as) United States
`a2) Patent Application Publication (0) Pub. No.: US 2005/0267346 Al
`
` Faberet al. (43) Pub. Date: Dec. 1, 2005
`
`
`US 20050267346A1
`
`(54) NON-INVASIVE BLOOD COMPONENT
`MEASUREMENT SYSTEM
`
`(52) US. Che eeececeesncsstertsenseneenneenes 600/322; 600/310
`
`(75)
`
`Inventors: Ralf T. Faber, Lexington, MA (US);
`Erik J. Schwendeman, Charlton, MA
`(US); Guangming Wang, Bedford, MA
`(US)
`
`Add
`d
`C
`orresponcence
`TOSS:
`bopenar LLP
`BOSTON MA 02205 (US)
`,
`(73) Assignee: 3Wave Optics, LLC
`
`(21) Appl. No.:
`;
`Filed:
`
`(22)
`
`11/048,005
`
`Jan. 31, 2005
`oo.
`Related U.S. Application Data
`(60) Provisional application No. 60/540,663, filed on Jan
`30. 2004
`PP
`Oe es
`,
`,
`
`,
`
`Publication Classification
`
`(SL)
`
`Tint, C07eee cccceeeeesccsssssnnneeecccceceensneeesess A61B 5/00
`
`(57)
`
`ABSTRACT
`
`Non-invasive, optical apparatus and methods for the direct
`measurement of hemoglobin derivatives and other analyte
`concentration levels in blood using diffuse reflection and
`transmission spectroscopy in the wavelength region 400-
`1350 nm whichincludesthe transparent tissue window from
`approximately 610 to 1311 nanometers and, using diffuse
`reflection spectroscopy, the mid-infrared region from 4.3-12
`microns in wavelength. Large area light collection tech-
`niques are utilized to provide a muchlarger pulsate signal
`than can be obtain with current sensor technology. Sensors
`used in separate or simultaneous precision measurements of
`both diffuse reflection and transmission, either separately or
`simultaneously, from pulsate, blood-perfused tissue for the
`subsequent determination of the blood analytes concentra-
`tions such as arterial blood oxygen saturation (SaO,), car-
`boxyh
`lobin
`(COHb
`h
`lobin
`(OHb),
`d
`oxyhemoglobin
`, oxyhemoglobin
`,
`deoxy-
`hemoglobin
`(dOHb), methemoglobin (metHb), water
`H20), hematocrit
`(HCT),
`glucose, cholesterol
`and
`proteins
`h
`i
`gl
`hol
`1
`and protei
`such as albumin and other analytes components.
`
`
`
`
`Input: absorption spectrum of blood sample, blood sample
`thickness,fitting iteration number, blood componentstofit,
`and the sequenceoffitting.
`
`
`Normalize the spectrum
`with the blood thickness
`
`
`
`Fit water concentration (see flow
`chart in(FIG. 6) for details)
`
`
`
`
`
`
`
`
`Fit red blood cell
`concentration
`
`Fit serum concentration
`
`Fit other components’
`concentration
`
`Fit glucose concentration
`
`
`
`
`
`
`Reach
`
`the iteration
`
`
`number?
`
`Yes
`
`Display each component's
`concentration
`
`APPLE 1071
`Apple v. Masimo
`IPR2022-01291
`
`1
`
`APPLE 1071
`Apple v. Masimo
`IPR2022-01291
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 1 of 13
`
`US 2005/0267346 Al
`
`
`
`
`
`wiO1-g'ges800N|9-9+
`
`
`
`
`
`urlG°g-2'9Ul@}Old-¢:
`
`|Olds
`
`ONISSAQVO0UdLAdLNO ulG-e'yJIE-M|
`6OL
`
`wanes.
