United States Patent (19)
`Chance
`
`|||||||||
`US005564417A
`11) Patent Number:
`5,564,417
`(45) Date of Patent:
`* Oct. 15, 1996
`
`54
`
`PATHLENGTH CORRECTED OXMETER
`AND THE LIKE
`
`FOREIGN PATENT DOCUMENTS
`WO92/20273 11/1992 WIPO.
`
`(75)
`
`Inventor: Britton Chance, Marathon, Fla.
`
`73
`
`Assignee: Non-Invasive Technology, Inc.,
`Philadelphia, Pa.
`
`Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5,553,614.
`
`21
`22
`
`Appl. No.: 31,945
`Filed:
`Mar 16, 1993
`
`Related U.S. Application Data
`
`Continuation-in-part of Ser. No. 645,590, Jan. 24, 1991.
`Int. Cl. ... A61N 5/02
`U.S. Cl. .......................... 128/633; 128/637; 128/664;
`128/665; 356/39; 356/341; 356/432
`Field of Search ..................................... 606/2, 10-12;
`128/633, 634, 664, 665, 897, 898; 356/4,
`5, 51, 39, 72, 319, 320, 323, 341, 432-436,
`256
`
`(63)
`(51)
`(52)
`
`58
`
`56
`
`References Cited
`U.S. PATENT DOCUMENTS
`2/1972
`Shaw ....................................... 128/633
`9/1980
`Jobsis.
`8/1981
`Jobsis.
`3/1982
`Jobsis et al. .
`4/1983
`Jobsis et al. .
`4/1985
`Jobsis et al. .
`Hamaguri et al..
`12/1987
`1/1989
`Smith .
`Johnson.
`1/1989
`2/1989
`Jobsis.
`4/1989
`Fricket al..
`5/1989
`Parker ..................................... 128/633
`11/1990
`Chance.
`Chance.
`6/1992
`12/1992
`Chance .
`2/1993
`Chance et al. .
`
`
`
`3,638,640
`4,223,680
`4,281,645
`4,321,930
`4,380,240
`4,510,938
`4,714,341
`4,800,495
`4,800,885
`4,805,623
`4,824,242
`4,827,934
`4,972,331
`5,119,815
`5,167,230
`5,187,672
`
`OTHER PUBLICATIONS
`Chance et al., “Photon Migration in Muscle and Brain",
`Photon Migration in Tissues, Academic Press/ New York
`1989.
`Chance, "Rapid and Sensitive Apectrophotometry, I. The
`Accelerated and Stopped-Flow Methods for the Measure
`ment of the Reaction Kinetics, etc.", The Review of Scientific
`Instruments, 22:619–638 (1951).
`Cui et al., "Experimental Study of Migration Depth for the
`Photons Measured at Sample Surface', Proceedings of
`Time-Resolved Spectroscopy and Imaging of Tissues, SPIE,
`1413: 180-191 (1991).
`Lakowicz, "Gigahertz Frequency-Domain Fluorometry:
`Resolution of Complex Intensity Decays, Picosecond Pro
`cesses and Future Developments”, Photon Migration in
`Tissues, pp. 169-185.
`(List continued on next page.)
`Primary Examiner-David M. Shay
`Attorney, Agent, or Firm-Fish & Richardson P.C.
`57)
`ABSTRACT
`A pathlength corrected spectrophotometer for tissue exami
`nation includes an oscillator for generating a carrier wave
`form of a selected frequency, an LED light source for
`generating light of a selected wavelength that is intensity
`modulated at the selected frequency introduced to a subject,
`and a photodiode detector for detecting light that has
`migrated in the tissue of the subject. The spectrophotometer
`also includes a phase detector for measuring a phase shift
`between the introduced and detected light, a magnitude
`detector for determination of light attenuation in the exam
`ined tissue, and a processor adapted to calculate the photon
`migration pathlength and determine a physiological property
`of the examined tissue based on the pathlength and on the
`attenuation data.
`
`30 Claims, 7 Drawing Sheets
`
`2
`
`4.
`
`37c
`
`...
`
`AGC
`60c 540
`45c
`
`" ".
`
`42c
`
`IPR2018-00294
`Apple Inc. EX1009 Page 1
`
`

