl passes through protective plate 96 to a photodiode 170.
  • the output signal of photodiode 160 is sent via parallel filters 171 and 174 to division amplifier 178 which produces on its output an AC signal S out .
  • the output signal S out which carries information only about circular dichroism caused by glucose absorption of the light, constitutes a probe electrical signal SP.
  • Reference electric signal SR and probe electric signal SP are then passed to phase-sensitive homodyne receiver 114.
  • An output of homodyne receiver 114 is provided as a feedback signal FS to piezoelectric controller 28.
  • Receiver 114 extracts the amplitude of probe electrical signal SP, which is sent to the input of microcontroller 116.
  • microcontroller 116 receives length measurement signal SL from sensor 98 and calibration data from memory unit 115. The signals are finally processed in a manner similar to the apparatus of the first embodiment.
  • Fig. 11 is a block diagram of an apparatus of a third embodiment utilizing direct frequency modulation of a laser diode.
  • Fig. 12 is a schematic structural view of a polarizing frequency shifter of Fig. 11 for use in conjunction with the third embodiment.
  • the parts identical with those of Figs. 1 and 2 will be designated by the same reference numerals but with an addition of 200.
  • Fig. 11 The apparatus shown in Fig. 11 is generally the same as the one of Fig. 1 with the following exceptions: piezo-transducer (PZT) 26, piezo controller 28, and feedback FS from electronic signal processing unit 34 to piezoelectric controller 28 are eliminated, while some new elements are introduced.
  • the new elements are a current controller 227 and a triangular wave generator 229, and feedback FS1 from electronic signal processing unit 234 to current controller 227 (Fig. 11) .
  • Current controller 227 is connected to laser diode 222 and to triangular wave generator 229. In fact, current controller 227 is an element of apparatus of Fig. 1, as well, but it has not been shown.
  • a polarizing frequency shifter (PFS) 224 is the same as PFS 24 with the exception that PZT 26 is removed.
  • phase modulation in PFS 224 may be expressed by the following formula:
  • ⁇ 0 is a statical phase shift
  • f is a PFS frequency
  • ⁇ is a frequency-to-current conversion factor of laser diode
  • ⁇ L is an optical-path difference in PFS 224
  • I a is an amplitude of current modulation produced by triangular wave generator 229
  • f garbage is a frequency of the triangular wave
  • 0 is an optical frequency of laser diode 222.
  • PFS 224 operates in the same manner as PFS 24, with the exception that both mirrors 248 and 250 are not subject to vibrations because the beam is modulated not by vibration of the mirrors but by directly changing the frequency of laser diode 222.
  • FIG. 13 A schematic block diagram of a fiber optic-based implementation of the invention is shown in Fig. 13.
  • the apparatus which is designated in general by reference numeral 320, includes a laser source 322 which produces a laser beam B, an optical phase modulator (OPM) 332 which receives laser beam B from laser source 322, a glucose measuring head 326 which contains a sensor in the form of a balanced receiver 328, and an electronic signal processing unit 330 connected to OPM 332 and to balanced receiver 328.
  • OPM optical phase modulator
  • Glucose measuring head 326 is connected to OPM 332 via a single-mode polarization-maintaining fiber-optic link 334.
  • Laser source 322 is preferably a laser diode which operates in the wavelength of 750 to 1000 nm (the near-infrared.range) , e.g., 850 nm, with a low-coherence length and preferably with a low-noise intensity and phase variation.
  • a laser source of such type is produced, e.g., by Spectra Diode Labs, San Jose, California.
  • Laser source 322 has a corresponding power-supply unit (not shown) . It should be understood that other light sources and other wavelength ranges corresponding to other optical activity peaks for glucose (and similar peaks for other blood constituents) could be used.
  • OPM 332 comprises the following elements, arranged sequentially in the direction of propagation of laser beam B emanating from laser beam source 322: an optical isolator 336 which prevents back reflection of laser light to laser source 322, an input polarizer 338, two fiber-optic arms 340 and 342 which are interconnected by means of an input optical coupler 344 and an output optical coupler 346, an optical phase shifter 348 which is attached to fiber-optic arm 340, a quarter-wave plate 350, a glucose reference cartridge 352, an output polarizer 354, and a photodiode 356.
