US20150018642A1 - Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof - Google Patents

Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof Download PDF

Info

Publication number
US20150018642A1
US20150018642A1 US13/941,369 US201313941369A US2015018642A1 US 20150018642 A1 US20150018642 A1 US 20150018642A1 US 201313941369 A US201313941369 A US 201313941369A US 2015018642 A1 US2015018642 A1 US 2015018642A1
Authority
US
United States
Prior art keywords
subject
analyzer
burst
signal
sample
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.)
Abandoned
Application number
US13/941,369
Inventor
Sandeep Gulati
Thomas George
Timothy Ruchti
Alan Abul-Haj
Kevin H. Hazen
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.)
ZYOMED CORP
Original Assignee
Sandeep Gulati
Thomas George
Timothy Ruchti
Alan Abul-Haj
Kevin H. Hazen
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
Application filed by Sandeep Gulati, Thomas George, Timothy Ruchti, Alan Abul-Haj, Kevin H. Hazen filed Critical Sandeep Gulati
Priority to US13/941,369 priority Critical patent/US20150018642A1/en
Priority to US13/941,389 priority patent/US9766126B2/en
Priority to US13/941,411 priority patent/US20150018646A1/en
Priority to US13/963,925 priority patent/US20150045636A1/en
Priority to US13/963,933 priority patent/US20150041656A1/en
Priority to US14/493,266 priority patent/US9351672B2/en
Priority to US14/493,234 priority patent/US9351671B2/en
Priority to US14/493,283 priority patent/US9585604B2/en
Priority to US14/504,065 priority patent/US20150018644A1/en
Publication of US20150018642A1 publication Critical patent/US20150018642A1/en
Assigned to ZYOMED CORP. reassignment ZYOMED CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABUL-HAJ, ALAN, HAZEN, KEVIN H., RUCHTI, TIMOTHY, GEORGE, THOMAS, GULATI, SANDEEP
Priority to US14/938,688 priority patent/US9375170B2/en
Priority to US14/943,990 priority patent/US20160151002A1/en
Priority to US14/965,782 priority patent/US20160249836A1/en
Priority to US14/965,807 priority patent/US20160242682A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28Investigating the spectrum
    • G01J3/42Absorption spectrometry; Double beam spectrometry; Flicker spectrometry; Reflection spectrometry
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0015Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system
    • A61B5/0022Monitoring a patient using a global network, e.g. telephone networks, internet
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/103Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/107Measuring physical dimensions, e.g. size of the entire body or parts thereof
    • A61B5/1079Measuring physical dimensions, e.g. size of the entire body or parts thereof using optical or photographic means
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring 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
    • A61B5/14551Measuring 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 for measuring blood gases
    • A61B5/14552Details of sensors specially adapted therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47Scattering, i.e. diffuse reflection
    • G01N21/4738Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474Details of optical heads therefor, e.g. using optical fibres
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47Scattering, i.e. diffuse reflection
    • G01N21/4738Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474Details of optical heads therefor, e.g. using optical fibres
    • G01N2021/4742Details of optical heads therefor, e.g. using optical fibres comprising optical fibres
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47Scattering, i.e. diffuse reflection
    • G01N21/4738Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474Details of optical heads therefor, e.g. using optical fibres
    • G01N2021/4742Details of optical heads therefor, e.g. using optical fibres comprising optical fibres
    • G01N2021/4747Concentric bundles
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00Features of devices classified in G01N21/00
    • G01N2201/08Optical fibres; light guides
    • G01N2201/0826Fibre array at source, distributing