`

`5,564,417
`Page 2
`
`OTHER PUBLICATIONS
`Sevick et al., "Analysis of absorption, scattering, and hemo
`globin saturation using phase modulation spectroscopy",
`Proceedings of Time-Resolved Spectroscopy and Imaging
`Tissues, SPIE, 1431:264-275 (1991).
`Sevick et al., "Photon migration in a model of the head
`measured using time-and frequency-domain, etc.', Pro
`ceedings of Time-Resolved Spectroscopy and Imaging Tis
`sues, SPIE, 1431:84-96 (1991).
`Sevick et al., "Quantitation of Time- and Frequency-Re
`solved Optical Spectra for the Determination of Tissue
`
`Oxygenation", Analytical Biochemistry, 195:001-0022
`(1991).
`Van der Zee et al., "Computed Point Spread Functions for
`Light in Tissue Using a Measured Volume Scattering Func
`tion', Advances in Experimental Medicine and Biology:
`Oxygen Transport to Tissue X, 222:191-197 (1988).
`Weng et al., "Measurement of Biological Tissue Metabolism
`Using Phase Modulation Spectroscopic Technology', Pro
`ceedings of Time-Resolved Spectroscopy and Imaging of
`Tissues, SPIE, 1431: 161-170 (1991).
`
`IPR2018-00294
`Apple Inc. EX1009 Page 2
`
`

`

`U.S. Patent
`
`Oct. 15, 1996
`
`Sheet 1 of 7
`
`5,564,417
`
`
`
`IPR2018-00294
`Apple Inc. EX1009 Page 3
`
`

`

`U.S. Patent
`
`Oct. 15, 1996
`
`Sheet 2 of 7
`
`5,564,417
`
`
`
`IPR2018-00294
`Apple Inc. EX1009 Page 4
`
`

`

`U.S. Patent
`
`Oct. 15, 1996
`
`Sheet 3 of 7
`
`5,564,417
`
`--5OV OK
`
`51723-04
`O.
`
`
`
`30a,b,c
`
`FIG. 3
`
`H%
`--8V
`NE5205N
`
`33
`
`-- 15W
`
`
`
`IPR2018-00294
`Apple Inc. EX1009 Page 5
`
`

`

`U.S. Patent
`
`Oct. 15, 1996
`
`Sheet 4 of 7
`
`5,564,417
`
`
`
`input
`
`input
`From
`AGC
`54
`
`IPR2018-00294
`Apple Inc. EX1009 Page 6
`
`

`

`U.S. Patent
`
`Oct. 15, 1996
`
`Sheet 5 of 7
`
`5,564,417
`
`
`
`
`
`
`
`
`
`
`
`%)
`C?EINIW\/XE
`
`EnSSL
`
`IPR2018-00294
`Apple Inc. EX1009 Page 7
`
`

`

`U.S. Patent
`US. Patent
`
`Oct. 15, 1996 .
`
`Sheet 6 of 7
`
`5,564,417
`5,564,417
`
`O._.
`
`IMFDQEOO
`
`2m<._<
`
`Emhm>w
`
`X:
`
`cm.0.“—
`
`
`
`
`
`><._n.m_o
`
`JOIHZOO
`
`
`
`
`mmoSmEo_-051; mm?83rIIIIIIL
`
`
`
`_.
`
`. 2mm
`
`|PR2018-00294
`
`Apple Inc. EX1009 Page 8
`
`IPR2018-00294
`Apple Inc. EX1009 Page 8
`
`
`
`
`

`

`fl
`
`0oEam1|szQRmmobjaowo7K.<PN128m._..SommwmmU.m:mmm
`
`
`
`a0
`
`6
`
`mEm-NW:5wmmm
`
`
`
`v.5
`
`NH:8+:<uEs.E.m:<m2%+$mmum?Agisvmonm
`
`5,564,417
`
`
`
` m$1.5I.3
`
`N)“
`
`
`
`|PR2018-00294
`
`Apple Inc. EX1009 Page 9
`
`IPR2018-00294
`Apple Inc. EX1009 Page 9
`
`
`
`
`