`
`[p/6xxsoyeny|[p/BxXUla}Old20):|p/Buxxx
`asoon|y:AW1dSIq}
`
`2
`
`
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 2 of 13
`
`US 2005/0267346 Al
`
`Linear Variable BandpassFilter
`(Center Wavelength (CWL) Continuously
`Changingin a Linear Fashion)
`
` eS
`
`co£
`OC
`
`CWL
`
`Wavelength —»
`
`Circular Variable BandpassFilter
`(Center Wavelength (CWL)
`Continuously Changing in a
`Circumferential Fashion)
`
`
`
`CWL
`
`Wavelength —»
`
`ZS
`‘OCc
`
`2£
`
`FIG. 2B
`
`3
`
`3
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 3 of 13
`
`US 2005/0267346 Al
`
`Discrete BandpassFilters
`(Each Filter Separate and Mounted in Wheel)
`
`Aa
`Intensity
`
`CWL
`
`Wavelength
`
`FIG. 2C
`
`4
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 4 of 13
`
`US 2005/0267346 Al
`
`Stage Il
`
`StageIll
`
`Ibtood = Ie
`
`Clamp -”
`Device
`
`Systolic
`
`Diastolic
`
`Iblood = larly
`
`FIG. 3
`
`5
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 5 of 13
`
`US 2005/0267346 Al
`
`Sample, 6
`
`53 soeo000gooogc00
`
`To Detector
`
`FIG. 4
`
`6
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 6 of 13
`
`US 2005/0267346 Al
`
`
`
`Input: absorption spectrum of blood sample, blood sample
`
`thickness, fitting iteration number, blood componentstofit,
`
`
`and the sequenceoffitting.
`
`
`Normalize the spectrum
`with the blood thickness
`
`
`
`Fit water concentration (see flow
`chart in(FIG. 6) for details)
`
`
`Fit red blood cell
`concentration
`
`
`
`Fit serum concentration
`
`Fit other components'
`concentration
`
`
`
`Fit glucose concentration
`
`
`
`
`Reach
`
`the iteration
`
`number?
`
`
`Yes
`
`Display each component's
`concentration
`
`FIG. 5
`
`7
`
`7
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 7 of 13
`
`US 2005/0267346 Al
`
`
`
`Input: Selecta fitting range(A, to 45) where the componenti has dominant
`peak(s), selecta fitting range for C; and step size of AC;, provide component
`
`
`
`i's spectrum Spectrum;,(4), provide other components’ spectra Spectrum((,),
`and their estimated concentrations C,.
`
`Set Cia starting value
`
`Increase C; by AC;
`
`
`
`Residue (4) = Measured Spectrum (1)-C;*Spectrum; (a) - Z
`C;*Spectrum, (A)
`
`Calculate linear least square
`fit (a * 1 + b) for Residue (A)
`
`
`
`
`
`Deviation = = [Residue (A) -
`(a * 2+ b)] for range (A, to
`
`Ao)
`
`
`
`Does
`C, reach the
`Final value?
`
`
`
`
`No
`
`Yes
`
`
`
`Search minimal
`Deviation and the
`corresponding C,
`
`Display component
`i's concentration C,
`
`42
`
`8
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 8 of 13
`
`US 2005/0267346 Al
`
`Clarke Error Grid Analysis of FTIR Measurement
`Results for Whole Blood Glucose
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`
`
`Measured(mg/dL)
`
`50
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350 400
`
`Reference (mg/dL)
`
`MEASUREDDATAat
`different times (dates)
`
`°
`
`FIG. 7
`
`9
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 9 of 13
`
`US 2005/0267346 Al
`
`7 20
`
`58
`
`blood/skin,
`tissue
`
`tissue
`
`bone
`
`blood ,24
`
`blood/skin,
`
`FIG. 8
`
`10
`
`10
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 10 of 13
`
`US 2005/0267346 Al
`
`
`
`
`
`ABSORPTIONFACTOR(cm"‘)
`
`0.30
`
`0.25
`
`0.20
`
`0.15
`
`0.10
`
`0.05
`
`DeoxyHb
`
`600
`
`700
`
`800
`
`900
`
`1000
`
`1100
`
`WAVELENGTH (nanometers)
`
`FIG. 9
`
`11
`
`11
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 11 of 13
`
`US 2005/0267346 Al
`
`
`
`FIG. 10
`
`12
`
`12
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 12 of 13
`
`US 2005/0267346 Al
`
`
`
`
`
`enoadssoueqiosayseaneAiag
`
`ulgo|BoweH
`
`
`
`oss008O0SZ2002O0S9#4009
`
`
`
`(uu)UBUa}aAeAA
`
`LLSls
`
`(nv) eoueqiosqy
`
`13
`
`13
`
`

`

`Patent Application Publication Dec. 1, 2005 Sheet 13 of 13
`
`US 2005/0267346 Al
`
`dOHb
`
`---OHb
`
`----COHb
`
`—-—MetHb
`
`550 40
`
`650
`
`
`
`Wavelength(nm)
`
`FIG.12
`
`35
`
`3
`
`N
`
`N
`
`-
`
`(ny) eoueqiosqy
`
`14
`
`
`
`
`
`
`
`HemoglobinDerivativesAbsorbanceSpectra
`
`14
`
`

`

`US 2005/0267346 Al
`
`Dec. 1, 2005
`
`NON-INVASIVE BLOOD COMPONENT
`MEASUREMENT SYSTEM
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the benefit of U.S. Provi-
`sional Patent Ser. No. 60/540,663 filed Jan. 30, 2004, the
`disclosure of which is incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates in general to the measure-
`ment and subsequent determination of solute concentrations.