Definitions

  • the present invention relates to a temporal resolution gating noninvasive analyzer for use in analyte concentration estimation.
  • Patents and literature related to the current invention are summarized herein.
  • Diabetes mellitus or diabetes is a chronic disease resulting in the improper production and/or use of insulin, a hormone that facilitates glucose uptake into cells. Diabetes is broadly categorized into four forms grouped by glucose concentration state: hyperinsulinemia (hypoglycemia), normal physiology, impaired glucose tolerance, and hypoinsulinemia (hyperglycemia).
  • Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and/or neuropathy.
  • Complications of diabetes include: heart disease, stroke, high blood pressure, kidney disease, nerve disease and related amputations, retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and/or fetal complications.
  • Diabetes is a common and increasingly prevalent disease. Currently, diabetes is a leading cause of death and disability worldwide. The World Health Organization estimates that the number of people with diabetes will grow to three hundred million by the year 2025.
  • the invention comprises a temporal resolution gating noninvasive analyzer apparatus and method of use thereof.
  • FIG. 1 illustrates an analyzer
  • FIG. 2 illustrates diffusely reflecting optical paths
  • FIG. 3 illustrates probing tissue layers using a spatial distribution method
  • FIG. 4 illustrates varying illumination zones relative to a detector
  • FIG. 5 illustrates varying detection zones relative to an illuminator
  • FIGS. 6(A-D) illustrate temporal resolution gating, FIG. 6A ; probabilistic optical paths for a first elapsed time, FIG. 6B ; probabilistic optical paths for a second elapsed time, FIG. 6C ; and a temporal distribution method, FIG. 6D ;
  • FIGS. 7(A-C) illustrate a fiber optic bundle, FIG. 7A ; a first example sample interface end of the fiber optic bundle, FIG. 7B ; and a second example sample interface end of the fiber optic bundle, FIG. 7C ;
  • FIGS. 8(A-C) illustrate a third example sample interface end of the fiber optic bundle, FIG. 8A ; a mask, FIG. 8B ; and a mask selector, FIG. 8C ;
  • FIGS. 9(A-B) illustrate a pathlength resolved sample interface for (1) a first subject, FIG. 9A and (2) a second subject, FIG. 9B .
  • the invention comprises a temporal resolution gating noninvasive analyzer apparatus and method of use thereof.
  • a temporal resolution gating noninvasive analyzer is used to determine an analyte property of a biomedical sample, such as a glucose concentration of a subject using light in the near-infrared region from 1000 to 2500 nanometers.
  • a data processing system analyzes data from an analyzer to estimate and/or determine an analyte property, such as concentration.
  • an analyzer using light interrogates the sample using one or more of:
  • Data from the analyzer is analyzed using a data processing system capable of using the information inherent in the resolved system data.
  • a data processing system uses interrelationships of chemistry based a-priori spectral information related to absorbance of a sample constituent and/or the effect of the environment, such as temperature, on the spectral information.
  • a data processing system uses a first mapping phase to set instrument control parameters for a particular subject, set of subjects, and/or class of subjects. Subsequently, the control parameters are used in a second data collection phase to collect spectra of the particular subject or class of subjects.
  • a data processing system uses information related to contact pressure on a tissue sample site.
  • a data processing system uses a combination of any of:
  • axes systems are separately defined for an analyzer and for an interface of the analyzer to a patient, where the patient is alternatively referred to as a subject.
  • an x-, y-, z-axes analyzer coordinate system is defined relative to the analyzer.
  • the x-axis is the in the direction of the mean optical path.
  • the y-axis crosses the mean optical path perpendicular to the x-axis.
  • the x-axis and y-axis define a x/y horizontal plane.
  • the z-axis is normal to the x/y plane.
  • the z-axis is aligned with gravity, which is normal to the x/y horizontal plane.
  • the x, y, z-analyzer coordinate system is defined separately for each optical path element.
  • the optical system is further defined to remove ambiguity.
  • an x, y, z-axes patient coordinate system is defined relative to a body part interfaced to the analyzer.
  • the x, y, z-axes body coordinate system moves with movement of the body part.
  • the x-axis is defined along the length of the body part
  • the y-axis is defined across the body part.
  • the analyzer interfaces to the forearm of the patient, then the x-axis runs longitudinally between the elbow and the wrist of the forearm and the y-axis runs across the forearm.
  • the x,y plane tangentially touches the skin surface at a central point of the interface of the analyzer to the body part, which is referred to as the center of the sample site, sample region, or sample site.
  • the z-axis is defined as orthogonal to the x,y plane. Rotation of an object is further used to define the orientation of the object to the sample site.
  • a sample probe of the analyzer is rotatable relative to the sample site.
  • Tilt refers to an off z-axis alignment, such as an off z-axis alignment of a probe of the analyzer relative to the sample site.
  • the analyzer comprises at least: a light source system 110 , a photon transport system 120 , a detector system 130 , and a data processing system 140 .
  • the analyzer 100 estimates and/or determines a physical property, a sample state, a constituent property, and/or a concentration of an analyte.
  • the analyzer 100 includes a sample interface 150 , which interfaces to a reference material 160 and/or to a subject 170 .
  • a subject 170 in the examples is representative of a person, animal, a prepared sample, and/or patient.
  • the analyzer 100 is used by a user to analyze the user, referred to herein as a subject 170 , and is used by a medical professional to analyze a patient.
  • the analyzer 100 optionally includes a system controller 180 .
  • the system controller 180 is used to control one or more of: the light source system 110 or a light source 112 thereof, the photon transport system 120 , the detector system 130 or a detector 132 thereof, the sample interface 150 , position of the reference 160 relative to the sample interface 150 , position of the subject 170 relative to the sample interface 150 , and communication to an outside system 190 , such as a smart phone 192 , and/or a remote system 194 using a wireless communication system 196 and/or hard wired communication system 198 .
  • the remote system includes a data processing system, a data storage system, and/or a data organization system.
  • the optional system controller 180 operates in any of a predetermined manner or in communication with the data processing system 140 .
  • the controller In the case of operation in communication with the data processing system 140 , the controller generates control statements using data and/or information about the current state of the analyzer 100 , current state of a surrounding environment 162 outside of the analyzer 100 , information generated by the data processing system 140 , and/or input from a sensor, such as a sample interface sensor 152 or an auxiliary system 10 or an auxiliary sensor 12 thereof.
  • the auxiliary system 10 is any system providing input to the analyzer 100 .
  • the optional system controller 180 is used to control: photon intensity of photons from the source using an intensity controller 122 , wavelength distribution of photons from the source 110 using a wavelength controller 124 , and/or physical routing of photons from the source 110 using a position controller 126 .
  • the optional outside system 190 is illustrated as using a smart phone 192 .
  • the smart phone 192 is optionally a cell phone, a tablet computer, a computer network, and/or a personal computer.
  • the smart phone 192 also refers to a feature phone, a mobile phone, a portable phone, and/or a cell phone.
  • the smart phone 192 includes hardware, software, and/or communication features carried by an individual that is optionally used to offload requirements of the analyzer 100 .
  • the smart phone 192 includes a user interface system, a memory system, a communication system, and/or a global positioning system.
  • the smart phone 192 is optionally used to link to the remote system 194 , such as a data processing system, a medical system, and/or an emergency system.
  • the remote system 194 such as a data processing system, a medical system, and/or an emergency system.
  • at least one calculation of the analyzer in noninvasively determining a glucose concentration of the subject 170 is performed using the smart phone 192 .
  • the analyzer gathers information from at least one auxiliary sensor 12 and relays that information and/or a processed form of that information to the smart phone 192 , where the auxiliary sensor is not integrated into the analyzer 100 .
  • the source system 110 generates photons in any of the visible, infrared, near-infrared, mid-infrared, and/or far-infrared spectral regions.
  • the source system generates photons in the near-infrared region from 1100 to 2500 nm or any range therein, such as within the range of about 1200 to 1800 nm; at wavelength longer than any of 800, 900, 1000, and 1100 nm; and/or at wavelengths shorter than any of 2600, 2500, 2000, or 1900 nm.
  • a photon transit system 200 through skin layers of the subject 170 is illustrated.
  • the photon transport system 120 guides light from a source 112 of the source system 110 to the subject 170 .
  • a contact gap 210 is present between a last optic of the photon transport system 120 and skin of the subject 170 .
  • the photon transport system 120 irradiates skin of the subject 170 over a narrow illumination zone, such as having an area of less than about 9, 4, 1, or 1 ⁇ 4mm 2 .
  • the photons are delivered to the skin of the subject 170 through an optic proximately contacting, but not actually contacting, the skin, such as within about 0.5, 1.0, or 2.0 millimeters of the skin.
  • the distance between the analyzer and the skin of the subject 170 is maintained with a vibration and/or shake reduction system, such as is used in a vibration reduction camera or lens.
  • the skin position is monitored with a sensor, output from the sensor is sent to the controller, and the controller controls an electro-mechanical element used to control a position of an element of the analyzer.
  • the photons are depicted as entering the skin at a single point.
  • the detection zone is a region of the skin surface where the detector system 130 gathers the traversing or diffusely reflected photons.
  • Various photons traversing or diffusely scattering through the skin encounter an epidermis 173 or epidermis layer, a dermis 174 or dermis layer, and subcutaneous fat 176 or a subcutaneous fat layer. As depicted in FIG.
  • the diffuse reflectance of the various photons through the skin detected by the detection system 130 follow a variety of optical paths through the tissue, such as shallow paths through the epidermis 173 , deeper paths through the epidermis 173 and dermis 174 , and still deeper paths through the epidermis 173 , dermis 174 , and subcutaneous fat 176 .
  • shallow paths through the epidermis 173 deeper paths through the epidermis 173 and dermis 174
  • still deeper paths through the epidermis 173 , dermis 174 , and subcutaneous fat 176 there exists a mean photon path for photons from entering the skin that are detected by the detection system 130 .
  • Beer's Law is used to described photon interaction with skin, though those skilled in the art understand deviation from Beer's Law result from sample scattering, index of refraction variation, inhomogeneity, turbidity, and/or absorbance out of a linear range of the analyzer 100 .
  • A absorbance
  • b pathlength
  • C concentration
  • spectral absorbance is used to determine concentration.
  • the absorbance is additionally related to pathlength.
  • determination of the optical pathlength traveled by the photons is useful in reducing error in the determined concentration.
  • Two methods, described infra, are optionally used to estimate pathlength: (1) spatial resolution of pathlength and (2) temporal resolution of pathlength.
  • the data and/or derived information from each of the spatial resolution method and temporal resolution method are each usable with the data processing system 140 .
  • Examples provide, infra, illustrate: (1) both cases of the spatial resolution method and (2) the temporal resolution method.
  • the photons in most examples are depicted as radially traversing from a range of input zones to a detection zone.
  • photons are optionally controlled from an input zone to a range of detection zones.
  • photons are optionally directed to a series of input zones, as a function of time, and for each input zone or set of input zones one or more detection zones are used.
  • the first method of spatial resolution contains two cases.
  • photons are depicted traversing from a range of input points on the skin to a radially located detector to derive photon interrogated sample path and/or depth information.
  • equivalent systems optionally use a single input zone of the photons to the skin and a plurality of radially located detector zones to determine optical sample photons paths and/or depth information.
  • a combination of the first two cases, such as multiple sources and multiple detectors, is optionally used to derive photon path information in the skin.
  • the photon transit system 200 of FIG. 2 is illustrated where the photon transport system 110 irradiates the skin of the subject 170 over a wide range of radial distance from the detection zone, such as at least about 0.1, 0.2, 0.3, 0.4, or 0.5 millimeters from the detection zone to less than about 1.0, 1.2, 1.4, 1.6, or 1.8 millimeters from the detection zone.
  • a mean photon path is provided as a function of radial distance from the illumination zone to the detection zone.
  • the mean optical path of the detected diffusely scattering photons increases in depth for photons in the near-infrared traveling through skin.
  • the photon transit system 200 uses a vector or array of illumination sources 400 , of the source system 110 , in a spatially resolved pathlength determination system.
  • the illumination sources are an array of fiber optic cables.
  • a set of seven fiber optics 401 , 402 , 403 , 404 , 405 , 406 , 407 are positioned, radially along the x,y plane of the subject 170 to provide a set of illuminations zones, relative to a detection fiber at a detection zone.
  • the third illumination fiber optic 403 /detector 132 combination yields a mean photon path having a third depth of penetration, d 3 , for a third fiber optic-to-detector radial distance, r 3 ;
  • the fifth illumination fiber optic 405 /detector 132 combination yields a mean photon path having a fifth depth of penetration, d 5 , for a fifth fiber optic-to-detector radial distance, r 5 ;
  • the seventh illumination fiber optic 407 /detector 132 combination yields a mean photon path having a seventh depth of penetration, d 7 , for a seventh fiber optic-to-detector radial distance, r 7 .
  • both a mean depth of penetration of the photons and a total optical pathlength increases with increasing fiber optic-to-detector distance, where the fiber optic-to-detector distance is less than about three millimeters.
  • the photon transit system 200 uses a vector or array of detectors 500 in the detection system 130 .
  • a single fiber optic source is used, which sends radially distributed light to an array of staring detectors or collection optics coupled to a set of detectors.
  • a set of seven detectors 501 , 502 , 503 , 504 , 505 , 506 , 507 are positioned, radially along the x,y plane to provide a set of detection zones, relative to an illumination zone.
  • the source 112 /second detector 502 combination yields a mean photon path having a second depth of penetration, d 2 , for a second source-to-detector radial distance, r 2 ;
  • the source 112 /fourth detector 504 combination yields a mean photon path having a fourth depth of penetration, d 4 , for a fourth source-to-detector radial distance, r 4 ;
  • the source 112 /sixth detector 506 combination yields a mean photon path having a sixth depth of penetration, d 6 , for a sixth source-to-detector radial distance, r 6 .
  • the number of source zones is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100 or more and the number of detection zones is optionally 1, 2, 3, 4, 5, 10, 20, 50, 500, 1000, 5000, 10,000, 100,000 or more.
  • the second method of temporal resolution is optionally performed in a number of manners.
  • a temporal resolution example is provided where photons are timed using a gating system and the elapsed time is used to determine photon paths in tissue.
  • FIGS. 6A-D an example of a temporally resolved gating system 600 is illustrated.
  • the time of flight of a photon is used to determine the pathlength, b.
  • an interrogation pulse 610 of one or more photons is introduced to the sample, which herein is skin of the subject 170 .
  • the interrogation pulse 610 is also referred to as a pump pulse or as a flash of light.
  • the interrogation pulse 610 is detected.
  • the gated detection times are at a first time 622 , t 1 ; a second time 624 , t 2 ; a third time 626 , t 3 ; and at an n th time 628 , t n , where n is a positive number.
  • the gated detection times 620 overlap.
  • the elapsed time used to detect the interrogation photons 610 is on the order of picoseconds, such as less than about 100, 10, or 1 picosecond.
  • the physical pathlength, b is determined using equation 2:
  • OPD c n ⁇ ( b ) ( eq . ⁇ 2 )
  • n is a mathematical representation of a series of indices of refraction of various constituents of skin and/or skin and surrounding tissue layers. More generally, observed pathlength is related to elapsed time of photon capture where the relationship of pathlength to temperature is optionally further determined using a measure of a tissue, such as an index of refraction.
  • FIG. 6B illustrative paths of the photons for the first gated detection time 622 are provided.
  • a first path, p 1a ; second path, p 1b ; and third path, p 1c , of photons in the tissue are illustrated.
  • the total pathlength, for a constant index of refraction is the same for each path.
  • the probability of each path also depends on the anisotropy of the tissue and the variable indices of refraction of traversed tissue voxels.
  • FIG. 6C illustrative paths of the photons for the second gated detection time 624 are provided.
  • a first path, p 2a ; second path, p 2b ; and third path, p 2c , of photons in the tissue are illustrated.
  • the total pathlength for the second elapsed time, t 2 is the same for each path.
  • the delay to the second gated detection time 624 is twice as long as the first gated detection time 622
  • the second pathlength, p 2 for the second gated detection time 624 is twice as long as the first pathlength, p 1 , for the first gated detection time 622 .
  • Knowledge of anisotropy is optionally used to decrease the probability spread of paths observed in the second set of pathlengths, p 2a , p 2b , p 2c .
  • a-priori knowledge of approximate physiological thickness of varying tissue layers such as an epidermal thickness of a patient, an average epidermal thickness of a population, a dermal thickness of a patient, and/or an average dermal thickness of a population is optionally used to reduce error in an estimation of pathlength, a product of pathlength and a molar absorptivity, and/or a glucose concentration by limiting bounds of probability of a photon traversing different pathways through the skin layers and still returning to the detection element with the elapsed time.
  • knowledge of an index of refraction of one or more sample constituents and/or a mathematical representation of probable indices of refraction is also optionally used to reduce error in estimation of a pathlength, molar absorptivity, and/or an analyte property concentration estimation.
  • knowledge of an incident point or region of light entering she skin of the subject relative to a detection zone is optionally used to further determine probability of a photon traversing dermal or subcutaneous fat layers along with bounding errors of pathlength in each layer.
  • mean pathlengths and trajectories are illustrated for three elapsed times, t 1 , t 2 , t 3 .
  • both a mean depth of penetration of the photons, d n ; the total radial distance traveled, r m ; and the total optical pathlength increases with increasing time, where the fiber optic-to-detector distance is less than about three millimeters.
  • time gates range from shorter than 100 picoseconds to about 1 picosecond or 100 nanoseconds.
  • both the spatial resolution method and temporal resolution method yield information on pathlength, b, which is optionally used by the data processing system 140 to reduce error in the determined concentration, C.
  • Beer's Law states that absorbance, A, is proportional to pathlength, b, times concentration, C. More precisely, Beer's Law includes a molar absorbance, ⁇ , term, as shown in equation 3:
  • spectroscopists consider the molar absorbance as a constant due to the difficulties in determination of the molar absorbance for a complex sample, such as skin of the subject 170 .
  • information related to the combined molar absorbance and pathlength product for skin tissue of individuals is optionally determined using one or both of the spatially resolved method and time resolved method, described supra.
  • the product of molar absorbance and pathlength relates at least to the dermal thickness of the particular individual or subject 170 being analyzed. Examples of spatially resolved analyzer methods used to provide information on the molar absorbance and/or pathlength usable in reduction of analyte property estimation or determination are provided infra.
  • an analyzer 100 using fiber optics is used to describe obtaining spatially resolved information, such as pathlength and/or molar absorbance, of skin of an individual, which is subsequently used by the data processing system 140 .
  • the use of fiber optics in the examples is used without limitation, without loss of generality, and for clarity of presentation. More generally, photons are delivered in quantities of one or more through free space, through optics, and/or off of reflectors to the skin of the subject 170 as a function of distance from a detection zone.
  • FIG. 7A an example of a fiber optic interface system 700 of the analyzer 100 to the subject 170 is provided, which is an example of the sample interface system 150 .
  • Light from the source system 110 of the analyzer 100 is coupled into a fiber optic illumination bundle 714 of a fiber optic bundle 710 .
  • the fiber optic illumination bundle 714 guides light to a sample site 178 of the subject 170 .
  • the sample site 178 has a surface area and a sample volume.
  • a sample interface tip 716 of the fiber optic bundle 710 contacts the subject 170 at the sample site 178 .
  • the sample interface tip 716 of the fiber optic bundle 710 proximately contacts the subject 170 at the sample site 178 , but leaves a gap 720 between the sample interface tip 716 of the fiber optic bundle 710 and the subject 170 .
  • the gap 720 is filled with a contact fluid and/or an optical contact fluid.
  • the gap 720 is filled with air, such as atmospheric air.
  • Light transported by the fiber optic bundle 710 to the subject 170 interacts with tissue of the subject 170 at the sample site 178 .
  • a portion of the light interacting with the sample site is collected with one or more fiber optic collection fibers 718 , which is optionally and preferably integrated into the fiber optic bundle 710 .
  • a single collection fiber 718 is used.
  • the collection fiber 718 transports collected light to the detector 132 of the detection system 130 .
  • the single collection fiber 718 is circumferentially surrounded by an optional spacer 730 , where the spacer has an average radial width of less than about 200, 150, 100, 50, or 25 micrometers.
  • the optional spacer 730 is circumferentially surrounded by a set of fiber optic elements 713 .
  • the set of fiber optic elements 713 are arranged into a set of radial dispersed fiber optic rings, such as a first ring 741 , a second ring 742 , a third ring 743 , a fourth ring 744 , and an n th ring 745 , where n comprises a positive integer of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the fiber optic elements 713 are in any configuration, such as in a close-packed configuration about the collection fiber 718 or in an about close-packed configuration about the collection fiber 718 .
  • the distance of each individual fiber optic of the set of fiber optic elements 713 , or light collection element, from the center of the collection fiber 718 is preferably known.
  • the centrally positioned collection fiber 718 is circumferentially surrounded by a set of spacer fibers 750 .
  • the spacer fibers combine to cover a radial distance from the outside of the collection fiber of less than about 300, 200, 150, 100, 75, 60, 50, or 40 micrometers.
  • the spacer fibers 750 are circumferentially surrounded by the radially dispersed fiber optic rings, such as the first ring 741 , the second ring 742 , the third ring 743 , the fourth ring 744 , and the n th ring 745 .
  • fiber diameters of the spacer fibers 750 are at least ten, twenty, or thirty percent larger or smaller than fiber diameters of the set of fiber optic elements 713 .
  • the fiber optic elements 713 are arranged in any spatial configuration radially outward from the spacer fibers 750 .
  • the set of fiber optic elements 713 and/or spacer fibers 750 optionally contain two, three, four, or more fiber optic diameters, such as any of about 40, 50, 60, 80, 100, 150, 200, or more micrometers.
  • smaller diameter fiber optics, or light collection optics are positioned closer to any detection fiber and progressively larger diameter fiber optics are positioned, relative to the smaller diameter fiber optics, further from the detection fiber.
  • a system for spatial illumination 800 of the sample site 178 of the subject 170 is provided.
  • the spatial illumination system 800 is used to control distances between illumination zones and detection zones as a function of time.
  • the collection fiber 718 or collection optic is circumferentially surrounded by the set of fiber optic elements 713 or irradiation points on the skin of the subject 170 .
  • the fiber optic elements 713 are depicted in a set of rings radially distributed from the collection fiber 718 .
  • the set of fiber optics 713 are optionally close packed, arranged in a random configuration, or arranged according to any criterion.
  • the distance of each fiber optic element of the set of fiber optic elements 713 from the collection fiber 718 is optionally determined using standard measurement techniques through use of an algorithm and/or through use of a dynamically adjustable optic used to deliver light to the sample, such as through air.
  • the radial distribution approach, described infra is optionally used for individual fiber optic elements and/or groups of fiber optic elements arranged in any configuration. More generally, the radial distribution approach, described infra, is optionally used for any set of illumination zone/detection zone distances using any form of illuminator and any form of detection system, such as through use of the spatially resolved system and/or the time resolved system.
  • FIG. 8B an example of a light input end 712 of the fiber optic bundle 710 is provided.
  • individual fibers of the set of fiber optics 713 having the same or closely spaced radial distances from the collection fiber 718 are grouped into a set of fiber optic bundles or a set of fiber optic bundlets 810 .
  • the seven fibers in the first ring circumferentially surrounding the collection fiber 718 are grouped into a first bundlet 811 .
  • the sixteen fibers in the second ring circumferentially surrounding the collection fiber 718 are grouped into a second bundlet 812 .
  • the fibers from the third, fourth, fifth, and sixth rings about the collection fiber 718 at the sample side illumination end 716 of the fiber bundle 710 are grouped into a third bundlet 813 , a fourth bundlet 814 , a fifth bundlet 815 , and a sixth bundlet 816 , respectively.
  • the individual fibers are not illustrated in the second, third, fourth, fifth, and sixth bundlets 812 , 813 , 814 , 815 , 816 .
  • Individual bundles and/or individual fibers of the set of fiber optic bundlets 810 are optionally selectively illuminated using a mask 820 , described infra.
  • a mask wheel 830 is illustrated.
  • the mask wheel 830 rotates, such as through use of a wheel motor 820 .
  • holes or apertures through the mask wheel 830 selectively pass light from the source system 110 to the fiber optic input end 712 of the fiber optic bundle 710 .
  • the apertures through the mask wheel are precisely located to align with (1) individual fiber optic elements of the set of fiber optics at the input end 712 of the fiber optic bundle or (2) individual bundlets of the set of fiber optic bundlets 810 .
  • an encoder or marker section 840 of the mask wheel 830 is used for tracking, determining, and/or validating wheel position in use.
  • FIG. 80 an example of use of the mask wheel 830 to selectively illuminate individual bundlets of the set of fiber optic bundlets 810 is provided.
  • the individual bundlets are each presented as uniform size, are exaggerated in size, and are repositioned on the wheel.
  • a first mask position, p 1 , 821 is illustrated at about the seven o'clock position.
  • the first mask position 821 figuratively illustrates an aperture passing light from the source system 110 to the first bundlet 811 while blocking light to the second through sixth bundlets 812 - 816 .
  • the mask wheel 830 is rotated such that a second mask position, p 2 , 822 is aligned with the input end 712 of the fiber optic bundle 710 .
  • the mask wheel 830 passes light from the illumination system 110 to the second bundlet 812 , while blocking light to the first bundlet 811 and blocking light to the third through six bundlets 813 - 816 .
  • the mask wheel uses a third mask position, p 3 , 823 to selectively pass light into only the fifth bundlet 815 .
  • the mask wheel uses a fourth mask position, p 4 , 824 to selectively pass light into only the sixth bundlet 816 .
  • the mask wheel 830 is rotated such that a fifth mask position, p 5 , 825 is aligned with the input end 712 of the fiber optic bundle 710 .
  • the mask wheel 830 passes light from the illumination system 110 to all of (1) the second bundlet 812 , (2) the third bundlet 813 , and (3) the fourth bundlet 814 , while blocking light to all of (1) the first bundlet 811 , (2) the fifth bundlet 815 , and (3) the sixth bundlet 816 .
  • p 6 , 826 of the mask wheel 830 passes light to the second through fifth bundlets 812 - 815 while blocking light to both the first bundlet 811 and sixth bundlet 816 .
  • the mask wheel 830 contains an integral number of n positions, where the n positions selectively illuminate and/or block any combination of: (1) the individual fibers of the set of fiber optics 713 and/or (2) bundlets 810 of the set of fiber optic optics 713 .
  • the filter wheel is optionally of any shape and uses any number of motors to position mask position openings relative to selected fiber optics. Still further, in practice the filter wheel is optionally any electro-mechanical and/or electro-optical system used to selectively illuminate the individual fibers of the set of fiber optics 713 . Yet still further, in practice the filter wheel is optionally any illumination system that selectively passes light to any illumination optic or illumination zone, where various illumination zones illuminate various regions of the subject 170 as a function of time. The various illumination zones alter the effectively probed sample site 178 or region of the subject 170 .
  • FIG. 9A and FIG. 9B examples of use of the spatial illumination system 800 is illustrated for a first subject 171 and a second subject 172 .
  • the photon transport system 120 in FIGS. 9A and 9B is used in any spatially resolved system and/or in any time resolved system to deliver photons as a function of radial distance to a detector or to a detection zone.
  • FIG. 9A , FIG. 8A , and FIG. 8C an example of application of the spatial illumination system 800 to the first subject 171 is provided.
  • the first position, p 1 , 821 of the filter wheel 830 is aligned with the light input end 712 of the fiber bundle, which results in the light from the first bundlet 811 , which corresponds to the first ring 741 , irradiating the sample site 178 at a first radial distance, r 1 , and a first depth, d 1 , which as illustrated in FIG. 9A has a mean optical path through the epidermis.
  • the filter wheel 830 at the second position 822 passes light to the second bundlet 812 , which corresponds to the second ring, irradiating the sample site 178 at a second increased distance and a second increased depth, which as illustrated in FIG. 9A has a mean optical path through the epidermis and dermis.
  • results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 8A is provided in Table 1.
  • results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 8A is provided in Table 2.
  • Table 2 results in a mean optical path through the epidermis and dermis, but not through the subcutaneous fat.
  • the mean optical path using the fifth radial fiber ring, f 5 for the second subject 172 has a deepest penetration depth into the dermis 174 .
  • the fifth radial fiber ring, f 5 yields photons probing the subcutaneous fat 176 for the first subject 171 and yields photons probing the dermis 174 of the second subject 172 .
  • the analyzer 100 is more optimally configured to not use both the fifth fiber ring, f 5 , and the sixth fiber ring, f 6 , for the first subject 171 .
  • analyzer 100 is more optimally configured to not use only the sixth fiber ring, f 6 , for the second subject 172 , as described infra.
  • light is delivered with known radial distance to the detection zone, such as with optics of the analyzer, without use of a fiber optic bundle and/or without the use of a filter wheel.
  • control of the irradiation zone/detection zone distance determines the deepest tissue layer probed.
  • photons are optionally delivered to the skin and the time resolved gating system is used to determine probably photon penetration depth.
  • Table 3 shows that at greater elapsed time to the n th gated detection period, the probability of the deepest penetration depth reaching deeper tissue layers increases.
  • a first optional two-phase measurement approach is herein described.
  • the photon transport system 120 provides interrogation photons to a particular test subject at controlled, but varying, radial distances from the detection system 130 .
  • One or more spectral markers, or an algorithmic/mathematical representation thereof, are used to determine the radial illumination distances best used for the particular test subject.
  • An output of the first phase is the data processing system 140 selecting how to illuminate/irradiate the subject 170 .
  • the system controller 180 controls the photon transport system 120 to deliver photons over selected conditions to the subject 170 .
  • several illustrative examples are provided, infra.
  • a first spectral marker is optionally related to the absorbance of the subcutaneous fat 176 for the first subject 171 .
  • the fifth and sixth radial positions of the fiber probe illustrated in FIG. 8A yield collected signals for the first subject 171 that contain larger than average fat absorbance features, which indicates that the fifth and sixth fiber rings of the example fiber bundle should not be used in the subsequent second data collection phase.
  • the data processing system 140 yields a result that the fifth and sixth radial fiber optic rings or distance of the fiber bundle 170 should not be used in the second data collection phase and that the fourth radial fiber optic ring or distance should be used in the second data collection phase.
  • the first sample mapping phase of the previous example is repeated for the second subject 172 .
  • the first sample mapping phase indicates that for the second subject, the sixth radial illumination ring of the fiber bundle illustrated in FIG. 8A should not be used, but that the fourth and fifth radial illumination ring should be used.
  • a particular subject is optionally probed in a sample mapping phase and results from the sample mapping phase are optionally used to configure analyzer parameters in a subsequent data collection phase.
  • the mapping phase and data collection phase occur within thirty seconds of each other.
  • the subject 170 does not move away from the sample interface 150 between the mapping phase and the data collection phase.
  • each of the spatial and temporal methods yield information on pathlength, b, and/or a product of the molar absorptivity and pathlength, which is not achieved using a standard spectrometer.
  • the sample interface tip 716 of the fiber optic bundle 710 includes optics that change the mean incident light angle of individual fibers of the fiber optic bundle 716 as they first hit the subject 170 .
  • a first optic at the end of a fiber in the first ring 741 aims light away from the collection fiber optic 718 ;
  • a second optic at the end of a fiber in the second ring 742 aims light nominally straight into the sample;
  • a third optic at the end of a fiber in the third ring 742 aims light toward the collection fiber 718 .
  • the mean direction of the incident light varies by greater than 5, 10, 15, 20, or 25 degrees.
  • Still yet another embodiment includes any combination and/or permutation of any of the analyzer and/or sensor elements described herein.
  • the terms “comprises”, “comprising”, or any variation thereof, are intended to reference a non-exclusive inclusion, such that a process, method, article, composition or apparatus that comprises a list of elements does not include only those elements recited, but may also include other elements not expressly listed or inherent to such process, method, article, composition or apparatus.
  • Other combinations and/or modifications of the above-described structures, arrangements, applications, proportions, elements, materials or components used in the practice of the present invention, in addition to those not specifically recited, may be varied or otherwise particularly adapted to specific environments, manufacturing specifications, design parameters or other operating requirements without departing from the general principles of the same.