  • Optical polarizer 338 polarizes laser beam B so that the direction of its polarization forms a 45° angle to axis X, where, as shown in Fig. 16a, axis X is one of coordinate axes of the reference X-Y coordinate system.
  • Fig. 16a is a graph illustrating position of the axis of polarization with respect to an X-Y reference coordinate plane at the output of polarizer 338.
  • Fiber-optic arms 340 and 342 are used to propagate light from laser source 322 to output quarter-wave plate 350. Each of fiber-optic arms 340 and 342 supports propagation of light in one of two orthogonally polarized modes.
  • fiber-optic arm 340 is oriented so that it can support propagation of light mode with Y-axis direction of polarization, as illustrated in Fig. 16b
  • fiber-optic arm 42 is oriented so that it can support propagation of light mode with X-axis direction, as illustrated in Fig. 16c.
  • fiber-optic arm 340 At its end facing optical polarizer 338, fiber-optic arm 340 has an optical lens 358 which is a GRIN rod microlens. From GRIN rod microlens 358, the laser beam is coupled into arm 340 and passes to input optical coupler 344.
  • Input optical coupler 344 is formed by fusing fiber ⁇ optic arms 340 and 342.
  • Commercial optical couplers are available, e.g., from SEASTAR Optics, Inc., Seattle, Washington. It is analogous in its action to a beam splitter with a 50:50 ratio, and splits laser beam B into two components Bl and B2. Beam component Bl propagates along fiber-optic arm 340 and beam component B2 propagates along fiber-optic arm 342. However, in as much as each arm supports a different one mode of propagation, the components Bl and B2 are not identical.
  • phase shifter 348 is made in the form of a thin-walled piezoceramic ring 360 around which fiber-optic arm 340 is wrapped to form a coil 362.
  • Piezoceramic ring 360 is electrically connected to electronic signal processing unit 330 (not shown) .
  • Unit 330 sends to piezoelectric ring 360 a signal FS, preferably an AC voltage which causes alternating contractions of piezoceramic ring 360, and thus phase modulates optical beam Bl.
  • phase shifter 348 is controlled by a piezoelectric controller 421 (shown in Fig. 17) .
  • Piezoelectric controller 421 is a conventional circuit that generates a modulating signal FS, e.g., a sawtooth or triangular waveform at a selected frequency f, preferably responsive to a feedback control signal FB from electronic signal processing unit 330 (as described below) , and causes ring 360 to vibrate accordingly.
  • Output optical coupler 346 also is formed by fusing optical fiber arms 340 and 342 to provide coherent mixing of the two light propagating modes of arms 340 and 342. As a result, each output portion 340a and 342a of a respective optical fiber arms 340 and 342 has a complementary coherent mixture of optical beams Bl and B2 with an orthogonal direction of polarization.
  • Each output portion 340a and 342a is terminated in a GRIN rod microlens, lenses 343 and 345, respectively.
  • GRIN rod microlens 343 is aligned with quarter wave plate 350 window 350a and GRIN rod microlens 345 is aligned with quarter wave plate 350 window 50b.
  • Quarter-wave plate 350 is a conventional device which introduces a phase delay equal to a quarter of the wavelength of the incident beam and is characterized by a fast axis and a slow axis. Quarter-wave plate 350 has a direction of its axis of polarization parallel to that of input polarizer 338.
  • the beam emitted from GRIN rod microlens 343, after passing through window 350a, is a polarized-modulated optical beam which is used as a reference optical beam BR.
  • the beam emitted from GRIN rod microlens 345, after passing through window 350b, is a polarized-modulated optical beam which is used as a measurement optical beam BM.
  • Reference optical beam BR is passed through a polarizer 354 and sensed by a photodetector 356 which produces an electrical reference signal SR corresponding to the phase of optical beam BR. It should be understood that measurement beam BM is used in the same manner as probe beam BP previously described.