`Morespecifically, it relates to a non-invasive, optical appa-
`ratus and method for the direct simultaneous measurement
`and monitoring of blood constituents.
`
`[0012] This technology could be used in a fast screening
`device, allowing doctors the early detection and monitoring
`of lung cancer. As is well known, the carboxyhemoglobin in
`cigarette smokers can increase up to 15% of the total
`hemoglobin, while it is less than 3% in a normal healthy
`person.
`
`[0013] Blood Glucose
`
`[0014] Many approaches of non-invasive blood glucose
`measurement have been suggested over the years. Known
`apparatus and techniques operate on a wide variety of
`principles such as spectroscopy, refractometry, total internal
`reflection, polarimetry, etc. Any blood glucose measuring
`system, however, must address certain problems and achieve
`certain performancecriteria. A practical blood glucose mea-
`surement system for patient use should be reliable and
`accurate, preferably at least to within 10 mg/dL.
`
`BACKGROUND OF THE INVENTION
`
`[0015] Sickle Cells
`
`[0003] While many medical procedures in hospitals are
`using non-invasive technology, the measurement and moni-
`toring of blood constituents is still an invasive procedure
`which requires the drawing of blood.
`
`[0004] Although the chemical blood analysis in hospitals
`and doctors practices is well established and precise,
`it
`requires multiple expensive devices to determine the various
`blood components.
`
`locations
`[0005] These devices might be in different
`within the hospital, which will makeit time consuming and
`expensive to get the full information. This adds time to
`diagnosis and treatment which is critical
`in emergency
`situations. It also requires practice, training, logistics and
`administrative support to make this cumbersome process
`work.
`
`is taken
`[0006] While oxygen saturation measurement
`non-invasively already, most of the other blood components
`have to be determined by blood analysis using blood
`samples drawn from the patient.
`
`[0007] Blood Oxygen Saturation, Sa02
`
`transmission pulse oximetry is a
`[0008] Conventional
`standard of care for many patient populations. The pulse
`oximeter also has become a vital instrument in the care of
`
`infants and children with cardio pulmonary disease.
`
`[0009] Recent advances in pulse oximetry technology
`have improved someaspects of pulse oximetry performance.
`However, monitoring challenges persist. The reliability,
`accuracy and clinical utility of pulse oximetry remain prob-
`lematic. For instance, patient care providers of hospitals
`have noticed a high incidence of false alarms. False alarms
`on oxygen saturation monitors present a serious patient
`safety issue, since they cannot be distinguished from true
`alarms.
`
`[0010] Carboxyhemoflobin, COHB
`
`{0011] The fast and cheep quantification of the carbon
`monoxide level in blood is another critical step, that can
`provide valuable information. For instance, the immediate
`measurement of carboxyhemoglobin in people who have
`been exposed to heavy smoke, like firefighters, could save
`lives. However, the device needs to be portable and easy
`enough to use in ambulance vehicle orfire trucks.
`
`[0016] Sickle cell disease is a blood condition seen most
`commonly in people of African ancestry. Patients with a
`high concentration of sickle cells may experience an under-
`supply of oxygen, which can cause severe difficulties. Basi-
`cally, decreasing the amount of sickle hemoglobin and
`increase the amount of fetal or normal hemoglobin by a
`variety of means could treat the disease. Therefore, a simple
`measure of how much sickle hemoglobin a patient has,
`might be of use in newborns and others who are having
`symptomsof sickle cell disease.
`
`[0017] U/S. Pat. Nos. 5,313,941, 5,666,956 and 6,445,938
`disclose optical, non-invasive blood glucose measurement
`systems.