Abstract

An analyzer apparatus and method of use thereof is configured to dynamically interrogate a sample. For example, an analyzer using light interrogates a tissue sample using a temporal resolution system on a time scale of less than about one hundred nanoseconds. Optionally, near-infrared photons are introduced to a sample with a known illumination zone to detection zone distance allowing calculation of parameters related to photon pathlength in tissue and/or molar absorptivity of an individual or group through the use of the speed of light and/or one or more indices of refraction. Optionally, more accurate estimation of tissue properties are achieved through use of: knowledge of incident photon angle relative to skin, angularly resolved detector positions, anisotropy, skin temperature, environmental information, information related to contact pressure, blood glucose concentration history, and/or a skin layer thickness, such as that of the epidermis and dermis.

Description

    CROSS REFERENCES TO RELATED APPLICATIONS
  • This application claims the benefit of:
  • U.S. provisional patent application No. 61/672,195 filed Jul. 16, 2012;
  • U.S. provisional patent application No. 61/700,291 filed Sep. 12, 2012; and
  • U.S. provisional patent application No. 61/700,294 filed Sep. 12, 2012,
  • all of which are incorporated herein in their entirety by this reference thereto.
  • TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to a temporal resolution gating noninvasive analyzer for use in analyte concentration estimation.
  • DESCRIPTION OF THE RELATED ART
  • Patents and literature related to the current invention are summarized herein.
  • Diabetes
  • Diabetes mellitus or diabetes is a chronic disease resulting in the improper production and/or use of insulin, a hormone that facilitates glucose uptake into cells. Diabetes is broadly categorized into four forms grouped by glucose concentration state: hyperinsulinemia (hypoglycemia), normal physiology, impaired glucose tolerance, and hypoinsulinemia (hyperglycemia).
  • Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and/or neuropathy. Complications of diabetes include: heart disease, stroke, high blood pressure, kidney disease, nerve disease and related amputations, retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and/or fetal complications.
  • Diabetes is a common and increasingly prevalent disease. Currently, diabetes is a leading cause of death and disability worldwide. The World Health Organization estimates that the number of people with diabetes will grow to three hundred million by the year 2025.
  • Long term clinical studies show that the onset of diabetes related complications is significantly reduced through proper control of blood glucose concentrations, The Diabetes Control and Complications Trial Research Group, “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus”, N. Eng. J. of Med., 1993, vol. 329, pp. 977-986.
  • Problem Statement
  • What is needed is a noninvasive glucose concentration analyzer having precision and accuracy suitable for treatment of diabetes mellitus.
  • SUMMARY OF THE INVENTION
  • The invention comprises a temporal resolution gating noninvasive analyzer apparatus and method of use thereof.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • A more complete understanding of the present invention is derived by referring to the detailed description and claims when considered in connection with the Figures, wherein like reference numbers refer to similar items throughout the Figures.
  • FIG. 1 illustrates an analyzer;
  • FIG. 2 illustrates diffusely reflecting optical paths;
  • FIG. 3 illustrates probing tissue layers using a spatial distribution method;
  • FIG. 4 illustrates varying illumination zones relative to a detector;
  • FIG. 5 illustrates varying detection zones relative to an illuminator;
  • FIGS. 6(A-D) illustrate temporal resolution gating, FIG. 6A; probabilistic optical paths for a first elapsed time, FIG. 6B; probabilistic optical paths for a second elapsed time, FIG. 6C; and a temporal distribution method, FIG. 6D;
  • FIGS. 7(A-C) illustrate a fiber optic bundle, FIG. 7A; a first example sample interface end of the fiber optic bundle, FIG. 7B; and a second example sample interface end of the fiber optic bundle, FIG. 7C;
  • FIGS. 8(A-C) illustrate a third example sample interface end of the fiber optic bundle, FIG. 8A; a mask, FIG. 8B; and a mask selector, FIG. 8C;
  • FIGS. 9(A-B) illustrate a pathlength resolved sample interface for (1) a first subject, FIG. 9A and (2) a second subject, FIG. 9B.
  • Elements and steps in the figures are illustrated for simplicity and clarity and have not necessarily been rendered according to any particular sequence. For example, steps that are performed concurrently or in a different order are illustrated in the figures to help improve understanding of embodiments of the present invention.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The invention comprises a temporal resolution gating noninvasive analyzer apparatus and method of use thereof.
  • In one embodiment, a temporal resolution gating noninvasive analyzer is used to determine an analyte property of a biomedical sample, such as a glucose concentration of a subject using light in the near-infrared region from 1000 to 2500 nanometers.
  • In another embodiment, a data processing system analyzes data from an analyzer to estimate and/or determine an analyte property, such as concentration.
  • In still another embodiment, an analyzer using light interrogates the sample using one or more of:
      • a spatially resolved system;
        • a radial distance resolved system;
      • a time resolved system, where the times are greater than about 1, 10, 100, or 1000 microseconds;
      • a picosecond timeframe resolved system, where times are less than about 1, 10, 100, or 1000 nanoseconds;
      • an incident angle resolved system; and
      • a collection angle resolved system.
  • Data from the analyzer is analyzed using a data processing system capable of using the information inherent in the resolved system data.
  • In another embodiment, a data processing system uses interrelationships of chemistry based a-priori spectral information related to absorbance of a sample constituent and/or the effect of the environment, such as temperature, on the spectral information.
  • In yet still another embodiment, a data processing system uses a first mapping phase to set instrument control parameters for a particular subject, set of subjects, and/or class of subjects. Subsequently, the control parameters are used in a second data collection phase to collect spectra of the particular subject or class of subjects.
  • In yet another embodiment, a data processing system uses information related to contact pressure on a tissue sample site.
  • In still yet another embodiment, a data processing system uses a combination of any of:
      • spatially resolved information;
      • temporally resolved information on a time scale of longer than about one microsecond;
      • temporally resolved information on a sub one hundred picosecond timeframe;
      • incident photon angle information;
      • photon collection angle information;
      • interrelationships of spectral absorbance and/or intensity information;
      • environmental information;
      • temperature information; and
      • information related to contact pressure on a tissue sample site.
    Axes
  • Herein, axes systems are separately defined for an analyzer and for an interface of the analyzer to a patient, where the patient is alternatively referred to as a subject.
  • Herein, when referring to the analyzer, an x-, y-, z-axes analyzer coordinate system is defined relative to the analyzer. The x-axis is the in the direction of the mean optical path. The y-axis crosses the mean optical path perpendicular to the x-axis. When the optical path is horizontal, the x-axis and y-axis define a x/y horizontal plane. The z-axis is normal to the x/y plane. When the optical path is moving horizontally, the z-axis is aligned with gravity, which is normal to the x/y horizontal plane. Hence, the x, y, z-analyzer coordinate system is defined separately for each optical path element. In any case where the mean optical path is not horizontal, the optical system is further defined to remove ambiguity.
  • Herein, when referring to the patient, an x, y, z-axes patient coordinate system is defined relative to a body part interfaced to the analyzer. Hence, the x, y, z-axes body coordinate system moves with movement of the body part. The x-axis is defined along the length of the body part, the y-axis is defined across the body part. As an illustrative example, if the analyzer interfaces to the forearm of the patient, then the x-axis runs longitudinally between the elbow and the wrist of the forearm and the y-axis runs across the forearm. Together, the x,y plane tangentially touches the skin surface at a central point of the interface of the analyzer to the body part, which is referred to as the center of the sample site, sample region, or sample site. The z-axis is defined as orthogonal to the x,y plane. Rotation of an object is further used to define the orientation of the object to the sample site. For example, in some cases a sample probe of the analyzer is rotatable relative to the sample site. Tilt refers to an off z-axis alignment, such as an off z-axis alignment of a probe of the analyzer relative to the sample site.
  • Analyzer
  • Referring now to FIG. 1, an analyzer 100 is illustrated. The analyzer comprises at least: a light source system 110, a photon transport system 120, a detector system 130, and a data processing system 140. In use the analyzer 100 estimates and/or determines a physical property, a sample state, a constituent property, and/or a concentration of an analyte.
  • Patient/Reference
  • Still referring to FIG. 1, an example of the analyzer 100 is presented. In this example, the analyzer 100 includes a sample interface 150, which interfaces to a reference material 160 and/or to a subject 170. Herein, for clarity of presentation a subject 170 in the examples is representative of a person, animal, a prepared sample, and/or patient. In practice, the analyzer 100 is used by a user to analyze the user, referred to herein as a subject 170, and is used by a medical professional to analyze a patient.
  • Controller
  • Still referring to FIG. 1, the analyzer 100 optionally includes a system controller 180. The system controller 180 is used to control one or more of: the light source system 110 or a light source 112 thereof, the photon transport system 120, the detector system 130 or a detector 132 thereof, the sample interface 150, position of the reference 160 relative to the sample interface 150, position of the subject 170 relative to the sample interface 150, and communication to an outside system 190, such as a smart phone 192, and/or a remote system 194 using a wireless communication system 196 and/or hard wired communication system 198. For example, the remote system includes a data processing system, a data storage system, and/or a data organization system.
  • Still referring to FIG. 1, the optional system controller 180 operates in any of a predetermined manner or in communication with the data processing system 140. In the case of operation in communication with the data processing system 140, the controller generates control statements using data and/or information about the current state of the analyzer 100, current state of a surrounding environment 162 outside of the analyzer 100, information generated by the data processing system 140, and/or input from a sensor, such as a sample interface sensor 152 or an auxiliary system 10 or an auxiliary sensor 12 thereof. Herein, the auxiliary system 10 is any system providing input to the analyzer 100.
  • Still referring to FIG. 1, the optional system controller 180 is used to control: photon intensity of photons from the source using an intensity controller 122, wavelength distribution of photons from the source 110 using a wavelength controller 124, and/or physical routing of photons from the source 110 using a position controller 126.
  • Still referring to FIG. 1, for clarity of presentation the optional outside system 190 is illustrated as using a smart phone 192. However, the smart phone 192 is optionally a cell phone, a tablet computer, a computer network, and/or a personal computer. Similarly, the smart phone 192 also refers to a feature phone, a mobile phone, a portable phone, and/or a cell phone. Generally, the smart phone 192 includes hardware, software, and/or communication features carried by an individual that is optionally used to offload requirements of the analyzer 100. For example, the smart phone 192 includes a user interface system, a memory system, a communication system, and/or a global positioning system. Further, the smart phone 192 is optionally used to link to the remote system 194, such as a data processing system, a medical system, and/or an emergency system. In another example at least one calculation of the analyzer in noninvasively determining a glucose concentration of the subject 170 is performed using the smart phone 192. In yet another example, the analyzer gathers information from at least one auxiliary sensor 12 and relays that information and/or a processed form of that information to the smart phone 192, where the auxiliary sensor is not integrated into the analyzer 100.
  • Source
  • Herein, the source system 110 generates photons in any of the visible, infrared, near-infrared, mid-infrared, and/or far-infrared spectral regions. In one case, the source system generates photons in the near-infrared region from 1100 to 2500 nm or any range therein, such as within the range of about 1200 to 1800 nm; at wavelength longer than any of 800, 900, 1000, and 1100 nm; and/or at wavelengths shorter than any of 2600, 2500, 2000, or 1900 nm.
  • Photon/Skin Interaction
  • Light interacts with skin through laws of physics to scatter and transmit through skin voxels.
  • Referring now to FIG. 2, for clarity of presentation and without limitation, in several examples provided herein a simplifying and non-limiting assumption is made, for some wavelengths and for some temperatures, that mean photon depth of penetration increases with mean radial distance between a photon illumination zone and a photon detection zone.
  • Referring still to FIG. 2, a photon transit system 200 through skin layers of the subject 170 is illustrated. In this example, the photon transport system 120 guides light from a source 112 of the source system 110 to the subject 170. Optionally, a contact gap 210 is present between a last optic of the photon transport system 120 and skin of the subject 170. Further, in this example, the photon transport system 120 irradiates skin of the subject 170 over a narrow illumination zone, such as having an area of less than about 9, 4, 1, or ¼mm2. Optionally, the photons are delivered to the skin of the subject 170 through an optic proximately contacting, but not actually contacting, the skin, such as within about 0.5, 1.0, or 2.0 millimeters of the skin. Optionally, the distance between the analyzer and the skin of the subject 170 is maintained with a vibration and/or shake reduction system, such as is used in a vibration reduction camera or lens. For example, the skin position is monitored with a sensor, output from the sensor is sent to the controller, and the controller controls an electro-mechanical element used to control a position of an element of the analyzer. For clarity of presentation, the photons are depicted as entering the skin at a single point. A portion of the photons traverse, or more particularly traverse through, the skin to a detection zone. The detection zone is a region of the skin surface where the detector system 130 gathers the traversing or diffusely reflected photons. Various photons traversing or diffusely scattering through the skin encounter an epidermis 173 or epidermis layer, a dermis 174 or dermis layer, and subcutaneous fat 176 or a subcutaneous fat layer. As depicted in FIG. 2, the diffuse reflectance of the various photons through the skin detected by the detection system 130 follow a variety of optical paths through the tissue, such as shallow paths through the epidermis 173, deeper paths through the epidermis 173 and dermis 174, and still deeper paths through the epidermis 173, dermis 174, and subcutaneous fat 176. However, for a large number of photons, there exists a mean photon path for photons from entering the skin that are detected by the detection system 130.
  • Pathlength
  • Herein, for clarity, without loss of generality, and without limitation, Beer's Law is used to described photon interaction with skin, though those skilled in the art understand deviation from Beer's Law result from sample scattering, index of refraction variation, inhomogeneity, turbidity, and/or absorbance out of a linear range of the analyzer 100.
  • Beer's Law, equation 1, states that:

  • A a bC  (eq. 1)
  • where A is absorbance, b is pathlength, and C is concentration. Typically, spectral absorbance is used to determine concentration. However, the absorbance is additionally related to pathlength. Hence, determination of the optical pathlength traveled by the photons is useful in reducing error in the determined concentration. Two methods, described infra, are optionally used to estimate pathlength: (1) spatial resolution of pathlength and (2) temporal resolution of pathlength.
  • Algorithm
  • The data and/or derived information from each of the spatial resolution method and temporal resolution method are each usable with the data processing system 140. Examples provide, infra, illustrate: (1) both cases of the spatial resolution method and (2) the temporal resolution method. However, for clarity of presentation and without limitation, the photons in most examples are depicted as radially traversing from a range of input zones to a detection zone. Similarly, photons are optionally controlled from an input zone to a range of detection zones. Still further, photons are optionally directed to a series of input zones, as a function of time, and for each input zone or set of input zones one or more detection zones are used.
  • Spatial Resolution
  • The first method of spatial resolution contains two cases. Herein, in a first case photons are depicted traversing from a range of input points on the skin to a radially located detector to derive photon interrogated sample path and/or depth information. However, in a second case, equivalent systems optionally use a single input zone of the photons to the skin and a plurality of radially located detector zones to determine optical sample photons paths and/or depth information. Still further, a combination of the first two cases, such as multiple sources and multiple detectors, is optionally used to derive photon path information in the skin.
  • In the first system, Referring now to FIG. 3, the photon transit system 200 of FIG. 2 is illustrated where the photon transport system 110 irradiates the skin of the subject 170 over a wide range of radial distance from the detection zone, such as at least about 0.1, 0.2, 0.3, 0.4, or 0.5 millimeters from the detection zone to less than about 1.0, 1.2, 1.4, 1.6, or 1.8 millimeters from the detection zone. In this example, a mean photon path is provided as a function of radial distance from the illumination zone to the detection zone. Generally, over a range of about zero to less than about two millimeters from the detection zone, the mean optical path of the detected diffusely scattering photons increases in depth for photons in the near-infrared traveling through skin.
  • In the first case of the spatial resolution method, referring now to FIG. 4, the photon transit system 200 uses a vector or array of illumination sources 400, of the source system 110, in a spatially resolved pathlength determination system. For example, the illumination sources are an array of fiber optic cables. In this example, a set of seven fiber optics 401, 402, 403, 404, 405, 406, 407 are positioned, radially along the x,y plane of the subject 170 to provide a set of illuminations zones, relative to a detection fiber at a detection zone. As illustrated the third illumination fiber optic 403/detector 132 combination yields a mean photon path having a third depth of penetration, d3, for a third fiber optic-to-detector radial distance, r3; the fifth illumination fiber optic 405/detector 132 combination yields a mean photon path having a fifth depth of penetration, d5, for a fifth fiber optic-to-detector radial distance, r5; and the seventh illumination fiber optic 407/detector 132 combination yields a mean photon path having a seventh depth of penetration, d7, for a seventh fiber optic-to-detector radial distance, r7. Generally, for photons in the near-infrared region from 1100 to 2500 nanometers both a mean depth of penetration of the photons and a total optical pathlength increases with increasing fiber optic-to-detector distance, where the fiber optic-to-detector distance is less than about three millimeters.
  • In the second case of the spatial resolution method, referring now to FIG. 5, the photon transit system 200 uses a vector or array of detectors 500 in the detection system 130. For example, a single fiber optic source is used, which sends radially distributed light to an array of staring detectors or collection optics coupled to a set of detectors. In this example, a set of seven detectors 501, 502, 503, 504, 505, 506, 507 are positioned, radially along the x,y plane to provide a set of detection zones, relative to an illumination zone. As illustrated the source 112/second detector 502 combination yields a mean photon path having a second depth of penetration, d2, for a second source-to-detector radial distance, r2; the source 112/fourth detector 504 combination yields a mean photon path having a fourth depth of penetration, d4, for a fourth source-to-detector radial distance, r4; and the source 112/sixth detector 506 combination yields a mean photon path having a sixth depth of penetration, d6, for a sixth source-to-detector radial distance, r6. Again, generally for photons in the near-infrared region from 1100 to 2500 nanometers both the mean depth of penetration of the photons into skin and the total optical pathlength in skin increases with increasing fiber optic-to-detector distance, where the fiber optic-to-detector distance is less than about three millimeters. Hence, data collected with an analyzer configured with a multiple detector design generally corresponds to the first case of a multiple source design.
  • Referring again to FIGS. 4 and 5, the number of source zones is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100 or more and the number of detection zones is optionally 1, 2, 3, 4, 5, 10, 20, 50, 500, 1000, 5000, 10,000, 100,000 or more.
  • Temporal Resolution
  • The second method of temporal resolution is optionally performed in a number of manners. For clarity of presentation and without limitation, a temporal resolution example is provided where photons are timed using a gating system and the elapsed time is used to determine photon paths in tissue.
  • Referring now to FIGS. 6A-D, an example of a temporally resolved gating system 600 is illustrated. Generally, in the temporal gating system 600 the time of flight of a photon is used to determine the pathlength, b. Referring now to FIG. 6A, at an initial time, t0, an interrogation pulse 610 of one or more photons is introduced to the sample, which herein is skin of the subject 170. The interrogation pulse 610 is also referred to as a pump pulse or as a flash of light. At one or more subsequent gated detection times 620, after passing through the sample the interrogation pulse 610 is detected. As illustrated, the gated detection times are at a first time 622, t1; a second time 624, t2; a third time 626, t3; and at an nth time 628, tn, where n is a positive number. Optionally, the gated detection times 620 overlap. For the near-infrared spectral region, the elapsed time used to detect the interrogation photons 610 is on the order of picoseconds, such as less than about 100, 10, or 1 picosecond. The physical pathlength, b, is determined using equation 2:
  • OPD = c n ( b ) ( eq . 2 )
  • where OPD is the optical path distance, c is the speed of light, n is the index of refraction of the sample, and b is the physical pathlength. Optionally, n is a mathematical representation of a series of indices of refraction of various constituents of skin and/or skin and surrounding tissue layers. More generally, observed pathlength is related to elapsed time of photon capture where the relationship of pathlength to temperature is optionally further determined using a measure of a tissue, such as an index of refraction.
  • Referring now to FIG. 6B, illustrative paths of the photons for the first gated detection time 622 are provided. A first path, p1a; second path, p1b; and third path, p1c, of photons in the tissue are illustrated. In each case, the total pathlength, for a constant index of refraction, is the same for each path. However, the probability of each path also depends on the anisotropy of the tissue and the variable indices of refraction of traversed tissue voxels.
  • Referring now to FIG. 6C, illustrative paths of the photons for the second gated detection time 624 are provided. A first path, p2a; second path, p2b; and third path, p2c, of photons in the tissue are illustrated. Again, in each case the total pathlength for the second elapsed time, t2, is the same for each path. Generally, if the delay to the second gated detection time 624 is twice as long as the first gated detection time 622, then the second pathlength, p2, for the second gated detection time 624 is twice as long as the first pathlength, p1, for the first gated detection time 622. Knowledge of anisotropy is optionally used to decrease the probability spread of paths observed in the second set of pathlengths, p2a, p2b, p2c. Similarly a-priori knowledge of approximate physiological thickness of varying tissue layers, such as an epidermal thickness of a patient, an average epidermal thickness of a population, a dermal thickness of a patient, and/or an average dermal thickness of a population is optionally used to reduce error in an estimation of pathlength, a product of pathlength and a molar absorptivity, and/or a glucose concentration by limiting bounds of probability of a photon traversing different pathways through the skin layers and still returning to the detection element with the elapsed time. Similarly, knowledge of an index of refraction of one or more sample constituents and/or a mathematical representation of probable indices of refraction is also optionally used to reduce error in estimation of a pathlength, molar absorptivity, and/or an analyte property concentration estimation. Still further, knowledge of an incident point or region of light entering she skin of the subject relative to a detection zone is optionally used to further determine probability of a photon traversing dermal or subcutaneous fat layers along with bounding errors of pathlength in each layer.
  • Referring now to FIG. 6D, mean pathlengths and trajectories are illustrated for three elapsed times, t1, t2, t3. As with the spatially resolved method, generally, for photons in the near-infrared region from 1100 to 2500 nanometers, both a mean depth of penetration of the photons, dn; the total radial distance traveled, rm; and the total optical pathlength increases with increasing time, where the fiber optic-to-detector distance is less than about three millimeters. Preferably, time gates range from shorter than 100 picoseconds to about 1 picosecond or 100 nanoseconds.
  • Spatial and Temporal Resolution
  • Hence, both the spatial resolution method and temporal resolution method yield information on pathlength, b, which is optionally used by the data processing system 140 to reduce error in the determined concentration, C.
  • Analyzer and Subject Variation
  • As described, supra, Beer's Law states that absorbance, A, is proportional to pathlength, b, times concentration, C. More precisely, Beer's Law includes a molar absorbance, ε, term, as shown in equation 3:

  • A=εbC  (eq. 3)
  • Typically, spectroscopists consider the molar absorbance as a constant due to the difficulties in determination of the molar absorbance for a complex sample, such as skin of the subject 170. However, information related to the combined molar absorbance and pathlength product for skin tissue of individuals is optionally determined using one or both of the spatially resolved method and time resolved method, described supra. In the field of noninvasive glucose concentration determination, the product of molar absorbance and pathlength relates at least to the dermal thickness of the particular individual or subject 170 being analyzed. Examples of spatially resolved analyzer methods used to provide information on the molar absorbance and/or pathlength usable in reduction of analyte property estimation or determination are provided infra.
  • Spatially Resolved Analyzer
  • Herein, an analyzer 100 using fiber optics is used to describe obtaining spatially resolved information, such as pathlength and/or molar absorbance, of skin of an individual, which is subsequently used by the data processing system 140. The use of fiber optics in the examples is used without limitation, without loss of generality, and for clarity of presentation. More generally, photons are delivered in quantities of one or more through free space, through optics, and/or off of reflectors to the skin of the subject 170 as a function of distance from a detection zone.
  • Referring now to FIG. 7A, an example of a fiber optic interface system 700 of the analyzer 100 to the subject 170 is provided, which is an example of the sample interface system 150. Light from the source system 110 of the analyzer 100 is coupled into a fiber optic illumination bundle 714 of a fiber optic bundle 710. The fiber optic illumination bundle 714 guides light to a sample site 178 of the subject 170. The sample site 178 has a surface area and a sample volume. In a first case, a sample interface tip 716 of the fiber optic bundle 710 contacts the subject 170 at the sample site 178. In a second case, the sample interface tip 716 of the fiber optic bundle 710 proximately contacts the subject 170 at the sample site 178, but leaves a gap 720 between the sample interface tip 716 of the fiber optic bundle 710 and the subject 170. In one instance, the gap 720 is filled with a contact fluid and/or an optical contact fluid. In a second instance, the gap 720 is filled with air, such as atmospheric air. Light transported by the fiber optic bundle 710 to the subject 170 interacts with tissue of the subject 170 at the sample site 178. A portion of the light interacting with the sample site is collected with one or more fiber optic collection fibers 718, which is optionally and preferably integrated into the fiber optic bundle 710. As illustrated, a single collection fiber 718 is used. The collection fiber 718 transports collected light to the detector 132 of the detection system 130.
  • Referring now to FIG. 7B, a first example of a sample side light collection end 716 of the fiber optic bundle 710 is illustrated. In this example, the single collection fiber 718 is circumferentially surrounded by an optional spacer 730, where the spacer has an average radial width of less than about 200, 150, 100, 50, or 25 micrometers. The optional spacer 730 is circumferentially surrounded by a set of fiber optic elements 713. As illustrated, the set of fiber optic elements 713 are arranged into a set of radial dispersed fiber optic rings, such as a first ring 741, a second ring 742, a third ring 743, a fourth ring 744, and an nth ring 745, where n comprises a positive integer of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the fiber optic elements 713 are in any configuration, such as in a close-packed configuration about the collection fiber 718 or in an about close-packed configuration about the collection fiber 718. The distance of each individual fiber optic of the set of fiber optic elements 713, or light collection element, from the center of the collection fiber 718 is preferably known.
  • Referring now to FIG. 7C, a second example of the sample side light collection end 716 of the fiber optic bundle 710 is provided. In this example, the centrally positioned collection fiber 718 is circumferentially surrounded by a set of spacer fibers 750. The spacer fibers combine to cover a radial distance from the outside of the collection fiber of less than about 300, 200, 150, 100, 75, 60, 50, or 40 micrometers. The spacer fibers 750 are circumferentially surrounded by the radially dispersed fiber optic rings, such as the first ring 741, the second ring 742, the third ring 743, the fourth ring 744, and the nth ring 745. Optionally, fiber diameters of the spacer fibers 750 are at least ten, twenty, or thirty percent larger or smaller than fiber diameters of the set of fiber optic elements 713. Further, optionally the fiber optic elements 713 are arranged in any spatial configuration radially outward from the spacer fibers 750. More generally, the set of fiber optic elements 713 and/or spacer fibers 750 optionally contain two, three, four, or more fiber optic diameters, such as any of about 40, 50, 60, 80, 100, 150, 200, or more micrometers. Optionally, smaller diameter fiber optics, or light collection optics, are positioned closer to any detection fiber and progressively larger diameter fiber optics are positioned, relative to the smaller diameter fiber optics, further from the detection fiber.
  • Radial Distribution System
  • Referring now to FIG. 8A-8C, a system for spatial illumination 800 of the sample site 178 of the subject 170 is provided. The spatial illumination system 800 is used to control distances between illumination zones and detection zones as a function of time.
  • Referring now to FIG. 8A, a third example of the sample side light collection end 716 of the fiber optic bundle 710 is provided. In this example, the collection fiber 718 or collection optic is circumferentially surrounded by the set of fiber optic elements 713 or irradiation points on the skin of the subject 170. For clarity of presentation and without loss of generality, the fiber optic elements 713 are depicted in a set of rings radially distributed from the collection fiber 718. However, it is understood that the set of fiber optics 713 are optionally close packed, arranged in a random configuration, or arranged according to any criterion. Notably, the distance of each fiber optic element of the set of fiber optic elements 713 from the collection fiber 718 is optionally determined using standard measurement techniques through use of an algorithm and/or through use of a dynamically adjustable optic used to deliver light to the sample, such as through air. Hence, the radial distribution approach, described infra, is optionally used for individual fiber optic elements and/or groups of fiber optic elements arranged in any configuration. More generally, the radial distribution approach, described infra, is optionally used for any set of illumination zone/detection zone distances using any form of illuminator and any form of detection system, such as through use of the spatially resolved system and/or the time resolved system.
  • Referring now to FIG. 8B, an example of a light input end 712 of the fiber optic bundle 710 is provided. In this example, individual fibers of the set of fiber optics 713 having the same or closely spaced radial distances from the collection fiber 718 are grouped into a set of fiber optic bundles or a set of fiber optic bundlets 810. As illustrated, the seven fibers in the first ring circumferentially surrounding the collection fiber 718 are grouped into a first bundlet 811. Similarly, the sixteen fibers in the second ring circumferentially surrounding the collection fiber 718 are grouped into a second bundlet 812. Similarly, the fibers from the third, fourth, fifth, and sixth rings about the collection fiber 718 at the sample side illumination end 716 of the fiber bundle 710 are grouped into a third bundlet 813, a fourth bundlet 814, a fifth bundlet 815, and a sixth bundlet 816, respectively. For clarity of presentation, the individual fibers are not illustrated in the second, third, fourth, fifth, and sixth bundlets 812, 813, 814, 815, 816. Individual bundles and/or individual fibers of the set of fiber optic bundlets 810 are optionally selectively illuminated using a mask 820, described infra.
  • Referring now to FIG. 8C and FIG. 7A, a mask wheel 830 is illustrated. Generally, the mask wheel 830 rotates, such as through use of a wheel motor 820. As a function of mask wheel rotation position, holes or apertures through the mask wheel 830 selectively pass light from the source system 110 to the fiber optic input end 712 of the fiber optic bundle 710. In practice, the apertures through the mask wheel are precisely located to align with (1) individual fiber optic elements of the set of fiber optics at the input end 712 of the fiber optic bundle or (2) individual bundlets of the set of fiber optic bundlets 810. Optionally an encoder or marker section 840 of the mask wheel 830 is used for tracking, determining, and/or validating wheel position in use.
  • Still referring to FIG. 80, an example of use of the mask wheel 830 to selectively illuminate individual bundlets of the set of fiber optic bundlets 810 is provided. Herein, for clarity of presentation the individual bundlets are each presented as uniform size, are exaggerated in size, and are repositioned on the wheel. For example, as illustrated a first mask position, p1, 821 is illustrated at about the seven o'clock position. The first mask position 821 figuratively illustrates an aperture passing light from the source system 110 to the first bundlet 811 while blocking light to the second through sixth bundlets 812-816. At a second point in time, the mask wheel 830 is rotated such that a second mask position, p2, 822 is aligned with the input end 712 of the fiber optic bundle 710. As illustrated, at the second point in time, the mask wheel 830 passes light from the illumination system 110 to the second bundlet 812, while blocking light to the first bundlet 811 and blocking light to the third through six bundlets 813-816. Similarly, at a third point in time the mask wheel uses a third mask position, p3, 823 to selectively pass light into only the fifth bundlet 815. Similarly, at a fourth point in time the mask wheel uses a fourth mask position, p4, 824 to selectively pass light into only the sixth bundlet 816.
  • Still referring to FIG. 80, thus far the immediately prior example has only shown individual illuminated bundlets as a function of time. However, combinations of bundlets are optionally illuminated as a function of time. In this continuing example, at a fifth point in time, the mask wheel 830 is rotated such that a fifth mask position, p5, 825 is aligned with the input end 712 of the fiber optic bundle 710. As illustrated, at the fifth point in time, the mask wheel 830 passes light from the illumination system 110 to all of (1) the second bundlet 812, (2) the third bundlet 813, and (3) the fourth bundlet 814, while blocking light to all of (1) the first bundlet 811, (2) the fifth bundlet 815, and (3) the sixth bundlet 816. Similarly, at a sixth point in time a sixth mask position, p6, 826 of the mask wheel 830 passes light to the second through fifth bundlets 812-815 while blocking light to both the first bundlet 811 and sixth bundlet 816.
  • In practice, the mask wheel 830 contains an integral number of n positions, where the n positions selectively illuminate and/or block any combination of: (1) the individual fibers of the set of fiber optics 713 and/or (2) bundlets 810 of the set of fiber optic optics 713. Further, the filter wheel is optionally of any shape and uses any number of motors to position mask position openings relative to selected fiber optics. Still further, in practice the filter wheel is optionally any electro-mechanical and/or electro-optical system used to selectively illuminate the individual fibers of the set of fiber optics 713. Yet still further, in practice the filter wheel is optionally any illumination system that selectively passes light to any illumination optic or illumination zone, where various illumination zones illuminate various regions of the subject 170 as a function of time. The various illumination zones alter the effectively probed sample site 178 or region of the subject 170.
  • Adaptive Subject Measurement
  • Referring now to FIG. 9A and FIG. 9B, examples of use of the spatial illumination system 800 is illustrated for a first subject 171 and a second subject 172. However, more generally the photon transport system 120 in FIGS. 9A and 9B is used in any spatially resolved system and/or in any time resolved system to deliver photons as a function of radial distance to a detector or to a detection zone.
  • Referring now to FIG. 9A, FIG. 8A, and FIG. 8C, an example of application of the spatial illumination system 800 to the first subject 171 is provided. At a first point in time, the first position, p1, 821 of the filter wheel 830 is aligned with the light input end 712 of the fiber bundle, which results in the light from the first bundlet 811, which corresponds to the first ring 741, irradiating the sample site 178 at a first radial distance, r1, and a first depth, d1, which as illustrated in FIG. 9A has a mean optical path through the epidermis. Similarly, at a second point in time, the filter wheel 830 at the second position 822 passes light to the second bundlet 812, which corresponds to the second ring, irradiating the sample site 178 at a second increased distance and a second increased depth, which as illustrated in FIG. 9A has a mean optical path through the epidermis and dermis. Similarly, results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 8A is provided in Table 1. The results of Table 1 demonstrate that for the first individual, the prime illumination rings for a blood analyte concentration determination are rings two through four as the first ring, sampling the epidermis, does not sample the blood filled dermis layer; rings two through four probe the blood filled dermis layer; and rings five and six penetrate through the dermis into the subcutaneous fat where photons are lost and the resultant signal-to-noise ratio for the blood analyte decreases.
  • TABLE 1
    Subject 1
    Illumination Ring Deepest Tissue Layer Probed
    1 Epidermis
    2 Dermis
    3 Dermis
    4 Dermis
    5 Subcutaneous Fat
    6 Subcutaneous Fat
  • Referring now to FIG. 9B and FIG. 8A, an example of application of the spatial illumination system 800 to the second subject 172 is provided. Results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 8A is provided in Table 2. For the second subject, it is noted that interrogation of the sample with the fifth radial fiber ring, f5, results in a mean optical path through the epidermis and dermis, but not through the subcutaneous fat. In stark contrast, the mean optical path using the fifth radial fiber ring, f5, for the second subject 172 has a deepest penetration depth into the dermis 174. Hence, the fifth radial fiber ring, f5, yields photons probing the subcutaneous fat 176 for the first subject 171 and yields photons probing the dermis 174 of the second subject 172. Hence, for a water soluble analyte and/or a blood borne analyte, such as glucose, the analyzer 100 is more optimally configured to not use both the fifth fiber ring, f5, and the sixth fiber ring, f6, for the first subject 171. However, analyzer 100 is more optimally configured to not use only the sixth fiber ring, f6, for the second subject 172, as described infra.
  • TABLE 2
    Subject 2
    Illumination Ring Deepest Tissue Layer Probed
    1 Epidermis
    2 Dermis
    3 Dermis
    4 Dermis
    5 Dermis
    6 Subcutaneous Fat
  • In yet another example, light is delivered with known radial distance to the detection zone, such as with optics of the analyzer, without use of a fiber optic bundle and/or without the use of a filter wheel. Just as the illumination ring determines the deepest tissue layer probed, control of the irradiation zone/detection zone distance determines the deepest tissue layer probed.
  • In still yet another example, referring again to time resolved spectroscopy, instead of delivering light through the filter wheel to force radial distance, photons are optionally delivered to the skin and the time resolved gating system is used to determine probably photon penetration depth. For example, Table 3 shows that at greater elapsed time to the nth gated detection period, the probability of the deepest penetration depth reaching deeper tissue layers increases.
  • TABLE 3
    Time Resolved Spectroscopy
    Elapsed Time (picoseconds) Deepest Tissue Layer Probed
    1 Epidermis
    10 Dermis
    50 Dermis
    100 Subcutaneous Fat
  • Two-Phase Measurement(s)
  • Still referring to FIG. 9A and FIG. 9B, a first optional two-phase measurement approach is herein described. Optionally, during a first sample mapping phase, the photon transport system 120 provides interrogation photons to a particular test subject at controlled, but varying, radial distances from the detection system 130. One or more spectral markers, or an algorithmic/mathematical representation thereof, are used to determine the radial illumination distances best used for the particular test subject. An output of the first phase is the data processing system 140 selecting how to illuminate/irradiate the subject 170. Subsequently, during a second data collection phase, the system controller 180 controls the photon transport system 120 to deliver photons over selected conditions to the subject 170. For clarity, several illustrative examples are provided, infra.
  • In a first example, a first spectral marker is optionally related to the absorbance of the subcutaneous fat 176 for the first subject 171. During the first sample mapping phase, the fifth and sixth radial positions of the fiber probe illustrated in FIG. 8A, yield collected signals for the first subject 171 that contain larger than average fat absorbance features, which indicates that the fifth and sixth fiber rings of the example fiber bundle should not be used in the subsequent second data collection phase. Still in the first sample mapping phase, probing the tissue of the subject with photons from the fourth fiber ring yields a reduced signal for the first spectral marker and/or a larger relative signal for a second spectral marker related to the dermis 174, such as a protein absorbance band or an algorithmic/mathematical representation thereof. Hence, the data processing system 140 yields a result that the fifth and sixth radial fiber optic rings or distance of the fiber bundle 170 should not be used in the second data collection phase and that the fourth radial fiber optic ring or distance should be used in the second data collection phase. Subsequently, in the second data collection phase, data collection for analyte determination ensues using the first through fourth radial positions of the fiber bundle, which yields a larger signal-to-noise ratio for dermis constituents, such as glucose, compared to the use of all six radial positions of the fiber bundle.
  • In a second example, the first sample mapping phase of the previous example is repeated for the second subject 172. The first sample mapping phase indicates that for the second subject, the sixth radial illumination ring of the fiber bundle illustrated in FIG. 8A should not be used, but that the fourth and fifth radial illumination ring should be used.
  • Generally, a particular subject is optionally probed in a sample mapping phase and results from the sample mapping phase are optionally used to configure analyzer parameters in a subsequent data collection phase. Optionally, the mapping phase and data collection phase occur within thirty seconds of each other. Optionally, the subject 170 does not move away from the sample interface 150 between the mapping phase and the data collection phase.
  • Further, generally each of the spatial and temporal methods yield information on pathlength, b, and/or a product of the molar absorptivity and pathlength, which is not achieved using a standard spectrometer.
  • In yet another embodiment, the sample interface tip 716 of the fiber optic bundle 710 includes optics that change the mean incident light angle of individual fibers of the fiber optic bundle 716 as they first hit the subject 170. For example, a first optic at the end of a fiber in the first ring 741 aims light away from the collection fiber optic 718; a second optic at the end of a fiber in the second ring 742 aims light nominally straight into the sample; and a third optic at the end of a fiber in the third ring 742 aims light toward the collection fiber 718. Generally, the mean direction of the incident light varies by greater than 5, 10, 15, 20, or 25 degrees.
  • Still yet another embodiment includes any combination and/or permutation of any of the analyzer and/or sensor elements described herein.
  • The particular implementations shown and described are illustrative of the invention and its best mode and are not intended to otherwise limit the scope of the present invention in any way. Indeed, for the sake of brevity, conventional manufacturing, connection, preparation, and other functional aspects of the system may not be described in detail. Furthermore, the connecting lines shown in the various figures are intended to represent exemplary functional relationships and/or physical couplings between the various elements. Many alternative or additional functional relationships or physical connections may be present in a practical system.
  • In the foregoing description, the invention has been described with reference to specific exemplary embodiments; however, it will be appreciated that various modifications and changes may be made without departing from the scope of the present invention as set forth herein. The description and figures are to be regarded in an illustrative manner, rather than a restrictive one and all such modifications are intended to be included within the scope of the present invention. Accordingly, the scope of the invention should be determined by the generic embodiments described herein and their legal equivalents rather than by merely the specific examples described above. For example, the steps recited in any method or process embodiment may be executed in any order and are not limited to the explicit order presented in the specific examples. Additionally, the components and/or elements recited in any apparatus embodiment may be assembled or otherwise operationally configured in a variety of permutations to produce substantially the same result as the present invention and are accordingly not limited to the specific configuration recited in the specific examples.
  • Benefits, other advantages and solutions to problems have been described above with regard to particular embodiments; however, any benefit, advantage, solution to problems or any element that may cause any particular benefit, advantage or solution to occur or to become more pronounced are not to be construed as critical, required or essential features or components.
  • As used herein, the terms “comprises”, “comprising”, or any variation thereof, are intended to reference a non-exclusive inclusion, such that a process, method, article, composition or apparatus that comprises a list of elements does not include only those elements recited, but may also include other elements not expressly listed or inherent to such process, method, article, composition or apparatus. Other combinations and/or modifications of the above-described structures, arrangements, applications, proportions, elements, materials or components used in the practice of the present invention, in addition to those not specifically recited, may be varied or otherwise particularly adapted to specific environments, manufacturing specifications, design parameters or other operating requirements without departing from the general principles of the same.
  • Although the invention has been described herein with reference to certain preferred embodiments, one skilled in the art will readily appreciate that other applications may be substituted for those set forth herein without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below.