  • Glucose measuring head 326 which receives the blood- carrying tissue to be measured, may be either securely attached to optical transducer 330 (not shown) or physically disconnected from optical transducer 330 for remote use and coupled to OPM 32 by an optical fiber link 334 (shown in Fig. 13, and shown in Figs. 6A and 6B as element 100 and 100B) . It receives measurement optical beam BM and, as discussed below, produces an output electrical measurement signal SM corresponding to the phase of the measurement optical beam BM after is has passed through the tissue. Signal SM is thus essentially the same as signal SP previously described.
  • Electronic signal processing unit 330 is connected to OPM 332, receives electric signals SR, SM, and a signal SL corresponding to the thickness of the tissue through which the optical beam BM passes and provides a piezoceramic control signal FS.
  • Unit 330 processes signals SR and SM and produces a measurement phase difference signal S ⁇ in the same manner described above.
  • Signal FS is used to provide a linear motion of piezoceramic ring 60 with a fixed frequency f and to avoid hysteresis.
  • Each output optical beam BR and BM is a polarized- modulated optical beam that is characterized by the strength of an electrical field E. As shown and previously described in connection with Fig. 3, each above-mentioned field E also can be represented by a coordinate system (axes X and Y) and a vector E * of polarization which rotates in the plane XY with a frequency f/2.
  • a cartridge 352 is preferably placed between quarterwave plate 350 and output polarizer 354 for calibration purposes, in the same manner as previously described with reference to Figs. 4, 4a and 4b.
  • measurement optical beam BM is passed through glucose measuring head 326 to balance receiver 328.
  • Glucose measuring head 326 and balanced receiver 328 operate in essentially the same manner as the different glucose heads and balanced receiver embodiments already discussed in connection with Figs. 1-8, with the understanding that beams BP, BPl, BP1-A and BP1-B of Figs. 1-8 correspond to beams BM, BMl, BMl-A and BMl-B in the embodiment of Fig. 14.
  • balanced receiver 328 functions to subtract out electronically the depolarized portion of the optical signal BMl and to leave only the polarized component. It has as its output an electrical measurement signal SM corresponding to the polarized component of passed measurement optical beam BMl.
  • electronic signal processing unit
  • 330 is similar to unit 30 already described in connection with Fig. 7 (the same elements given the same reference numbers are the same except as otherwise indicated) and includes a phase-sensitive homodyne receiver 114, which receives the reference electric signal SR and the measurement electric signal SM and produces on its output an electric signal S ⁇ which is proportional to a blood glucose concentration, a microcontroller 116, which processes signal S ⁇ in order to convert it into a glucose-concentration signal S G , and an analog-digital (A/D) converter 118 which receives, e.g., signal S G and converts it into digital information C G .
  • the output of A/D converter 118 is passed to display 119 for displaying the obtained information about the concentration of glucose in the blood.
  • Electronic signal processing unit 330 also contains a piezocontroller 421 which is connected via a feedback signal FB with phase-sensitive homodyne receiver 114.
  • Piezocontroller 421 is connected to phase shifter 448 (Fig. 2) .
  • Piezocontroller 421 is a device which controls waveforms of an AC voltage signal FS supplied to phase shifter 448.
  • each measurement procedure preferably begins with calibration of apparatus 320 in any of the manners already described (substituting signal SM for SP, BM for BP, etc. ) . Operation of apparatus 320 of the invention of Figs. 13 and 14 for measuring the blood-glucose concentration will be now described for the case of glucose measuring head 326 built into the apparatus (i.e., for non-remote version).
  • laser diode 322 When an apparatus 320 is switched on, laser diode 322 generates a laser beam B which is directed to fiber-optic arm 340.
  • beam B passes through input optical coupler 344, it is split into two mutually-orthogonal beam components Bl and B2.
  • the other, i.e., beam component B2 which propagates through arm 342, remains unchanged.
  • output coupler 346 both beam components Bl and B2 are coherently mixed.
  • each output portion 340a and 342a of respective optical fiber arm 340 and 342 has a complementary coherent mixture of optical beams Bl and B2 with an orthogonal direction of polarization.