`

`1
`PATHLENGTH CORRECTED OXMETER
`AND THE LIKE
`
`5,564,417
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`This application is a continuation-in-part of application
`Ser. No. 07/645,590 filed Jan. 24, 1991 incorporated by
`reference as if fully set forth herein.
`BACKGROUND OF THE INVENTION
`The present invention relates to a wearable tissue spec
`trophotometer for in vivo examination of tissue of a specific
`target region.
`Continuous wave (CW) tissue oximeters have been
`widely used to determine in vivo concentration of an opti
`cally absorbing pigment (e.g., hemoglobin, oxyhemoglobin)
`in biological tissue. The CW oximeters measure attenuation
`of continuous light in the tissue and evaluate the concen
`tration based on the Beer Lambert equation or modified Beer
`Lambert absorbance equation. The Beer Lambert equation
`(1) describes the relationship between the concentration of
`an absorbent constituent (C), the extinction coefficient (e),
`the photon migration pathlength <L>, and the attenuated
`light intensity (III).
`
`10
`
`15
`
`20
`
`25
`
`(1)
`
`The CW spectrophotometric techniques can not determinee,
`C, and <L> at the same time. If one could assume that the
`photon pathlength were constant and uniform throughout all
`subjects, direct quantitation of the constituent concentration
`(C) using CW oximeters would be possible.
`In tissue, the optical migration pathlength varies with the
`size, structure, and physiology of the internal tissue exam
`ined by the CW oximeters. For example, in the brain, the
`gray and white matter and the structures thereof are different
`in various individuals. In addition, the photon migration
`pathlength itself is a function of the relative concentration of
`absorbing constituents. As a result, the pathlength through
`an organ with a high blood hemoglobin concentration, for
`example, will be different from the same with a low blood
`hemoglobin concentration. Furthermore, the pathlength is
`frequently dependent upon the wavelength of the light since
`the absorption coefficient of many tissue constituents is
`wavelength dependent. Thus, where possible, it is advanta
`geous to measure the pathlength directly when quantifying
`the hemoglobin concentration in tissue.
`
`30
`
`35
`
`40
`
`45
`
`SUMMARY OF THE INVENTION
`In one aspect, the present invention is a pathlength
`corrected oximeter that utilizes principles of continuous
`wave spectroscopy and phase modulation spectroscopy. The
`oximeter is a compact unit constructed to be worn by a
`subject on the body over long periods of activity. The
`oximeter is also suitable for tissue monitoring in critical care
`facilities, in operating rooms while undergoing surgery or in
`trauma related situations.
`The oximeter is mounted on a body-conformable support
`structure placed on the skin. The support structure encap
`sulates several light emitting diodes (LEDs) generating light
`of different wavelengths introduced into the examined tissue
`and several photodiode detectors with interference filters for
`wavelength specific detection. Since both the LEDs and the
`photodiodes are placed directly on the skin, there is no need
`to use optical fibers. The distance between the LEDs and the
`
`50
`
`55
`
`60
`
`65
`
`2
`diode detectors is selected to examine a targeted tissue
`region. The support structure also includes a conformable
`barrier, located between the LEDs and the diode detectors,
`designed to reduce detection of light that migrates subcuta
`neously from the source to the detector. The support struc