Claims (23)

1. An apparatus for determination of an analyte property of a subject, comprising:
a near-infrared analyzer, comprising:
a source configured to deliver a sub-microsecond burst of near-infrared light in the range of 1000 to 2500 nanometers;
a temporal resolution gating system configured to collect signal from the burst of near-infrared light during a time period of at least one time delayed gated window, the time period comprising a period greater than one femtosecond and less than one nanosecond after a midpoint of the burst of the near-infrared light; and
a data processing system configured to use the signal and the time period of the at least one delayed gated window in determination of a glucose concentration.
2. The apparatus of claim 1, said data processing system configured to resolve a pathlength of the near-infrared light in the subject using the signal from the burst of near-infrared light in the at least one time delayed gated window, the pathlength used in said data processing system in the determination of the glucose concentration.
3. The apparatus of claim 1, said data processing system configured to use the time period of the at least one time delayed gated window in determination of a product of pathlength and molar absorptivity.
4. The apparatus of claim 1, wherein said analyzer further comprises:
at least one optic configured to vary radial distance, by at least one millimeter as a function of time, between a middle of an illumination zone of the burst of near-infrared light on the subject and a middle of a detection zone of a detection optic of said analyzer.
5. The apparatus of claim 4, wherein the radial distance comprises a set of at least four mean distances as a function of scan number, wherein the signal comprises a set of at least ten sub-signals correlating to said set of four mean distances.
6. The apparatus of claim 1, wherein said data processing system uses a database, said database configured to store at least one physiology parameter, said physiology parameter comprising at least one of an epidermal thickness and a dermal thickness, said data processing system configured to use at least one of the epidermal thickness and the dermal thickness in the determination of the glucose concentration.
7. The apparatus of claim 1, in the determination of the glucose concentration, said data processing system configured to use at least one of:
an anisotropy value; and
an index of refraction.
8. The apparatus of claim 1, in the determination of the glucose concentration, said data processing system configured to use at least one of:
a scattering coefficient; and
an absorbance of any of water, protein, and fat.
9. The apparatus of claim 1, wherein said analyzer further comprises:
a sample interface configured to not contact the subject during collection of the signal.
10. The apparatus of claim 1, wherein said analyzer further comprises:
a sample interface configured to contact at least one of the subject and a coupling fluid during collection of the signal.
11. The apparatus of claim 1, wherein said analyzer further comprises:
a fiber optic bundle comprising:
a first fiber optic configured to deliver the burst of the near-infrared light to the subject, said first fiber optic comprising a first cross-sectional area; and
a second fiber optic configured to deliver the burst of the near-infrared light to the subject, said second fiber optic comprising a second cross-sectional area, said second cross-sectional area at least ten percent larger than said first cross-sectional area.
12. The apparatus of claim 1, wherein said analyzer further comprises:
a vibration reduction system, wherein said vibration reduction system maintains a gap between a sample interface of said analyzer and the subject by monitoring shaking of the subject and adjusting physical position of said sample interface relative to the subject.
13. The apparatus of claim 1, wherein said analyzer further comprises:
a first sample side optic configured to deliver the burst of light to the subject at a first mean incident angle relative to an axis normal to a sample site of the subject,
a second sample side optic configured to deliver the burst of light to the subject at a second mean incident angle relative to the axis normal to the sample site of the subject, the first mean incident angle at least ten degrees larger than the second mean incident angle.
14. A method for determination of an analyte property of a subject having skin, comprising the steps of:
delivering a spectral burst of near-infrared light at least within the range of 1000 to 2500 nanometers from a source of an analyzer to an illumination region of the skin of the subject;
generating a signal during at least one time period using a temporal resolution gating system to detect the burst of light in at least one time delayed gated window between one hundred picoseconds and one hundred nanoseconds after origination of the burst of the near-infrared light; and
processing the signal using the at least one time period and the signal to generate a glucose concentration of the subject.
15. The method of claim 14, wherein said step of processing uses the time of said at least one time delayed gated window and the signal to generate an optical pathlength of the burst of the near-infrared light in the subject.
16. The method of claim 14, wherein said step of processing estimates a molar absorptivity of the subject.
17. The method of claim 14, further comprising the step of:
adapting an optical configuration of the analyzer using the molar absorptivity.
18. The method of claim 14, wherein said step of processing further comprises the steps of:
sending a form of the signal to a smart phone;
analyzing the form of the signal using the smart phone to generate a result; and
using said smart phone to convey the result to the subject.
19. The method of claim 14, further comprising the steps of:
using said analyzer to gather information from a sensor external to said analyzer; and
relaying a form of the information to a cell phone.
20. The method of claim 14, further comprising the step of:
varying radial distance of the burst of light onto the subject relative to a zone monitored by a detector of said analyzer by at least one millimeter in a ten second time period.
21. A method for determination of a glucose concentration of a subject, comprising the steps of:
using a temporal resolution analyzer to time near-infrared photon traversal through skin using a time resolved gating system and to gather a signal at a detection time period of the time resolved gating system; and
using the detection time period and the signal to noninvasively determine a glucose concentration of the subject.
22. The method of claim 21, wherein said detection time comprises a time period greater than one femtosecond and less than one nanosecond after generation of a burst of light by said analyzer, wherein the signal is collected during said time period.
23. The method of claim 21, wherein said detection time comprises a time period greater than ten microseconds and less than one-tenth of a second after generation of a burst of light by said analyzer, wherein the signal is collected during said time period.
US13/941,369 2012-07-16 2013-07-12 Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof Abandoned US20150018642A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US13/941,369 US20150018642A1 (en) 2013-07-12 2013-07-12 Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof
US13/941,389 US9766126B2 (en) 2013-07-12 2013-07-12 Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
US13/941,411 US20150018646A1 (en) 2013-07-12 2013-07-12 Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof
US13/963,925 US20150045636A1 (en) 2013-07-12 2013-08-09 Multiplexed / pathlength resolved noninvasive analyzer apparatus and method of use thereof
US13/963,933 US20150041656A1 (en) 2013-07-12 2013-08-09 Multiplexed noninvasive analyzer apparatus and method of use thereof
US14/493,283 US9585604B2 (en) 2012-07-16 2014-09-22 Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US14/493,234 US9351671B2 (en) 2012-07-16 2014-09-22 Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof
US14/493,266 US9351672B2 (en) 2012-07-16 2014-09-22 Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US14/504,065 US20150018644A1 (en) 2012-07-16 2014-10-01 Multiplexed pathlength resolved noninvasive analyzer apparatus with non-uniform detector array and method of use thereof
US14/938,688 US9375170B2 (en) 2012-07-16 2015-11-11 Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US14/943,990 US20160151002A1 (en) 2012-07-16 2015-11-17 Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US14/965,782 US20160249836A1 (en) 2012-07-16 2015-12-10 Sample optical pathlength control using a noninvasive analyzer apparatus and method of use thereof
US14/965,807 US20160242682A1 (en) 2012-07-16 2015-12-10 Noninvasive analyzer apparatus and method of use thereof for separating distributed probing photons emerging from a sample

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US13/941,369 US20150018642A1 (en) 2013-07-12 2013-07-12 Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/941,389 Continuation-In-Part US9766126B2 (en) 2012-07-16 2013-07-12 Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof

Publications (1)

Publication Number Publication Date
US20150018642A1 true US20150018642A1 (en) 2015-01-15

Family

ID=52276852

Family Applications (5)

Application Number Title Priority Date Filing Date
US13/941,389 Expired - Fee Related US9766126B2 (en) 2012-07-16 2013-07-12 Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
US13/941,411 Abandoned US20150018646A1 (en) 2012-07-16 2013-07-12 Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof
US13/941,369 Abandoned US20150018642A1 (en) 2012-07-16 2013-07-12 Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof
US13/963,933 Abandoned US20150041656A1 (en) 2012-07-16 2013-08-09 Multiplexed noninvasive analyzer apparatus and method of use thereof
US13/963,925 Abandoned US20150045636A1 (en) 2012-07-16 2013-08-09 Multiplexed / pathlength resolved noninvasive analyzer apparatus and method of use thereof

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US13/941,389 Expired - Fee Related US9766126B2 (en) 2012-07-16 2013-07-12 Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
US13/941,411 Abandoned US20150018646A1 (en) 2012-07-16 2013-07-12 Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/963,933 Abandoned US20150041656A1 (en) 2012-07-16 2013-08-09 Multiplexed noninvasive analyzer apparatus and method of use thereof
US13/963,925 Abandoned US20150045636A1 (en) 2012-07-16 2013-08-09 Multiplexed / pathlength resolved noninvasive analyzer apparatus and method of use thereof

Country Status (1)

Country Link
US (5) US9766126B2 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011848A1 (en) * 2012-07-16 2015-01-08 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof
US9351672B2 (en) 2012-07-16 2016-05-31 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US20160192885A1 (en) * 2015-01-07 2016-07-07 Samsung Electronics Co., Ltd. Apparatus and method for measuring biological signal
US9442065B2 (en) 2014-09-29 2016-09-13 Zyomed Corp. Systems and methods for synthesis of zyotons for use in collision computing for noninvasive blood glucose and other measurements
US9554738B1 (en) 2016-03-30 2017-01-31 Zyomed Corp. Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing
US9585604B2 (en) 2012-07-16 2017-03-07 Zyomed Corp. Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US9766126B2 (en) 2013-07-12 2017-09-19 Zyomed Corp. Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
EP3581096A1 (en) * 2018-06-11 2019-12-18 MediaTek Inc. Opto-mechanical design of biosensor for human body signal detection
US11020027B2 (en) 2017-09-18 2021-06-01 Samsung Electronics Co., Ltd. Apparatus and method for estimating glucose exposure and generating glucose exposure estimation model
US11579080B2 (en) 2017-09-29 2023-02-14 Apple Inc. Resolve path optical sampling architectures
US11585749B2 (en) * 2015-09-01 2023-02-21 Apple Inc. Reference switch architectures for noncontact sensing of substances
US11726036B2 (en) 2014-12-23 2023-08-15 Apple Inc. Optical inspection system and method including accounting for variations of optical path length within a sample
US11852318B2 (en) 2020-09-09 2023-12-26 Apple Inc. Optical system for noise mitigation

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10607507B2 (en) 2015-11-24 2020-03-31 Medibotics Arcuate wearable device with a circumferential or annular array of spectroscopic sensors for measuring hydration level
US9582035B2 (en) 2014-02-25 2017-02-28 Medibotics Llc Wearable computing devices and methods for the wrist and/or forearm
US20150018644A1 (en) * 2012-07-16 2015-01-15 Sandeep Gulati Multiplexed pathlength resolved noninvasive analyzer apparatus with non-uniform detector array and method of use thereof
US20160242682A1 (en) * 2012-07-16 2016-08-25 Sandeep Gulati Noninvasive analyzer apparatus and method of use thereof for separating distributed probing photons emerging from a sample
US10207363B2 (en) * 2014-03-24 2019-02-19 James Eldon Craig Additive manufacturing temperature controller/sensor apparatus and method of use thereof
JP6606082B2 (en) * 2014-09-05 2019-11-13 Phcホールディングス株式会社 Glucose concentration determination method and glucose concentration measurement device
US9869590B2 (en) * 2015-05-29 2018-01-16 Xerox Corporation Spatially-resolved FWA spectrophotometer using micropatterned optical filters
US9702689B2 (en) 2015-06-18 2017-07-11 Xerox Corporation Use of a full width array imaging sensor to measure real time film thicknesses on film manufacturing equipment
JP2018533013A (en) * 2015-10-20 2018-11-08 カレッジ・アンド・カザカ・エレクトロニック・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Optical confirmation of sun protection factor of sunscreen or other radiation protection agent
KR102444674B1 (en) 2015-11-20 2022-09-16 삼성전자주식회사 Optical measuring apparatus and electronic device including the same
US10393652B2 (en) * 2016-01-26 2019-08-27 Tubitak Portable optical apparatus for diffuse reflectance spectroscopy
CN106137218B (en) * 2016-07-30 2019-03-19 哈尔滨工业大学 A kind of method of the infrared composite absorption accurate measurement change of blood sugar of non-intruding
US10942257B2 (en) 2016-12-31 2021-03-09 Innovusion Ireland Limited 2D scanning high precision LiDAR using combination of rotating concave mirror and beam steering devices
US11642070B2 (en) * 2017-07-18 2023-05-09 Headwall Photonics, Inc. Diagnostic system and methods for simultaneously detecting light at multiple detection locations in a spectroscopic system
WO2019210105A1 (en) 2018-04-27 2019-10-31 Hydrostasis, Inc. Tissue hydration monitor
WO2024028469A1 (en) * 2022-08-04 2024-02-08 ams Sensors Germany GmbH Method for determining a substance concentration and detector device

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3700891A (en) * 1967-07-27 1972-10-24 Karl Friedrich Luft Device for the nondispersive infrared gas analysis
US5229841A (en) * 1991-07-10 1993-07-20 Eaton Corporation Color sensor employing optical fiber bundles with varied diameters
US5655530A (en) * 1995-08-09 1997-08-12 Rio Grande Medical Technologies, Inc. Method for non-invasive blood analyte measurement with improved optical interface
US5957841A (en) * 1997-03-25 1999-09-28 Matsushita Electric Works, Ltd. Method of determining a glucose concentration in a target by using near-infrared spectroscopy
US6016435A (en) * 1996-11-26 2000-01-18 Matsushita Electric Works Ltd. Device for non-invasive determination of a glucose concentration in the blood of a subject
US6353226B1 (en) * 1998-11-23 2002-03-05 Abbott Laboratories Non-invasive sensor capable of determining optical parameters in a sample having multiple layers
US6456870B1 (en) * 1999-07-22 2002-09-24 Sensys Medical, Inc. Non-invasive method of determining skin thickness and characterizing layers of skin tissue in vivo
US6512937B2 (en) * 1999-07-22 2003-01-28 Sensys Medical, Inc. Multi-tier method of developing localized calibration models for non-invasive blood analyte prediction
US20030208113A1 (en) * 2001-07-18 2003-11-06 Mault James R Closed loop glycemic index system
US6844994B2 (en) * 2000-09-20 2005-01-18 Carl Zeiss Smt Ag Optical element deformation system
US7147153B2 (en) * 2003-04-04 2006-12-12 Lumidigm, Inc. Multispectral biometric sensor
US20070255141A1 (en) * 2006-01-20 2007-11-01 Esenaliev Rinat O Noninvasive glucose sensing methods and systems
US7620212B1 (en) * 2002-08-13 2009-11-17 Lumidigm, Inc. Electro-optical sensor
US8082015B2 (en) * 2004-04-13 2011-12-20 The Trustees Of The University Of Pennsylvania Optical measurement of tissue blood flow, hemodynamics and oxygenation