`
`[0018] US. Pat. No. 5,313,941 discloses a non-invasive
`sensing device that can be used for blood glucose determi-
`nations. Long wavelength range infrared energy is passed
`through an appendage(finger) containing venous or capil-
`lary blood flow. The infrared energy is synchronized with the
`diastole and systole phase of the cardiac cycle. ‘The mea-
`surements are made by monitoring strong and distinguish-
`able infrared absorption of the desired blood analyte. Appli-
`cants are not aware of any working device results from such
`a device that were presented to the public, nor any product
`of this type introduced for public use.
`
`[0019] U.S. Pat. No. 5,666,956 describes another non-
`invasive device that uses the natural thermal infrared emis-
`sion from the tympanic membrane (ear drum) to detect
`blood glucose concentration in human bodytissue. A portion
`of this thermal radiation is collected and analyzed using
`various mid-infrared filtering schemes to a detector with
`further electronic processing. Results are shown fortesting
`on a non-diabetic individual. Such a device developed by
`Infratec, Inc. has been clinically tested and reported in 2002.
`
`[0020] U/S. Pat. No. 6,445,938 discloses a “method for
`determining blood glucose levels from a single surface of
`the skin”. A device using this method is described in the
`patent which uses attenuated total reflection (ATR) mid-
`infrared spectroscopy to measure bloodglucosein the outer
`skin of a fingertip. Prototype devices using this method have
`been developed by MedOptix, Inc.
`
`[0021] Detection of carboxyhemoglobin and met-hemo-
`globin concentrations in blood is important during emer-
`gency situations such as carbon dioxide poisoning due to
`
`15
`
`15
`
`

`

`US 2005/0267346 Al
`
`Dec. 1, 2005
`
`smoke inhalation, residential heating systems, automobile
`exhausts as well as drug overdose. They are usually mea-
`sured from invasively drawn arterial blood samplesthat are
`measured in a specialized spectrometer known as a CO-
`oximeter.
`
`[0022] U.S. Pat. Nos. 6,115,621, 6,397,093 B1 and 6,104,
`938 disclose optical, non-invasive oximeter measurement
`systems that attempt to address these issues.
`
`[0023] U.S. Pat. No. 6,115,621 describes an oximeter
`sensor that uses an offset
`light emitter and detector. It
`increases the diffused light optical path length through the
`blood-perfused tissue by incorporating a reflective planer
`surface on each tissue exposed side of the sensor. Sensor
`designs are shown for application to the ear lobe and nose.
`
`[0024] U.S. Pat. No. 6,397,093 B1 describes using a
`modified conventional, two wavelength pulse oximeter and
`sensor to measure carboxyhemoglobin non-invasively. Vari-
`ous predetermined calibration curves are used in the analy-
`sis.
`
`[0025] U.S. Pat. No. 6,104,938 describes the apparatus
`and method to measure fractional oxygen saturation (OHb/
`total Hb) non-invasively. Four wavelengths in the red and
`near-infrared are used in the oximeter sensor design. Mea-
`surements can be made in either transmission or reflection.
`
`SUMMARYOF THE INVENTION
`
`[0026] This invention relates in general to apparatus and
`methods used in precision measurements of diffuse reflec-
`tion and transmission electromagnetic radiation, either sepa-
`rately or simultaneously, from pulsate, blood-perfused tissue
`for the subsequent determination of the blood analytes
`concentrations such as arterial blood oxygen saturation
`(SaO,),
`carboxyhemoglobin
`(COHb),
`oxyhemoglobin
`(OHb),
`deoxyhemoglobin
`(dOHb), methemoglobin
`(metHb), water (H20), hematocrit (HCT), glucose, choles-
`terol and proteins such as albumin. This diffusely reflected
`and transmitted light includes somescattered light, butit is
`predominantly reflected or transmitted.
`
`[0027] Morespecifically, it relates to non-invasive, optical
`apparatus and methodsfor the direct measurement of hemo-
`globin derivatives and other analyte concentration levels in
`blood using a) both diffuse reflection and diffuse transmis-
`sion spectroscopy in the approximate wavelength region
`400-1350 nm—which includes the transparent “tissue win-
`dow” from approximately 610 to 1311 nanometers; and b)
`using diffuse reflection spectrometry and operating in the
`mid-infrared region, from 4.3-12 microns in wavelength.
`Large area lightcollection techniquesare utilized to provide
`a muchlarger pulsate signal than can be obtain with current
`sensor technology.