`ture may further include means for preventing escape of
`photons from the skin without being detected; the photon
`escape preventing means are located around the LEDs and
`the photodiode detectors.
`The LEDs, the diode detectors, and the electronic control
`circuitry of the oximeter are powered by a battery pack
`adapted to be worn on the body or by the standard 50/60 Hz
`supply. The electronic circuitry includes a processor for
`directing operation of the sources, the detectors and for
`directing the data acquisition and processing. The data may
`be displayed on a readout device worn by the user, sent by
`telemetry to a remote location or accumulated in a memory
`for later use.
`The Oximeter is adapted to measure the attenuation of
`light migrating from the source to the detector and also to
`determine the average migration pathlength. The migration
`pathlength and the intensity attenuation data are then used
`for direct quantitation of a tissue property.
`In another aspect, the invention is a spectrophotometer for
`tissue examination utilizing a measured average pathlength
`of migrating photons, including
`an oscillator adapted to generate a carrier waveform of a
`Selected frequency comparable to an average migration time
`of photons scattered in tissue on paths from an optical input
`port to an optical detection port; a light source, operatively
`connected to the oscillator, adapted to generate light of a
`selected wavelength that is intensity modulated at the fre
`quency and introduced to a subject at the input port; a
`photodiode detector adapted to detect, at the detection port,
`light of the selected wavelength that has migrated in the
`tissue of the subject between the input and detection ports;
`a phase detector, operatively connected to receive signals
`from the oscillator and the diode detector, adapted to mea
`sure a phase shift between the introduced and the detected
`light; and a processor adapted to calculate pathlength based
`on the phase shift, and determine a physiological property of
`the examined tissue based on the pathlength.
`In another aspect, the invention is a spectrophotometer for
`tissue examination utilizing a measured average pathlength
`of migrating photons, including an oscillator adapted to
`generate a carrier waveform of a selected frequency com
`parable to an average migration time of photons scattered in
`tissue on paths from an optical input port to an optical
`detection port; a light source, operatively connected to the
`oscillator, adapted to generate light of a selected wavelength
`that is intensity modulated at the frequency and introduced
`to a subject at the input port; a photodiode detector adapted
`to detect, at the detection port, light of the selected wave
`length that has migrated in the tissue of the subject between
`the input and detection ports; a phase splitter adapted to
`produce, based on the carrier waveform, first and second
`reference phase signals of predefined substantially different
`phase, first and second double balanced mixers adapted to
`correlate the reference phase signals and signals of the
`detected radiation to produce therefrom a real output signal
`and an imaginary output signal, respectively; and a proces
`sor adapted to calculate, on the basis of the real output signal
`and the imaginary output signal, a phase shift between the
`introduced light and the detected light, and determine a
`physiological property of the examined tissue based on the
`phase shift.
`
`IPR2018-00294
`Apple Inc. EX1009 Page 10
`
`