  • These beams then pass through windows 350a and 350b of a quarter-wave plate 350 and are transformed into linear-polarized waves, respectively to form optical beams BR and BM.
  • the direction of polarization of these waves rotates with the frequency corresponding to that of phase shifter 348.
  • Measurement optical beam BM is sent directly to glucose measuring head 326.
  • Reference optical beam BR is sent to reference photodetector 356 via cell cartridge 352 and polarizer 354.
  • Reference photodetector 356 produces a reference electrical signal SR.
  • the patient inserts his/her finger F into opening 82 against spring-loaded stop element 84 and adjusts the position of finger F so that nail bed NB is aligned with the position of side opening 90.
  • spring-loaded pressure element 88 applies a pressure to finger F behind the measurement portion, whereby the amount of blood in the finger flesh to be measured is increased to increase the sensitivity of measurements.
  • Measuring beam BM passes out lens 104 and through the blood of finger F and becomes passed measurement beam BMl (BPl in Fig. 6A) . Transmission of measuring beam BM (BP in Fig.
  • phase difference signal S ⁇ phase difference signal
  • microcontroller 116 produces a signal S G proportional to the concentration of glucose.
  • Signal S G is converted by A/D converter 118 into a digital glucose concentration information C G which can be shown and/or indicated on display 119.
  • the apparatus uses averaging techniques for the measurements to extract the best signal to noise information and may require up to several seconds to produce a glucose concentration measurement. Averaging will average out variations in blood volume due to pulsatile blood flow, motion artifact and other movements.
  • the optical phase modulator 332 is modified by deleting quarter wave plate 350.
  • the thus modified apparatus 320 can then be used to determine the phase shift due to, e.g., blood glucose, based on circular dichroism in the same manner as the system based on circular dichroism previously described.
  • apparatus 320 may have small dimensions of about 40 cm x 15 cm x 20 cm, or less. This allows the use of the apparatus as a home and portable monitoring device. Use of customizable ASIC devices and/or customized integrated circuits will permit reducing the size further.
  • a rechargeable battery (or replaceable battery) may be used to operate the system electronics to permit portable use.
  • the invention provides methods and apparatus for non-invasive precision phase- sensitive measurement of blood glucose. These methods and apparatus do not involve the use of mechanically moving parts, result in low-noise measurements, operate in the frequency range beyond that of mechanical vibrations, are suitable for use at home or as a portable blood monitoring device, utilize processing electronics which allow glucose- level measurements through high-scattering tissue, and are not restricted for use with an eye but applicable to other blood-carrying body parts.
  • the device and methods use a single near infrared light source, e.g., a single laser diode.
  • the device obtains a measurement from perfused blood-carrying tissue in effective real time, rather than from aqueous eye humor in which changes in the glucose concentration may lag behind the blood glucose concentration by two hours.
  • cartridge 59 may be removable, stored separately, and inserted when necessary, rather than be incorporated into apparatus 20.
  • the thin walled piezoceramic body 360 may have configurations other than a ring and can be made, e.g., as a strip to which the optic-fiber arm 340 may be attached.
  • Apparatus 20 may be equipped with memory 115 of sufficient capacity for storing a log of the patient's measurements, e.g., date, time and values. It also may be equipped for storing information regarding medication dosages administered, e.g., units of insulin, using a suitable keypad or other data entry system.
  • apparatus 20 is constructed for use as a hospital or clinic-based unit, it may contain or be provided with more substantial computing functions such as calibration data for each patient it will service, maintain a log of each patient's measurements and also may include additional electronic circuitry for improving the accuracy of measurements. For example, a feedback signal may be sent to the laser source to stabilize amplitude and phase noise variation of the laser beam.
  • the present invention is particularly useful for monitoring blood constituents which undergo short term changes, such as glucose, in the presence of other optically active blood or tissue constituents (whether less dominant than, e.g., glucose), e.g., protein, which either do not change or change very slowly with time.