`
`In one form of the invention useful in the measure-
`[0028]
`ment of blood analytes in the mid-infrared (MIR) wave-
`length region typically from 5 to 10 micron, the device has
`four principal components:
`
`[0029] A first componentis a tunable MIRlight source of
`n=2 specific, discrete spectral bands consisting of either a
`light source with peak blackbody wavelength between 9 and
`11 micronspassing through spectralfilters or a spectrometer,
`MIR diodes, Lead-salt lasers, and Distributive Feed Back
`
`(DFB) or Multi-mode Quantum Cascade Lasers (QCL),
`composed of three or morelasers.
`
`[0030] Asecond componentis a sensorthat utilizes lenses
`and reflective optics to collect diffuse reflected and scattered
`light from the tissue site, containing spectral (light intensity)
`information about the whole blood’s current glucose, pro-
`teins, water and blood analyte concentrations.
`
`[0031] A third componentis an analyzer with algorithms
`for computing blood analyte concentrations. One algorithm
`is an iterative constituent sequenced algorithm for correlat-
`ing diffuse collected light signals with a set of blood
`constituents. Each constituent is associated with one of the
`n spectral bands, successively. The other algorithm is a
`residual least squares curve fitting algorithm thatfits col-
`lected diffuse light signals from blood pulsate tissue to a
`curve.
`
`[0032] A fourth componentis output electronics that dis-
`plays the current concentration levels measured for blood
`analytes. This information may bestored electronically in
`random access memory (RAM) or other digital storage
`media for retrieval at a later time.
`
`In another form of the present invention, an optical
`[0033]
`apparatus and methodsfor the direct measurement of hemo-
`globin derivatives and other analyte concentration levels in
`blood uses both diffuse reflection and diffuse transmission
`
`spectroscopy in the approximate wavelength region 400-
`1350 nm, which includes the transparent “tissue window”
`from approximately 610 to 1311 nanometers.
`
`[0034] This form of the invention also has four principal
`components.
`
`is a light emitter consisting of
`[0035] One component
`Quartz halogen, white light LED, discrete wavelength LEDs
`or diode lasers.
`
`[0036] A second component is a pair of detectors with
`optics that collect the diffusely transmitted and reflected
`light from the blood-perfused tissues. The transmission
`detector is optimally located and facing the emitter so that it
`most efficiently collects the diffuse light from tissue (e.g.
`finger, earlobe, toe, or foot) placed between detector and
`emitter. The reflection detector is facing the illuminated
`tissue from the emitter and is located next to the emitter with
`
`an optimal separation. Both detectors may consist of silicon
`photodiodes and optics such as multimodefiber, lens, lenses,
`or optimized reflectors of parabolic or ellipsoidal shape. The
`output signals from each of the sensor’s two detectors are
`proportional to light intensity. These signals are sent by
`multimode fibers or electrical cable to the analyzer for
`further analysis.
`
`is an analyzer which may
`{0037] A third component
`consist of a personal computer and Digital Signal Processor
`(DSP) board or standard oximeter electronics. Computa-
`tional analysis incorporates algorithms based on either an
`exactly determined or over-determined system of equations
`to calculate the total and ratio of concentrations of the blood
`analytes.
`
`[0038] A fourth is an output electronics which may include
`display and audio-visual alarm electronics for “real time”
`results and digital storage using read-only memory (ROM
`for digital storage (results, trends, alarms,etc.)
`
`16
`
`16
`
`

`

`US 2005/0267346 Al
`
`Dec. 1, 2005
`
`[0039] These and other features and objects of the present
`invention will be more fully understood from the following
`detailed description of the invention, which should be read
`in light of the accompanying drawings.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`DESCRIPTION OF THE INVENTION
`
`[0054] FIG. 1 shows in schematic form an apparatus
`particularly useful for an accurate, direct, non-invasive
`measurement of the blood glucose level. The invention is
`based on detecting and analyzing by diffuse reflection and
`optical spectroscopy the fundamental molecular vibrational
`modes of glucose, proteins and water in the mid-infrared
`(MIR) wavelength region from 5 to 10 micron.
`[0055] MIR light from light source 1 such as onesavail-
`able from Thermo-Oriel with spectral radiant emission peak
`[0041] FIG. 2a shows a schematic representation of a
`blackbody wavelength between 9 and 11 microns passes
`typical linear variable bandpassfilter’s physical configura-
`througharotating filter wheel 2 composedofspectral filters.