Family Cites Families (161)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1333838A (en) * 1971-06-24 1973-10-17 Hawker Siddeley Dynamics Ltd Viewing systems
US4583545A (en) 1984-07-03 1986-04-22 Towe Bruce C Noninvasive biomagnesonic method of biocurrent measurement
JPH06103257B2 (en) 1988-12-19 1994-12-14 大塚電子株式会社 Method and apparatus for measuring absorption coefficient of substance using light scattering
US5237178A (en) 1990-06-27 1993-08-17 Rosenthal Robert D Non-invasive near-infrared quantitative measurement instrument
US5086229A (en) 1989-01-19 1992-02-04 Futrex, Inc. Non-invasive measurement of blood glucose
US4975581A (en) 1989-06-21 1990-12-04 University Of New Mexico Method of and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids
US5324979A (en) 1990-09-26 1994-06-28 Futrex, Inc. Method and means for generating synthetic spectra allowing quantitative measurement in near infrared measuring instruments
US6263221B1 (en) 1991-01-24 2001-07-17 Non-Invasive Technology Quantitative analyses of biological tissue using phase modulation spectroscopy
IL107396A (en) 1992-11-09 1997-02-18 Boehringer Mannheim Gmbh Method and apparatus for analytical determination of glucose in a biological matrix
US5553616A (en) 1993-11-30 1996-09-10 Florida Institute Of Technology Determination of concentrations of biological substances using raman spectroscopy and artificial neural network discriminator
US5492118A (en) 1993-12-16 1996-02-20 Board Of Trustees Of The University Of Illinois Determining material concentrations in tissues
US5459317A (en) 1994-02-14 1995-10-17 Ohio University Method and apparatus for non-invasive detection of physiological chemicals, particularly glucose
US6957094B2 (en) 1994-12-02 2005-10-18 Non-Invasive Technology, Inc. Examination of scattering properties of biological tissue
SG38866A1 (en) 1995-07-31 1997-04-17 Instrumentation Metrics Inc Liquid correlation spectrometry
US6240306B1 (en) 1995-08-09 2001-05-29 Rio Grande Medical Technologies, Inc. Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration
US5636633A (en) 1995-08-09 1997-06-10 Rio Grande Medical Technologies, Inc. Diffuse reflectance monitoring apparatus
US6152876A (en) 1997-04-18 2000-11-28 Rio Grande Medical Technologies, Inc. Method for non-invasive blood analyte measurement with improved optical interface
EP0862829B1 (en) 1995-11-07 2003-05-14 California Institute Of Technology An image sensor with high dynamic range linear output
US5747806A (en) 1996-02-02 1998-05-05 Instrumentation Metrics, Inc Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy
US6040578A (en) 1996-02-02 2000-03-21 Instrumentation Metrics, Inc. Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy
US6544193B2 (en) 1996-09-04 2003-04-08 Marcio Marc Abreu Noninvasive measurement of chemical substances
CN1209930A (en) 1996-10-31 1999-03-03 马库斯·伯姆 Colour image sensor for short-time exposure
US6122042A (en) 1997-02-07 2000-09-19 Wunderman; Irwin Devices and methods for optically identifying characteristics of material objects
US6188705B1 (en) 1997-05-16 2001-02-13 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Fiber grating coupled light source capable of tunable, single frequency operation
US7890158B2 (en) 2001-06-05 2011-02-15 Lumidigm, Inc. Apparatus and method of biometric determination using specialized optical spectroscopy systems
US6871169B1 (en) 1997-08-14 2005-03-22 Sensys Medical, Inc. Combinative multivariate calibration that enhances prediction ability through removal of over-modeled regions
US6115673A (en) 1997-08-14 2000-09-05 Instrumentation Metrics, Inc. Method and apparatus for generating basis sets for use in spectroscopic analysis
US7039446B2 (en) 2001-01-26 2006-05-02 Sensys Medical, Inc. Indirect measurement of tissue analytes through tissue properties
US7010336B2 (en) 1997-08-14 2006-03-07 Sensys Medical, Inc. Measurement site dependent data preprocessing method for robust calibration and prediction
US7206623B2 (en) 2000-05-02 2007-04-17 Sensys Medical, Inc. Optical sampling interface system for in vivo measurement of tissue
US7383069B2 (en) 1997-08-14 2008-06-03 Sensys Medical, Inc. Method of sample control and calibration adjustment for use with a noninvasive analyzer
US6415167B1 (en) 2000-05-02 2002-07-02 Instrumentation Metrics, Inc. Fiber optic probe placement guide
DE19748211A1 (en) * 1997-10-31 1999-05-06 Zeiss Carl Fa Optical array system and reader for microtiter plates
US6114699A (en) 1997-11-26 2000-09-05 The United States Of America As Represented By The Secretary Of Agriculture Prediction of total dietary fiber in cereal products using near-infrared reflectance spectroscopy
US20070167704A1 (en) 1998-02-13 2007-07-19 Britton Chance Transabdominal examination, monitoring and imaging of tissue
US6728560B2 (en) 1998-04-06 2004-04-27 The General Hospital Corporation Non-invasive tissue glucose level monitoring
US6526298B1 (en) 1998-05-18 2003-02-25 Abbott Laboratories Method for the non-invasive determination of analytes in a selected volume of tissue
US6662031B1 (en) 1998-05-18 2003-12-09 Abbott Laboratoies Method and device for the noninvasive determination of hemoglobin and hematocrit
US6662030B2 (en) 1998-05-18 2003-12-09 Abbott Laboratories Non-invasive sensor having controllable temperature feature
US6615061B1 (en) 1998-11-23 2003-09-02 Abbott Laboratories Optical sensor having a selectable sampling distance for determination of analytes
US6556301B2 (en) * 1998-11-26 2003-04-29 Infrared Integrated Systems Ltd. Versatile filter based spectrophotometer
US6067463A (en) 1999-01-05 2000-05-23 Abbott Laboratories Method and apparatus for non-invasively measuring the amount of glucose in blood
US6280381B1 (en) 1999-07-22 2001-08-28 Instrumentation Metrics, Inc. Intelligent system for noninvasive blood analyte prediction
US6493566B1 (en) 1999-01-22 2002-12-10 Instrumentation Metrics, Inc. Classification system for sex determination and tissue characterization
US6864978B1 (en) 1999-07-22 2005-03-08 Sensys Medical, Inc. Method of characterizing spectrometer instruments and providing calibration models to compensate for instrument variation
US6501982B1 (en) 1999-01-22 2002-12-31 Sensys Medical, Inc. System for the noninvasive estimation of relative age
US7436511B2 (en) 1999-01-22 2008-10-14 Sensys Medical, Inc. Analyte filter method and apparatus
US6405065B1 (en) 1999-01-22 2002-06-11 Instrumentation Metrics, Inc. Non-invasive in vivo tissue classification using near-infrared measurements
US6587702B1 (en) 1999-01-22 2003-07-01 Instrumentation Metrics, Inc Classification and characterization of tissue through features related to adipose tissue
US6245511B1 (en) 1999-02-22 2001-06-12 Vialogy Corp Method and apparatus for exponentially convergent therapy effectiveness monitoring using DNA microarray based viral load measurements
US7299080B2 (en) 1999-10-08 2007-11-20 Sensys Medical, Inc. Compact apparatus for noninvasive measurement of glucose through near-infrared spectroscopy
US6675029B2 (en) 1999-07-22 2004-01-06 Sensys Medical, Inc. Apparatus and method for quantification of tissue hydration using diffuse reflectance spectroscopy
US6697654B2 (en) 1999-07-22 2004-02-24 Sensys Medical, Inc. Targeted interference subtraction applied to near-infrared measurement of analytes
US6442408B1 (en) 1999-07-22 2002-08-27 Instrumentation Metrics, Inc. Method for quantification of stratum corneum hydration using diffuse reflectance spectroscopy
US6512936B1 (en) 1999-07-22 2003-01-28 Sensys Medical, Inc. Multi-tier method of classifying sample spectra for non-invasive blood analyte prediction
US6475800B1 (en) 1999-07-22 2002-11-05 Instrumentation Metrics, Inc. Intra-serum and intra-gel for modeling human skin tissue
USRE41333E1 (en) 1999-07-22 2010-05-11 Sensys Medical, Inc. Multi-tier method of developing localized calibration models for non-invasive blood analyte prediction
US6411373B1 (en) 1999-10-08 2002-06-25 Instrumentation Metrics, Inc. Fiber optic illumination and detection patterns, shapes, and locations for use in spectroscopic analysis
US7317938B2 (en) 1999-10-08 2008-01-08 Sensys Medical, Inc. Method of adapting in-vitro models to aid in noninvasive glucose determination
JP3796086B2 (en) * 1999-12-27 2006-07-12 株式会社日立製作所 Biological light measurement device
US6594513B1 (en) 2000-01-12 2003-07-15 Paul D. Jobsis Method and apparatus for determining oxygen saturation of blood in body organs
US6587196B1 (en) 2000-01-26 2003-07-01 Sensys Medical, Inc. Oscillating mechanism driven monochromator
US6587199B1 (en) 2000-02-25 2003-07-01 Sensys Medical, Inc. Embedded data acquisition and control system for non-invasive glucose prediction instrument
US20030139667A1 (en) 2000-04-13 2003-07-24 Hewko Mark D. Tissue viability/health monitor utilizing near infrared spectroscopy
US7509153B2 (en) 2000-09-26 2009-03-24 Sensys Medical, Inc. Method and apparatus for control of skin perfusion for indirect glucose measurement
US7519406B2 (en) 2004-04-28 2009-04-14 Sensys Medical, Inc. Noninvasive analyzer sample probe interface method and apparatus
US6534012B1 (en) 2000-08-02 2003-03-18 Sensys Medical, Inc. Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling
US7606608B2 (en) 2000-05-02 2009-10-20 Sensys Medical, Inc. Optical sampling interface system for in-vivo measurement of tissue
US6839584B2 (en) 2000-05-02 2005-01-04 Instrumentation Metrics, Inc. Method and apparatus for minimizing spectral interference due to within and between sample variations during in-situ spectral sampling of tissue
US7395158B2 (en) 2000-05-30 2008-07-01 Sensys Medical, Inc. Method of screening for disorders of glucose metabolism
US6487429B2 (en) 2000-05-30 2002-11-26 Sensys Medical, Inc. Use of targeted glycemic profiles in the calibration of a noninvasive blood glucose monitor
AU2001275366A1 (en) 2000-06-15 2001-12-24 Instrumentation Metrics, Inc. Classification and screening of test subjects according to optical thickness of skin
US6571117B1 (en) 2000-08-11 2003-05-27 Ralf Marbach Capillary sweet spot imaging for improving the tracking accuracy and SNR of noninvasive blood analysis methods
US6640117B2 (en) 2000-09-26 2003-10-28 Sensys Medical, Inc. Method and apparatus for minimizing spectral effects attributable to tissue state variations during NIR-based non-invasive blood analyte determination
US6816241B2 (en) 2000-09-26 2004-11-09 Sensys Medical, Inc. LED light source-based instrument for non-invasive blood analyte determination
IL138884A (en) 2000-10-05 2006-07-05 Conmed Corp Pulse oximeter and a method of its operation
US8500274B2 (en) 2000-11-03 2013-08-06 High Performance Optics, Inc. Dual-filter ophthalmic lens to reduce risk of macular degeneration
US7383076B2 (en) 2000-11-27 2008-06-03 The General Hospital Corporation Fluorescence-mediated molecular tomography
US6697652B2 (en) 2001-01-19 2004-02-24 Massachusetts Institute Of Technology Fluorescence, reflectance and light scattering spectroscopy for measuring tissue
IL156844A0 (en) 2001-01-26 2004-02-08 Sensys Medical Inc Noninvasive measurement of glucose through the optical properties of tissue
US6574490B2 (en) 2001-04-11 2003-06-03 Rio Grande Medical Technologies, Inc. System for non-invasive measurement of glucose in humans
US8174394B2 (en) 2001-04-11 2012-05-08 Trutouch Technologies, Inc. System for noninvasive determination of analytes in tissue
US6876931B2 (en) 2001-08-03 2005-04-05 Sensys Medical Inc. Automatic process for sample selection during multivariate calibration
US6788965B2 (en) 2001-08-03 2004-09-07 Sensys Medical, Inc. Intelligent system for detecting errors and determining failure modes in noninvasive measurement of blood and tissue analytes
US20040162678A1 (en) 2001-08-13 2004-08-19 Donald Hetzel Method of screening for disorders of glucose metabolism
US6801309B1 (en) * 2001-10-16 2004-10-05 Therma-Wave, Inc. Detector array with scattered light correction
US6989891B2 (en) 2001-11-08 2006-01-24 Optiscan Biomedical Corporation Device and method for in vitro determination of analyte concentrations within body fluids
US7009180B2 (en) 2001-12-14 2006-03-07 Optiscan Biomedical Corp. Pathlength-independent methods for optically determining material composition
US6640197B2 (en) * 2002-02-08 2003-10-28 Agilent Technologies, Inc. Self aligning sensor array system
EP2400288A1 (en) 2002-02-11 2011-12-28 Bayer Corporation Non-invasive system for the determination of analytes in body fluids
US20050187439A1 (en) 2003-03-07 2005-08-25 Blank Thomas B. Sampling interface system for in-vivo estimation of tissue analyte concentration
US8718738B2 (en) 2002-03-08 2014-05-06 Glt Acquisition Corp. Method and apparatus for coupling a sample probe with a sample site
US20050054908A1 (en) 2003-03-07 2005-03-10 Blank Thomas B. Photostimulation method and apparatus in combination with glucose determination
JP4189322B2 (en) 2002-03-08 2008-12-03 センシス メディカル インク Compact instrument for non-invasive measurement of glucose by near infrared spectroscopy
US6998247B2 (en) 2002-03-08 2006-02-14 Sensys Medical, Inc. Method and apparatus using alternative site glucose determinations to calibrate and maintain noninvasive and implantable analyzers
US7697966B2 (en) 2002-03-08 2010-04-13 Sensys Medical, Inc. Noninvasive targeting system method and apparatus
US20070149868A1 (en) 2002-03-08 2007-06-28 Blank Thomas B Method and Apparatus for Photostimulation Enhanced Analyte Property Estimation
US6868138B2 (en) 2002-05-29 2005-03-15 The Regents Of The University Of Michigan Method, processor and computed tomography (CT) machine for generating images utilizing high and low sensitivity data collected from a flat panel detector having an extended dynamic range
US7333843B2 (en) 2002-06-12 2008-02-19 Sensys Medical, Inc. Apparatus and method for easing use of a spectrophotometric based noninvasive analyzer
US6956649B2 (en) 2002-11-26 2005-10-18 Sensys Medical, Inc. Spectroscopic system and method using a ceramic optical reference
US20040132168A1 (en) 2003-01-06 2004-07-08 Peter Rule Sample element for reagentless whole blood glucose meter
US20050033127A1 (en) 2003-01-30 2005-02-10 Euro-Celtique, S.A. Wireless blood glucose monitoring system
US6836678B2 (en) 2003-02-13 2004-12-28 Xiang Zheng Tu Non-invasive blood glucose monitor
US7015782B2 (en) 2003-02-19 2006-03-21 Sensys Medical, Inc. Magneto-mechanical apparatus
US20050159656A1 (en) 2003-03-07 2005-07-21 Hockersmith Linda J. Method and apparatus for presentation of noninvasive glucose concentration information
US7640140B2 (en) 2003-03-07 2009-12-29 Sensys Medical, Inc. Method of processing noninvasive spectra
US7620674B2 (en) 2003-03-07 2009-11-17 Sensys Medical, Inc. Method and apparatus for enhanced estimation of an analyte property through multiple region transformation
US7751594B2 (en) 2003-04-04 2010-07-06 Lumidigm, Inc. White-light spectral biometric sensors
US20070293744A1 (en) 2003-04-16 2007-12-20 Monfre Stephen L Apparatus and method for easing use of a spectrophotometric based noninvasive analyzer
EP1634061A4 (en) 2003-04-30 2007-11-21 Univ Mcgill Method and system for measuring lactate levels in vivo
US6943881B2 (en) 2003-06-04 2005-09-13 Tomophase Corporation Measurements of optical inhomogeneity and other properties in substances using propagation modes of light
CA2577587A1 (en) 2003-08-21 2005-03-03 Mcgill University Method and apparatus for analyzing amniotic fluid
US20050124869A1 (en) 2003-12-08 2005-06-09 John Hefti Non-invasive, in vivo substance measurement systems
WO2005070291A1 (en) 2004-01-08 2005-08-04 Inlight Solutions, Inc. Noninvasive determination of alcohol in tissue
US7356364B1 (en) 2004-01-23 2008-04-08 University Of Hawai'i Device for optical monitoring of constituent in tissue or body fluid sample using wavelength modulation spectroscopy, such as for blood glucose levels
US7848605B2 (en) 2004-05-24 2010-12-07 Trutouch Technologies, Inc. Method of making optical probes for non-invasive analyte measurements
US20080319286A1 (en) 2004-05-24 2008-12-25 Trent Ridder Optical Probes for Non-Invasive Analyte Measurements
DE102004035494A1 (en) 2004-07-22 2006-02-09 Giesecke & Devrient Gmbh Device and method for checking value documents
USD526719S1 (en) 2004-11-19 2006-08-15 Sensys Medical, Inc. Noninvasive glucose analyzer
USD529616S1 (en) 2004-11-19 2006-10-03 Sensys Medical, Inc. Noninvasive glucose analyzer
GB0426993D0 (en) 2004-12-09 2005-01-12 Council Cent Lab Res Councils Apparatus for depth-selective raman spectroscopy
US20080306363A1 (en) 2005-01-06 2008-12-11 Lightouch Medical, Inc. Specialized Human Servo Device And Process For Tissue Modulation Of Human Fingerprints
US7767949B2 (en) 2005-01-18 2010-08-03 Rearden, Llc Apparatus and method for capturing still images and video using coded aperture techniques
US20110184260A1 (en) 2005-02-09 2011-07-28 Robinson M Ries Methods and Apparatuses for Noninvasive Determinations of Analytes
US20060217602A1 (en) 2005-03-04 2006-09-28 Alan Abul-Haj Method and apparatus for noninvasive targeting
US7593230B2 (en) 2005-05-05 2009-09-22 Sensys Medical, Inc. Apparatus for absorbing and dissipating excess heat generated by a system
US7698105B2 (en) 2005-05-23 2010-04-13 Sensys Medical, Inc. Method and apparatus for improving performance of noninvasive analyte property estimation
US20070030482A1 (en) * 2005-08-08 2007-02-08 Zhenghua Ji Spectrophotometer with adjustable light pathlength
CA2944254A1 (en) 2005-10-24 2007-05-03 Marcio Marc Abreu Apparatus and method for measuring biologic parameters
US20070161876A1 (en) 2005-11-18 2007-07-12 Spectrx, Inc. Method and apparatus for rapid detection and diagnosis of tissue abnormalities
DE602006019133D1 (en) 2005-11-30 2011-02-03 Toshiba Medical Sys Corp METHOD FOR NON-INVASIVE GLUCOSE MEASUREMENT
US20100230610A1 (en) * 2006-03-28 2010-09-16 Koninklijke Philips Electronics N.V. Integrated device having an array of photodetectors and an array of sample sites
WO2007140270A2 (en) 2006-05-25 2007-12-06 Vialogy Corp. Analyzing information gathered using multiple analytical techniques
US7488930B2 (en) 2006-06-02 2009-02-10 Medeikon Corporation Multi-channel low coherence interferometer
US8326390B2 (en) 2006-07-25 2012-12-04 Edward Belotserkovsky Optical non-invasive blood monitoring system and method
WO2008019382A2 (en) 2006-08-07 2008-02-14 Vialogy Llc.. Quantum resonance interferometry for detecting signals
US8712504B2 (en) 2006-09-28 2014-04-29 The Florida International University Board Of Trustees Hand-held optical probe based imaging system with 3D tracking facilities
US8170326B2 (en) 2007-01-03 2012-05-01 Vialogy Corp. Multi parallax exploitation for omni-directional imaging electronic eye
US8346327B2 (en) 2007-03-09 2013-01-01 Covidien Lp Method for identification of sensor site by local skin spectrum data
US8175665B2 (en) 2007-03-09 2012-05-08 Nellcor Puritan Bennett Llc Method and apparatus for spectroscopic tissue analyte measurement
US8285010B2 (en) 2007-03-21 2012-10-09 Lumidigm, Inc. Biometrics based on locally consistent features
US7508524B2 (en) 2007-07-20 2009-03-24 Vanderbilt University Combined raman spectroscopy-optical coherence tomography (RS-OCT) system and applications of the same
US8115934B2 (en) 2008-01-18 2012-02-14 The Board Of Trustees Of The University Of Illinois Device and method for imaging the ear using optical coherence tomography
ES2733076T3 (en) 2008-03-05 2019-11-27 Tamir Gil Obtaining instant spectral images of the eye
EP2384182A4 (en) 2008-04-30 2016-10-19 Univ Texas An apparatus and method for noninvasive evaluation of a target versus a non-target
US20110139990A1 (en) * 2008-09-04 2011-06-16 University Of Florida Research Foundation, Inc. Mems-based ftir spectrometer
US20100113899A1 (en) 2008-11-06 2010-05-06 Mark Ries Robinson Alignment System for Optically Sampling a Hand
US9020581B2 (en) * 2008-12-05 2015-04-28 Vanderbilt University Spatially offset Raman spectroscopy of layered soft tissues and applications of same
US20100160747A1 (en) 2008-12-12 2010-06-24 Mark Ries Robinson Selection of preferred sampling location on hand via minimization of sampling error, and optical alignment for repeatably sampling tissue
US20120059232A1 (en) 2008-12-24 2012-03-08 Glusense, Ltd. Implantable optical glucose sensing
US9395473B2 (en) 2009-03-20 2016-07-19 Nanolambda, Inc. Nano-optic filter array based sensor
US8538499B2 (en) 2009-09-23 2013-09-17 Lightouch Medical, Inc. Process and apparatus for non-invasive, continuous in vivo measurement of hematocrit
US20120130215A1 (en) 2010-05-05 2012-05-24 Ilya Fine Optical measurement of parameters related to motion of light-scattering particles within a fluid by manipulating analog electrical signals
JP5445407B2 (en) 2010-09-08 2014-03-19 横河電機株式会社 Biological information measuring device
US20130261413A1 (en) 2010-10-14 2013-10-03 Hitachi, Ltd. Equipment for in vivo data acquisition and analysis
US8791514B2 (en) * 2011-07-06 2014-07-29 Siemens Medical Solutions Usa, Inc. Providing variable cell density and sizes in a radiation detector
US9766126B2 (en) 2013-07-12 2017-09-19 Zyomed Corp. Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
US9351672B2 (en) 2012-07-16 2016-05-31 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US20150018644A1 (en) 2012-07-16 2015-01-15 Sandeep Gulati Multiplexed pathlength resolved noninvasive analyzer apparatus with non-uniform detector array and method of use thereof
US9585604B2 (en) 2012-07-16 2017-03-07 Zyomed Corp. Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US9267842B2 (en) * 2013-01-21 2016-02-23 Sciaps, Inc. Automated focusing, cleaning, and multiple location sampling spectrometer system