`

`5,564,417
`
`3
`In another aspect, the invention is a spectrophotometer for
`tissue examination utilizing a measured average pathlength
`of migrating photons, comprising a first oscillator adapted to
`generate a carrier waveform of a first selected frequency
`comparable to an average migration time of photons scat
`tered in tissue on paths from an optical input port to an
`optical detection port; a light source, operatively connected
`to the oscillator, adapted to generate light of a selected
`wavelength, intensity modulated at the first frequency, that
`is introduced to a subject at the input port; a photodiode
`detector adapted to detect, at the detection port, light of the
`wavelength that has migrated in the tissue of the subject
`between the input and detection ports, the detector produc
`ing a detection signal at the first frequency corresponding to
`the detected light; a second oscillator adapted to generate a
`carrier waveform of a second frequency that is offset on the
`order of 10 Hz from the first frequency; a reference mixer,
`connected to the first and second oscillators, adapted to
`generate a reference signal of a frequency approximately
`equal to the difference between the first and second frequen
`cies; a mixer connected to receive signals from the second
`oscillator and the detection signal and adapted to convert the
`detection signal to the difference frequency; a phase detec
`tor, operatively connected to receive signals from the refer
`ence mixer and the converted detection signal, adapted to
`measure a phase shift between the introduced light and the
`detected light; and a processor adapted to calculate the
`pathlength based on the phase shift, and to determine a
`physiological property of the examined tissue based on the
`pathlength.
`Preferred embodiments of these aspects may include one
`or more of the following features.
`The spectrophotometer may further include a magnitude
`detector, connected to the photodiode detector, adapted to
`measure magnitude of the detected light, and the processor
`is further adapted to receive the magnitude for determination
`of the physiological property.
`The spectrophotometer may further include a low fre
`quency oximeter circuit, switchably connected to the source
`and the photodiode, adapted to determine absorption of light
`at the wavelength; and the processor is further adapted to
`receive absorption values from the oximeter circuit for
`determination of the physiological property.
`The spectrophotometer may further include two auto
`matic gain controls adapted to level signals corresponding to
`the introduced light and the detected light, both the leveled
`signals being introduced to the phase detector.
`The photodiode detector may further include a substan
`tially single wavelength filter.
`The spectrophotometer may further include a second light
`source, operatively connected to the oscillator, adapted to
`generate light of a second selected wavelength that is
`intensity modulated at the first frequency, the radiation being
`introduced to a subject at a second input port; the photodiode
`detector further adapted to detect alternately, at the detection
`port, light of the first and second wavelengths that have
`migrated in the tissue of the subject between the first and the
`second input ports and the detection port, respectively; the
`phase detector further adapted to receive alternately signals
`corresponding to the detected first and second wavelengths;
`and the processor further adapted to receive alternately
`phase shifts from the phase detector, the phase shifts being
`Subsequently used for determination of the physiological
`property of the tissue.
`The spectrophotometer may further include a second light
`source, operatively connected to the oscillator, adapted to
`
`10
`
`5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`generate light of a second selected wavelength that is
`intensity modulated at the first frequency, the radiation being
`introduced to a subject at a second input port; a second
`photodiode detector adapted to detect, at a second detection
`port, light of the second wavelength that has migrated in the
`tissue of the subject between the second input port and the
`second detection port, respectively; a second phase detector,
`operatively connected to receive a reference signal and a
`detection signal from the third diode detector, adapted to
`measure a phase shift between the introduced and the
`detected light at the second wavelength; and the processor
`further adapted to receive a second phase shift at the second
`wavelength, the first and second phase shifts being subse
`quently used for determination of the physiological property
`of the tissue.
`The two wavelength spectrophotometer may further
`include a third light source, operatively connected to the
`oscillator, adapted to generate light of a third selected
`wavelength that is intensity modulated at the first frequency,
`the radiation being introduced to a subject at a third input
`port; a third photodiode detector adapted to detect, at a third
`detection port, light of the third wavelength that has
`migrated in the tissue of the subject between the third input
`port and the third detection port, respectively; a third phase
`detector, operatively connected to receive a reference signal
`and a detection signal from the third diode detector, adapted
`to measure a phase shift between the introduced and the
`detected light at the third wavelength; and the processor
`further adapted to receive phase shifts from the phase
`detector, the first second and third phase shifts being sub
`sequently used for determination of the physiological prop
`erty of the tissue.
`The two or three wavelength spectrophotometer may
`further include a first, a second (or a third) magnitude
`detector connected to the first, second (or third) photodiode
`detectors, respectively, the magnitude detectors being
`adapted to measure magnitude of the detected light at each
`of the wavelengths; and the processor further adapted to
`receive the magnitudes for determination of the physiologi
`cal property of the tissue.
`The light source may be a light emitting diode for
`generating light of a selected wavelength in the visible or
`infra-red range.
`The photodiode detector may be a PIN diode or an
`avalanche diode.
`The examined physiological property of the tissue may be
`hemoglobin oxygenation, myoglobin, cytochrome iron and
`copper, melanin, glucose or other.
`
`BRIEF DESCRIPTION OF THE DRAWENG
`FIG. 1 is a block diagram of a pathlength corrected
`oximeter in accordance with the present invention.
`FIG. 2 is a schematic circuit diagram of a 50.1 MHz
`(50.125 MHz) oscillator used in the oximeter of FIG. 1.
`FIG. 3 is a schematic circuit diagram of a PIN diode and
`a preamplifier used in the oximeter of FIG. I.
`FIG. 4 is a schematic circuit diagram of a magnitude
`detector used in the oximeter of FIG. 1.
`FIG. 5 is a schematic circuit diagram of a 25 kHz filter
`used in the oximeter of FIG. 1.
`FIG. 6 is a schematic diagram of an AGC circuit of the
`Oximeter of FIG 1.
`FIG. 7 is a schematic circuit diagram of a phase detector
`of the oximeter of FIG. 1.
`
`IPR2018-00294
`Apple Inc. EX1009 Page 11
`
`