`tion and spectral characteristics for use in the apparatus of
`Other technologies, such as MIR diodes, Lead-salt lasers,
`FIG.1;
`and Distributive Feed Back (DFB) or Multi-mode Quantum
`Cascade Lasers (QCL) mayalso be used as a tunable light
`source.
`
`[0040] FIG. 1 shows in schematic form one form of the
`apparatus for non-invasive analysis of blood components in
`the mid-infrared wavelength region;
`
`[0042] FIG. 25 shows a schematic representation of a
`typical circular variable bandpass filter’s physical configu-
`ration and spectral characteristics;
`
`[0043] FIG. 2c shows a schematic representation of a
`typical discrete bandpassfilter’s physical configuration and
`spectral characteristics;
`
`[0044] FIG. 3 shows in a schematic form various blood
`flow volume change due to cardiac cycle and body site
`clamping;
`
`[0045] FIG. 4 shows a schematic of a diffuse reflection
`light collection system for use with an FT-IR Spectrometer
`as the light source in a mid-range non-invasive apparatus
`otherwise of the general type shown in FIG.1;
`
`[0046] FIG. 5 shows a flow chart for determining the
`blood analyte concentration illustrating one implementation
`of an iterative, constituent-sequenced algorithm for use with
`the apparatus of this invention;
`
`[0047] FIG. 6 shows a flow chart for one form of a
`residual least squares algorithm for use with the apparatus of
`the invention to fit one component concentration using the
`collected diffuse light signals at a given wavelength or
`bandwidth associated with that one component;
`
`[0048] FIG. 7 shows a Clarke Error grid analysis of
`measurement results for determining whole blood glucose
`concentration;
`
`[0049] FIG. 8 shows a schematic of the invention appa-
`ratus for large area light collection of diffuse reflection and
`transmission from pulsate, blood-perfuse tissue;
`
`[0050] FIG. 9 shows a graph of the absorbance versus
`wavelength spectra from 600 to 1100 nanometers of oxy
`(OHb) and deoxy (dHb) hemoglobin and liquid water;
`
`[0051] FIG. 10 shows in schematic form an alternative
`embodiment of apparatus according to this invention for
`analysis of blood components in the visible, near infrared
`wavelength region using diffuse reflectance and transmis-
`sion;
`
`[0052] FIG. 11 shows a graph of the relative optical
`absorbance of four hemoglobin types versus wavelength in
`the visible and near infrared from 450 to 1000 nanometers;
`
`[0053] FIG. 12 shows a graph of the relative optical
`absorbance of four hemoglobin types versus wavelength in
`the visible from 500 to 650 nanometers
`
`[0056] The filter wheel 2 is composed of three or more
`MIRoptically transmitting filters. Typical variations of the
`wheel assembly are shown in FIGS. 2a, 2b and 2c. Onefilter
`11 passes only the mid-IR light necessary for measuring
`glucose signal (8.5-10 micron). Anotherfilter 12 passes only
`the mid-IR light necessary for measuring a protein signal
`(6.7-8.5 microns). The third filter 13 passes only the MIR
`light necessary to measure the water signal (4.3-5 zm). The
`filters 11, 12 and 13 are typically composed of multilayer
`thin films deposited onto an optically transmitting substrate.
`In addition, filters 11 and 12 are narrow bandpass circular
`variable (FIG. 2a), linearly variable (FIG. 2b) or discrete
`(FIG.2c) filters with center wavelength from 6.7-10 micron
`while filter 13 is a broad bandpassfilter centered from 4.3-5
`micron. The rotation or movementof the filter wheel 2 is
`detected by a motor optical encoder (e.g. one from Encoder
`Products Co.) and synchronizing pulses with timing infor-
`mation (filter position at a given time) is sent to the pro-
`cessing unit 9. Other methods such as grating-dispersion
`based spectrometers from manufacturers such as Jobin-Yvon
`may be used to separate the glucose, protein and water MIR
`spectral regions.
`[0057] This filtered light is transmitted by a MIR optical
`light fiber/waveguide 3 such as one manufactured by such
`suppliers as CeramOptec or Amorphous Materials.