  • other optically active blood or tissue constituents whether less dominant than, e.g., glucose
  • protein e.g., protein
  • short term and long term averaging techniques may be used to control the effects of a change in the other optically active components.
  • the start-up calibration using two or more invasive glucose measurements could be infrequently used, e.g., once a year or when the patient's weight has changed significantly.
  • the invention also may be useful for identifying the concentration of an optically active substance that is added to blood and selectively bonds to a desired blood constituent.
  • substances such as optically active monoclonal antibodies that bind to specific antigenic determinants of a selected blood constituent or cell subpopulation may be used. This provides for indirectly measuring noninvasively blood components that are not significantly or sufficiently optically active for diagnostic and therapeutic purposes.

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Abstract

L'invention concerne un procédé et un appareil de mesure non invasive de la glycémie. Ledit procédé consiste à produire un faisceau laser polarisé et modulé, à mesurer l'écart de phase engendré par exemple par un doigt (F) ou un lobe d'oreille (E) d'un sujet, à mesurer l'écart de phase entre un signal de référence (SR) et un signal de sonde/mesure (SP, SM), et à traiter les données obtenues qui sont ensuite présentées sous forme de glycémie. L'appareil se compose d'une source laser infrarouge (22), d'une unité de placement de fréquence polarisée (24) qui produit un faisceau laser infrarouge polarisé/modulé, d'un transducteur piézoélectrique (26) commandant ladite unité de déplacement de fréquence polarisée (24), d'un transducteur optique (30) présentant une tête (32) de mesure de la glycémie. Cette dernière comporte une entrée optique pour la réception du faisceau laser et un récepteur équilibré (62). Le faisceau de la sonde, une fois qu'il a traversé le doigt, est converti en un signal électrique de sonde, le faisceau de référence est converti en un signal électrique de référence, les signaux électriques de la sonde et de référence sont comparés, et l'écart de phase ainsi obtenu est traité par une unité de traitement (34) des signaux électroniques, laquelle présente les résultats sous la forme de glycémie. D'autres modes de réalisation basés sur la mesure du dichroïsme circulaire dû à la présence de glucose dans le sang sont également décrits. L'unité de déplacement de la fréquence polarisée peut être à base de cristaux optiques ou de fibres optiques.
EP94905335A 1992-12-10 1993-12-07 Non-invasive blood glucose measurement. Withdrawn EP0626819A4 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US98871592A 1992-12-10 1992-12-10
US988715 1992-12-10
US08/007,568 US5398681A (en) 1992-12-10 1993-01-22 Pocket-type instrument for non-invasive measurement of blood glucose concentration
US08/071,321 US5448992A (en) 1992-12-10 1993-06-01 Method and apparatus for non-invasive phase sensitive measurement of blood glucose concentration
PCT/US1993/011807 WO1994013199A1 (fr) 1992-12-10 1993-12-07 Mesure non invasive de la glycemie
US71321 2002-02-08
US7568 2004-12-08

Publications (2)

Publication Number Publication Date
EP0626819A1 true EP0626819A1 (fr) 1994-12-07
EP0626819A4 EP0626819A4 (en) 1996-10-23

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EP94905335A Withdrawn EP0626819A4 (en) 1992-12-10 1993-12-07 Non-invasive blood glucose measurement.

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EP (1) EP0626819A4 (fr)
JP (1) JPH07506039A (fr)
WO (1) WO1994013199A1 (fr)

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JP6886473B2 (ja) * 2016-02-04 2021-06-16 ノヴァ バイオメディカル コーポレイション 全血中のヘモグロビンパラメータを決定するための分析システム及び方法
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
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KR102534002B1 (ko) * 2018-02-14 2023-05-19 삼성전자주식회사 복수 개의 수신부들을 이용하여 생체 정보를 감지하는 센서를 포함하는 전자 장치 및 제어 방법
JP6533632B1 (ja) 2019-03-15 2019-06-19 日本分光株式会社 円二色性測定装置および円二色性測定方法
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JPH07506039A (ja) 1995-07-06
EP0626819A4 (en) 1996-10-23
WO1994013199A1 (fr) 1994-06-23

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