`

`5,564,417
`
`S
`FIG. 8A is a plan view of a source-detector probe of the
`Oximeter.
`FIG. 8B is a transverse cross-sectional view taken onlines
`8B of FIG. 8A further showing the photon migration.
`FIG. 8C is a block diagram of another embodiment
`depicting the source-detector probe of the oximeter switch
`ably connected to a low frequency oximeter.
`FIG. 9 is a block diagram of another embodiment of a
`phase modulation spectrophotometer.
`
`6
`tion pathlength used in calculation algorithms performed by
`processor 70.
`FIG. 2 shows a schematic circuit diagram of a precision
`oscillator used as the 50.1 MHz master oscillator 10 and
`50.125 MHz local oscillator 14. The oscillator crystals are
`neutralized for operation in the fundamental resonance
`mode; this achieves long-term stability. Both oscillators are
`thermally coupled so that their frequency difference is
`maintained constant at 25 kHz if a frequency drift occurs.
`PIN diodes 24a, 24b, and 24c are directly connected to
`their respective preamplifiers 30a, 30b, and 30c, as shown in
`FIG. 3. The oximeter uses PIN silicon photodiodes S1723
`04 with 10 mmx10 mm sensitive area and spectral response
`in the range of 320 nm to 1060 nm. The detection signal is
`amplified by stages 29 and 31, each providing about 20 dB
`amplification. The NE5205N operational amplifier is pow
`ered at +8V to operate in a high gain regime. The 8V signal
`is supplied by a voltage regulator 33. The amplified detec
`tion signals (32a, 32b, and 32c) are sent to magnitude
`detectors 36a,36b, and 36c, shown in FIG. 4. The magnitude
`values (37a, 37b, and 37c) are sent to processor 70 that
`calculates the light attenuation ratio or logarithm thereof as
`shown Eq. 1.
`Also referring to FIG. 5, the AGC circuit uses MC 1350
`integrated circuit for amplification that maintains the input
`signal of phase detector 60 at substantially constant levels.
`The amount of gain is selected to be equal for AGCs, 50 and
`52. The signal amplitude is controlled by a feedback net
`work 53. The AGCs provide a substantially constant ampli
`tude of the detected and reference signals to eliminate
`variations in the detected phase shift due to cross talk
`between amplitude and phase changes in the phase detector.
`Referring to FIG. 6, each phase detector includes a
`Schmitt trigger that converts the substantially sinusoidal
`detection signal (54a, 54b, 54c) and reference signal (56a,
`56b, 56c) to square waves. The square waves are input to a
`detector that has complementary MOS silicon-gate transis
`tors. The phase shift signal is sent to processor 70.
`The oximeter is calibrated by measuring the phase shift
`for a selected distance in a known medium, i.e., using a
`standard delay unit, and by switching the length of a
`connector wire to change the electrical delay between master
`oscillator 10 and local oscillator 14.
`Referring to FIGS. 8A and 8B source-detector probe 20
`includes several LEDs (22a, 22b, 22c) of selected wave
`lengths and PIN photodiodes (24a, 24b, 24c) mounted in a
`body-conformable support structure 21. Structure 21 also
`includes a photon escape barrier 27 made of a material with
`selected scattering and absorption properties (for example,
`styrofoam) designed to return escaping photons back to the
`examined tissue. The support structure further includes a
`second conformable barrier 28, located between the LEDs
`and the diode detectors, designed to absorb photons directly
`propagating from the source to the detector and thus prevent
`detection of photons that migrate subcutaneously. Support
`structure 21 also includes electronic circuitry 29 encapsu
`lated by an electronic shield 21a.
`Each PIN diode is provided with an evaporated single
`wavelength film filter (25a, 25b, 25c). The filters eliminate
`the cross talk of different wavelength signals and allow
`continuous operation of the three light sources, i.e., no time
`sharing is needed.
`The use of photodiode detectors has substantial advan
`tages when compared with the photomultiplier tube used in
`standard phase modulation systems. The photodiodes are
`placed directly on the skin, i.e., no optical fibers are needed.
`
`10
`
`15
`
`25
`
`30
`
`35
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`One preferred embodiment of the pathlength corrected
`oximeter utilizes three LEDs for generation of light at three
`selected wavelengths intensity modulated at a frequency of
`50.1 MHz and coupled directly to the examined tissue. At
`each wavelength, the introduced light is altered by the tissue
`and is detected by a wide area photodiode placed against the
`skin. The introduced and detected radiations are compared to
`determine their relative phase shift that corresponds to an
`average pathlength of the migrating photons and, further
`more, the light attenuation is determined.
`Referring to FIG. 1, the oximeter includes a master
`oscillator 10 operating at 50.1 MHz connected to a power
`amplifier 15 of sufficient output power to drive LEDs 22a,
`22b, and 22c (for example HLP 20RG or HLP4ORG made
`by Hitachi) that emit 760 nm, 840 nm, and 905 nm (or 950
`mm) light, respectively. A second local oscillator 14 operat
`ing at 50,125 MHz and mixer 12 are used to generate a
`reference frequency 13 of 25 kHz. Each LED directly
`positioned on the skin has an appropriate heat sink to
`eliminate uncomfortable temperature increases that could
`also alter blood perfusion of the surrounding tissue. Three
`PIN diode detectors 24a, 24b, and 24c are placed at a
`distance of approximately 5 cm from the LEDs and have a
`detection area of about 1 cm. Photons migrating a few
`centimeters deep into the tissue are detected by the respec
`tive PIN diodes. The source-detector separation can be
`increased or decreased to capture deeper or shallower
`migrating photons. The signals from PIN diodes 24a, 24b,
`and 24c are amplified by preamplifiers 30a, 30b, and 30c,
`respectively.
`The amplified signals (32a, 32b, 32c) are sent to magni
`tude detectors 36a, 36b, and 36c and to mixers 40a, 40b, and
`40c, respectively. The magnitude detectors are used to
`determine intensity values of detected signals at each wave
`length to be used in Eq. 1. Each mixer, connected to receive
`50
`a 50,125 MHz reference signal (41a, 41b, 41c) from local
`oscillator 14, converts the detection signal to a 25 kHz
`frequency signal (42a, 42b, 42c). The mixers are high
`dynamic range frequency mixers, model SRA-1H, commer
`cially available from Mini-Circuits (Brooklyn N.Y.). The
`detection signals (42a, 42b, and 42c) are filtered by filters
`45a, 45b, 45c, respectively.
`Phase detectors 60a, 60b, and 60c are used to determine
`phase shift between the input signal and the detected signal
`at each wavelength. Each phase detector receives the 25 kHz
`60
`detection signal (54a, 54b, 54c) and the 25 kHz reference
`signal (56a, 56b, 56c), both of which are automatically
`leveled by automatic gain controls 50 and 52 to cover the
`dynamic range of signal changes. Phase detectors 60a, 60b,
`and 60c generate phase shift signals (62a, 62b, 62c) corre
`65
`sponding to the migration delay of photons at each wave
`length. Each phase shift signal is proportional to the migra
`
`45
`
`55
`
`IPR2018-00294
`Apple Inc. EX1009 Page 12
`
`

`

`7
`Furthermore, there is no need to use a high voltage power
`supply that is necessary for the photomultiplier tube. The
`photodiodes are much smaller and are easy to place close to
`the skin. Advantages of the photomultiplier tube are a huge
`multiplication gain and a possibility of direct mixing at the
`photomultiplier; this cannot be achieved directly by a pho
`todiode. This invention envisions the use of several different
`photodiodes such as PIN diode, avalanche diode, and other.
`The processor uses algorithms that are based on equations
`described by E. M. Sevick et al. in "Quantitation of Time
`and Frequency-Resolved Optical Spectra for the Determi
`nation of Tissue Oxygenation' published in Analytical Bio
`chemistry 195, 330 Apr. 15, 1991 which is incorporated by
`reference as if fully set forth herein.
`At each wavelength, the phase shift (0) (62a, 62b, 62c)
`is used to calculate the pathlength as follows:
`(2)
`0=tan-i?-is-tan-1-2EEP -se 2nfall se
`wherein f is modulation frequency of the introduced light
`which is in the range of 10 MHz to 100 MHz; t is the photon
`migration delay time, c is the speed of photons in the
`scattering medium; and L is the migration pathlength.
`Equation (2) is valid at low modulation frequencies, i.e.,
`21cf-luc. The modulation frequency of 50 MHz was
`selected due to the frequency limitation of the LEDs and
`photodiodes. However, for faster LEDs and photodiodes it
`may be desirable to use higher modulation frequencies that
`increase the phase shift. At high modulation frequencies,
`i.e., 27tf>>uc, the phase shift is no longer proportional to
`the mean time of flight <te.
`o'-ap\d-of 1-1}
`wherein p is the source-detector separation; (1-g) u is
`effective scattering coefficient; f is modulation frequency
`and 4. is absorption coefficient at wavelength W. At two
`wavelength, the ratio of absorption coefficients is deter
`mined as follows:
`
`A.
`
`(3)
`
`(4)
`
`e1-el
`02-0:2
`2
`wherein 0, represents background scattering and absorp
`tion.
`The wavelengths are in the visible and infra-red range and
`are selected to have absorbance sensitive (or insensitive) to
`various tissue components such as water, cytochrome iron
`and copper, oxy- and deoxygenated forms of hemoglobin,
`myoglobin, melanin, glucose and other.
`For oxygenated and deoxygenated hemoblogin, the
`absorption coefficient written in terms of Beer Lambert
`relationship is as follows:
`(5)
`= e, (Hb) + eu (HbO2) + o'
`and ea' are extinction coefficients for
`wherein ea
`hemoglobin and deoxyhemoglobin that can be stored in a
`look up table; Hb), HbO2) are the tissue concentration of
`hemoglobin and oxyhemoglobin, respectively; o' is back
`ground absorbance. The hemoglobin saturation is conven
`tionally defined as follows:
`
`45
`
`50
`
`55
`
`60
`
`(HbO2)
`(Hb) (HbO,
`For a three wavelength measurement, the hemoglobin satu
`ration can be calculated using Eqs. (5) and (6) as follows:
`
`(6)
`
`65
`
`5,564,417
`
`10
`
`5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`(7)
`
`8
`achi-ii)-(cis- i)
`(eiho, - elio) -(e), -ei)-
`al(cio, -(cio)-(ei-ei)
`
`where
`
`.
`
`3 - ?
`2. 3-2
`
`Thus, processor 70 determines Ybased on Eq. (7) using Eq.
`(2) to determine the average migration pathlength L that is
`then used in Eq. (1) and to determine -
`for each wave
`length 1, 2, 3.
`Referring to FIG. 8C in another embodiment, the spec
`trophotometer's electronics includes a low frequency mod
`ule, as shown for example in FIGS. 2 and 4 of U.S. Pat. No.
`5,167,230, and a high frequency module switchably coupled
`to the same source-detector probe 20. The low frequency
`module and the arrangement of the source-detector probe are
`substantially similar to the hemoglobinometer described in a
`copending U.S. patent application Ser. No. 701,127 filed
`May 16, 1991 which is incorporated by reference as if fully
`set forth herein. The low frequency module corresponds to
`a standard oximeter with modulation frequencies in the
`range of a few hertz to 10' hertz and is adapted to provide
`intensity attenuation data at two or three wavelengths. FIG.
`8C depicts an analog embodiment of the low frequency
`oximeter coupled to source-detector probe 20 by switches
`100a, 100b, and 100c. The light detected by photodetectors
`24a and 24a is amplified by amplifiers 120a and 120b and
`sent to three manipulative circuits that take the difference
`(123), the sum (124) and the derivative (125) of the signal.
`The difference circuit (123) subtracts 760 nm minus 850 mm
`to obtain a signal representing deoxygenation. The sum
`circuit (124) takes a weighted sum of the 760 nm and 850 nm
`signals that is a representative of the blood volume changes
`in the tissue. The derivative circuit takes the simple deriva
`tive to show the rate of change of both of the signals. The
`derivative triggers alarm circuitry 134 based upon estab
`lished standards, for example, in monitoring aviators for
`possible black-out conditions and for apnea. Then, the LEDs
`are switched to the high frequency phase modulation unit,
`similar to the unit of FIG. 1, which determines the average
`pathlength at each wavelength. The attenuation and path
`length data are sent to processor 70 for determination of a
`physiological property of the examined tissue.
`In another embodiment, the pathlength corrected oximeter
`utilizes the same LED sources (22a, 22b, 22c) sinusoidally
`modulated at a selected frequency comparable to the average
`migration time of photons scattered in the examined tissue
`on paths from the optical input port of the LED's to the
`optical detect