`It
`is
`focused by a MIR transmitting lens or lenses 7 through a
`plastic speculum 5 onto a body site 6 which contains
`capillary or venous blood to be analyzed. Blood volumeat
`the site can be regulated by two suggested methods. One
`method is venous occlusion clamping, with inflation/defla-
`tion cuffs from D.E. Hokanson,Inc. or others, where venous
`blood flow from the site to the heart is stopped but arterial
`blood flow continuesto the site from the heart. This stoppage
`increases blood pool volume with time the at the bodysite
`(FIG. 3). Measurements are made before and after clamp-
`ing. Another method requires site measurements to be made
`in synchronization with the diastole and systole phases of
`the cardiac cycle (FIG. 3). A pulse oximeter with plethys-
`mographic electronic output, for example one from Nellcor
`Puritan Bennett Inc., can be used for the trigger synchroni-
`zation. Both methods allow spectral measurements to be
`made when blood volumeat the site is a maximum and
`
`minimum. This will be used in the elimination of interfering
`effects of various intervening materials like tissue, melanin,
`collagen and fat.
`[0058] The diffuse reflected and scattered light from the
`site, containing spectral (light intensity) information about
`
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`the whole blood’s current glucose, proteins and water con-
`centration,is collected by the lens or lenses 7 and re-focused
`onto another MIR light optical fiber/waveguide 4.
`
`[0059] The light is transmitted through an optical light
`fiber/waveguide 4 illuminating a high sensitivity mid-IR
`detector 8,
`typically composed of a Mercury Cadmium
`Telluride (HgCdTe, MCT) sensor element. MIR microbo-
`lometers, diode sensor element or arrays may also be used.
`The sensor may be cooled either thermoelectrically or with
`liquid nitrogen using a detector Dewar. In addition,
`the
`detector signal is further amplified with associated “pre-
`amp” electronics. A suitable detector of this type, with
`Dewar and pre-amp electronics, can be purchased from
`Judson Technologies.
`
`[0060] The detector’s amplified analog output from the
`mid-IR detector 8 is digitized by an analog-to-digital con-
`verter from such manufacturers as Analog Devices. This
`digital signal with its associated synchronized encoder tim-
`ing information from the filter wheel 2 is sent to a Central
`Processing Unit/Digital Signal Processor, CPU/DSP 9 which
`performs further signal processing. An example of this
`device may consist of a personal computer and DSP PC
`board from Texas Instruments. Using the digitized detector/
`timing signal, the CPU/DSP 9 executes a computer code,
`written in such computer languages as Microsoft Visual
`Basic (VB). The encoder timing pulse from the filter wheel
`2 is converted to a known MIR wavelength position. A two
`dimensional array is then calculated which consists of the
`wavelength and its corresponding intensity value from the
`detector 8 output. This array output forms three MIR spec-
`trum (intensity versus wavelength) corresponding to mea-
`sured blood glucose, protein and water.
`
`[0061] FIG. 4 showsapparatus 50 that can be used in the
`mid-IR measurement apparatus. It directs an interrogating
`beam 51 of radiation in the mid-IR range, produced by a
`spectrometer 1 (FIG. 1),
`to the tissue sample 6. It also
`collects the interrogating light diffusely reflected from the
`pulsating, blood-perfused tissue 6. A mirror 52 directs the
`interrogating beam from the spectrometer, through an open-
`ing 60, onto the sample 6. As shown,the angle of incidence
`of the light beam onthe tissue is substantially normal. The
`light 53 scattered and diffusely reflected from the pulsating,
`blood-perfused tissue is intercepted by a reflector 54 that is
`1) curved concavely with respect to the tissue, and 2) angled
`to direct the collected, diffusely reflected light 53 to a pair
`of planar mirrors 56, 58, which,in turn, direct this light onto
`a suitable light detector, such as the detector 8 in FIG. 1. The
`reflector 54 is preferably curved along an ellipsoidal path
`when viewed in cross-section as shown in FIG.4.
`
`[0062] The opening 60 within the reflector 54 both allows
`the interrogating beam 51 to pass through the reflector 54,
`and allows specular reflections from the sample to bypass
`detection and measurement by passing back through the
`opening 60, rather than being collected and directed to the
`detector 8. This specular reflection is indicated by arrow
`heads 53a.
`
`In operation, this apparatus eliminates interfering
`[0063]
`effects due to tissue, melanin, collagen and fat are eliminated
`by subtracting the spectrum at minimum blood volume from
`maximum blood volume at
`the body site. The resultant
`spectrum is the whole blood from the body site’s capillaries
`or veins. Glucose, protein and water concentration in the
`
`whole blood are determined as follows. Analysis is per-
`formed by execution of additional computer code using flow
`chart shown in FIG. 5 written in such computer languages
`as Microsoft Visual Basic (VB). Each of n spectral regions
`(e.g. one each for glucose, protein and water) is compared to
`a corresponding glucose, protein and water calibration spec-
`tral data typically stored electronically in random access
`memory (ROM). The measured spectral intensities are mul-
`tiplied by a constant and compared to their corresponding
`calibration spectrum intensity value until a least squares
`residual between the two spectra are minimized using the
`method shown in the flow chart of FIG. 6. This computed
`constant with the minimal residual
`is multiplied by the
`known calibration concentration and becomesthe true con-
`
`centration of the chemical in the whole blood of the body
`site. The method is reiterated many times for all compo-
`nents.
`
`In the prior art, data at just a few wavelengths was
`[0064]
`used to calculate component concentrations in the blood.
`This practice is very difficult; among other reasons, because:
`
`1. There are many components in the blood
`[0065]
`and their spectra overlap with each other. For
`example,
`the glucose peaks at 9-10 um region is
`overwhelmed by water base line and protein peaks.
`
`2. Each component concentration is changing
`[0066]
`over time.
`
`3. Some component concentrations are even
`[0067]
`lower than 0.1%.
`
`4. There are noise, DC offset, and drift in the
`[0068]
`spectra due to instrument and sampling.
`
`In the method depicted in FIG.5, all spectra data
`[0069]
`over entire measurement range is used to provide the best
`fitting for all the components. This method convergesfast to
`a global minimumin thefitting process.
`
`[0070] FIG.7 is an example ofactual in-vitro whole blood
`measurements using a Fourier Transform-Infrared (FT-IR)
`spectrometer and the analysis software plotted on a Clarke
`Error Grid. (From Clarke, W. L., et al., Diabetes Care, Vol.
`10;5; 622-628 (1987), the disclosure of which is incorpo-
`rated by reference.
`
`{0071]
`follows:
`
`In the Clark Error grid, zones A-E are defined as
`
`[0072] Zone A—Clinically accurate within +20% of
`the Reference.
`
`[0073] Zonc B—Errorgreater than +20%, but would
`lead to benign or no treatment.
`
`[0074] Zone C—Errors would lead to unnecessary
`corrective treatment.
`
`[0075] Zone D—Potentially dangerous failure to
`detect hypo- or hyperglycemia.
`
`[0076] Zone E—Erroneous treatment of hypo- or
`hyperglycemia.
`
`[0077] The output electronics 10 using e.g. liquid crystal
`(LCD)andor visible diode technologies displays the current
`concentration levels measured for blood glucose, protein
`and water. This information may bestored electronically in
`
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`random access memory (RAM)or other digital storage
`media for retrieval at a later time.
`
`[0078] FIG. 10 shows in schematic form an apparatus 21
`of the present invention particularly useful for an accurate,
`direct, non-invasive measurement of hemoglobin deriva-
`tives and other analyte concentrations in blood using inter-
`rogating radiation in the visible and near infrared, from
`approximately 400-1350 nanometers. The analyzer unit 1
`may be portable or rack mounted.
`
`[0079] FIG. 8 showsthis detection concept schematically.
`A multiple wavelength light source 21, consisting,
`for
`example, of a halogen bulb, LED, or diodelaser illuminates
`a body part 22 such as a finger, toe or foot. The light passes
`through various layers which may include skin, blood (both
`venous andarterial pulsate), tissue, cartilage and bone. As
`the light passes through the body part it is absorbed and
`scattered. The scattered light from the arterial pulsate blood
`24 is diffusely reflected 27 and transmitted 25 through the
`body part. Large area light collection detectors 26 and 28
`capture this diffuse light for analysis.
`
`large core multimodefibers lens, lenses or optimized reflec-
`tors of parabolic or ellipsoidal shape collect
`the diffuse
`transmitted 25 and reflected light 27 emanating from the
`irradiated tissue 22 and couple it into multimodefibers 44
`and 46, respectively. Direct light from the emitter 1s blocked
`from the diffuse reflector detector by an optical barrier 48.
`The solid angle collection area of the emitter and two
`detectors are designed to maximize the two detectors signal-
`to-noise (S/N) ratio and also reduc