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3700891A (en) * 1967-07-27 1972-10-24 Karl Friedrich Luft Device for the nondispersive infrared gas analysis
US5229841A (en) * 1991-07-10 1993-07-20 Eaton Corporation Color sensor employing optical fiber bundles with varied diameters
US5655530A (en) * 1995-08-09 1997-08-12 Rio Grande Medical Technologies, Inc. Method for non-invasive blood analyte measurement with improved optical interface
US6016435A (en) * 1996-11-26 2000-01-18 Matsushita Electric Works Ltd. Device for non-invasive determination of a glucose concentration in the blood of a subject
US5957841A (en) * 1997-03-25 1999-09-28 Matsushita Electric Works, Ltd. Method of determining a glucose concentration in a target by using near-infrared spectroscopy
US6353226B1 (en) * 1998-11-23 2002-03-05 Abbott Laboratories Non-invasive sensor capable of determining optical parameters in a sample having multiple layers
US6456870B1 (en) * 1999-07-22 2002-09-24 Sensys Medical, Inc. Non-invasive method of determining skin thickness and characterizing layers of skin tissue in vivo
US6512937B2 (en) * 1999-07-22 2003-01-28 Sensys Medical, Inc. Multi-tier method of developing localized calibration models for non-invasive blood analyte prediction
US6844994B2 (en) * 2000-09-20 2005-01-18 Carl Zeiss Smt Ag Optical element deformation system
US20030208113A1 (en) * 2001-07-18 2003-11-06 Mault James R Closed loop glycemic index system
US7620212B1 (en) * 2002-08-13 2009-11-17 Lumidigm, Inc. Electro-optical sensor
US7147153B2 (en) * 2003-04-04 2006-12-12 Lumidigm, Inc. Multispectral biometric sensor
US8082015B2 (en) * 2004-04-13 2011-12-20 The Trustees Of The University Of Pennsylvania Optical measurement of tissue blood flow, hemodynamics and oxygenation
US20070255141A1 (en) * 2006-01-20 2007-11-01 Esenaliev Rinat O Noninvasive glucose sensing methods and systems

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
Bykov et al. Monte Carlo Simulation of Light Propagation in human tissues and Noninvasive Glucos Sensing. 2008 in "Handbook of Optical Sensing of Glucose in Biological Fluids and Tissues" Tuchin Edt., Taylor&Francis, Chap.3 p.65-95. *
Bykov et al. Monte Carlo Simulation of Light Propagation in human tissues and Noninvasive Glucos Sensing. 2008 in"Handbook of Optical Sensing of Glucose in Biological Fluids and Tissues" Tuchin Edt., Taylor&Francis, Chap.3 p.65-95. *
Chaiken et al. Analyzing near-infrared scattering from human skin to monitor changes in hematocrit. 2011 J.Biomed.Optics 16:097005-1 - 097005-18. *
Chaiken et al. Analyzing near-infrared scattering from human skin to monitor changes in hematocrit. 2011 J.Biomed.Optics16:097005-1 - 097005-18. *
Decker et al. 1968 Applied Optics 7:2205-2209. *
Delpy et al. Estimation of optical pathlength through tissue from direct time of flight measurement. 1988 Phys.Med.Biol. 33:1433-1442. *
Durduran et al. 2010 Rep. Prog. Phys. 73:076701-1 43 pages *
Farrell et al. A diffusion theory model of spatially resolved steady-state diffuse reflectance for the noninvasive determination of tissue optical properties.1992 Am. Assoc. Phys. Med. 19:879-888. *
Flock et al. Monte-Carlo modeling of light propagation in highly scattering tissues II.Comparison with measurements in phantoms. 1989 IEEE Trans Biomeda Engina 36:1169-1173. *
Kirillin et al. 2008 Quantum Electronics 38:486-490. *
Kirillin et al. Application of time gating in the measurement of glucose level in a three-layer biotissue model by using ultrashort laser pulses. 2008 Quantum Electronics 38:486-490. *
Kirillin et al. Application of time gating in the measurement of glucose level in a three-layer biotissue model by using ultrashortlaser pulses. 2008 Quantum Electronics 38:486-490. *
Tearney et al. Scanning single-mode fiber optic catheter-endoscope for optical coherence tomography. 1996 Optics Let. 21:543-545. *
Tearney et al. Scanning single-mode fiber optic catheter-endoscope for optical coherence tomography. 1996 Optics Let.21:543-545. *
Thilwind et al. 2009 J.Biomed.Optics 14:024026-1 - 024026-9. *
Thilwind et al. Improved depth resolution in near-infrared diffuse reflectance spectroscopy using obliquely oriented fibers. 2009 J.Biomed.Optics 14:024026-1 - 024026-9. *
Thilwind et al. Improved depth resolution in near-infrared diffuse reflectance spectroscopy using obliquely oriented fibers. 2009J.Biomed.Optics 14:024026-1 - 024026-9. *
Xu et al. 2003 Proc. SPIE 5068:104-111. *
Xu et al. The interface between probe and skin in non-invasive glucose sensing. 2003 Proc. SPIE 5068:104-111. *
Yen et al. Calculated Calibration Models For Glucose In Cutaneous Tissue From Temperature Modulation Of Localized Reflectance Measurements. 2004 Proc. SPIE 5771:166-173. *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011848A1 (en) * 2012-07-16 2015-01-08 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof
US9351671B2 (en) * 2012-07-16 2016-05-31 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof
US9351672B2 (en) 2012-07-16 2016-05-31 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US9375170B2 (en) 2012-07-16 2016-06-28 Timothy Ruchti Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US9585604B2 (en) 2012-07-16 2017-03-07 Zyomed Corp. Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US9766126B2 (en) 2013-07-12 2017-09-19 Zyomed Corp. Dynamic radially controlled light input to a noninvasive analyzer apparatus and method of use thereof
US9442065B2 (en) 2014-09-29 2016-09-13 Zyomed Corp. Systems and methods for synthesis of zyotons for use in collision computing for noninvasive blood glucose and other measurements
US9448164B2 (en) 2014-09-29 2016-09-20 Zyomed Corp. Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
US9453794B2 (en) 2014-09-29 2016-09-27 Zyomed Corp. Systems and methods for blood glucose and other analyte detection and measurement using collision computing
US9459203B2 (en) 2014-09-29 2016-10-04 Zyomed, Corp. Systems and methods for generating and using projector curve sets for universal calibration for noninvasive blood glucose and other measurements
US9459201B2 (en) 2014-09-29 2016-10-04 Zyomed Corp. Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
US9459202B2 (en) 2014-09-29 2016-10-04 Zyomed Corp. Systems and methods for collision computing for detection and noninvasive measurement of blood glucose and other substances and events
US9448165B2 (en) 2014-09-29 2016-09-20 Zyomed Corp. Systems and methods for control of illumination or radiation collection for blood glucose and other analyte detection and measurement using collision computing
US9610018B2 (en) 2014-09-29 2017-04-04 Zyomed Corp. Systems and methods for measurement of heart rate and other heart-related characteristics from photoplethysmographic (PPG) signals using collision computing
US11726036B2 (en) 2014-12-23 2023-08-15 Apple Inc. Optical inspection system and method including accounting for variations of optical path length within a sample
US10314539B2 (en) * 2015-01-07 2019-06-11 Samsung Electronics Co., Ltd. Apparatus and method for measuring biological signal
US20160192885A1 (en) * 2015-01-07 2016-07-07 Samsung Electronics Co., Ltd. Apparatus and method for measuring biological signal
US11357450B2 (en) 2015-01-07 2022-06-14 Samsung Electronics Co., Ltd. Apparatus and method for measuring biological signal
US11585749B2 (en) * 2015-09-01 2023-02-21 Apple Inc. Reference switch architectures for noncontact sensing of substances
US20230204497A1 (en) * 2015-09-01 2023-06-29 Apple Inc. Reference Switch Architectures for Noncontact Sensing of Substances
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
US11642050B2 (en) 2017-09-18 2023-05-09 Samsung Electronics Co., Ltd. Apparatus and method for estimating glucose exposure and generating glucose exposure estimation model
US11020027B2 (en) 2017-09-18 2021-06-01 Samsung Electronics Co., Ltd. Apparatus and method for estimating glucose exposure and generating glucose exposure estimation model
US11579080B2 (en) 2017-09-29 2023-02-14 Apple Inc. Resolve path optical sampling architectures
EP3581096A1 (en) * 2018-06-11 2019-12-18 MediaTek Inc. Opto-mechanical design of biosensor for human body signal detection
US11852318B2 (en) 2020-09-09 2023-12-26 Apple Inc. Optical system for noise mitigation

Also Published As

Publication number Publication date
US9766126B2 (en) 2017-09-19
US20150015888A1 (en) 2015-01-15
US20150018646A1 (en) 2015-01-15
US20150045636A1 (en) 2015-02-12
US20150041656A1 (en) 2015-02-12

Similar Documents

Publication Publication Date Title
US20150018642A1 (en) Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof
US9585604B2 (en) Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof
US9351671B2 (en) Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof
US9375170B2 (en) Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof
US11832940B2 (en) Non-invasive medical monitoring device for blood analyte measurements
US20150018644A1 (en) Multiplexed pathlength resolved noninvasive analyzer apparatus with non-uniform detector array and method of use thereof
Yadav et al. Near-infrared LED based non-invasive blood glucose sensor
US20160249836A1 (en) Sample optical pathlength control using a noninvasive analyzer apparatus and method of use thereof
Blank et al. Clinical results from a noninvasive blood glucose monitor
US7698105B2 (en) Method and apparatus for improving performance of noninvasive analyte property estimation
US8452356B2 (en) Optical microneedle-based spectrometer
US20160242682A1 (en) Noninvasive analyzer apparatus and method of use thereof for separating distributed probing photons emerging from a sample
US20040267105A1 (en) Apparatus and method for easing use of a spectrophotometric based noninvasive analyzer
US20060217602A1 (en) Method and apparatus for noninvasive targeting
TW201625925A (en) Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
Lacerenza et al. Wearable and wireless time-domain near-infrared spectroscopy system for brain and muscle hemodynamic monitoring
CN107427266A (en) Matter concentration measuring method in matter concentration measuring apparatus and blood in blood
CN101933809A (en) Multiband reflection spectrum noninvasive blood component measuring device and method
US20230263436A1 (en) Blood-Solute Calculation with a Mobile Device Using Non-Invasive Spectroscopy
Davison et al. Recent progress and perspectives on non-invasive glucose sensors
US20190380630A1 (en) Noninvasive mid-infrared in vivo glucose sensor
US10779755B2 (en) Non-invasive blood sugar measurement method and device using optical reflectometry
JP2006296660A (en) Biological information measuring method, biological information measuring optical element and biological information measuring apparatus
US11892400B1 (en) Reflective depth interrogation for analyte measurement in liquids
Ye Near-infrared spectroscopic sensing of important metabolic biomarkers for people with type I diabetes

Legal Events

Date Code Title Description
AS Assignment

Owner name: ZYOMED CORP., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GULATI, SANDEEP;GEORGE, THOMAS;RUCHTI, TIMOTHY;AND OTHERS;SIGNING DATES FROM 20150402 TO 20150409;REEL/FRAME:035737/0519

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION