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

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 toFIG. 1, ananalyzer100 is illustrated. The analyzer comprises at least: alight source system110, aphoton transport system120, adetector system130, and adata processing system140. In use theanalyzer100 estimates and/or determines a physical property, a sample state, a constituent property, and/or a concentration of an analyte.
Patient/Reference
• Still referring toFIG. 1, an example of theanalyzer100 is presented. In this example, theanalyzer100 includes asample interface150, which interfaces to areference material160 and/or to a subject170. Herein, for clarity of presentation a subject170 in the examples is representative of a person, animal, a prepared sample, and/or patient. In practice, theanalyzer100 is used by a user to analyze the user, referred to herein as a subject170, and is used by a medical professional to analyze a patient.
Controller
• Still referring toFIG. 1, theanalyzer100 optionally includes asystem controller180. Thesystem controller180 is used to control one or more of: thelight source system110 or alight source112 thereof, thephoton transport system120, thedetector system130 or adetector132 thereof, thesample interface150, position of thereference160 relative to thesample interface150, position of the subject170 relative to thesample interface150, and communication to anoutside system190, such as asmart phone192, and/or aremote system194 using awireless communication system196 and/or hardwired communication system198. For example, the remote system includes a data processing system, a data storage system, and/or a data organization system.
• Still referring toFIG. 1, theoptional system controller180 operates in any of a predetermined manner or in communication with thedata processing system140. In the case of operation in communication with thedata processing system140, the controller generates control statements using data and/or information about the current state of theanalyzer100, current state of a surroundingenvironment162 outside of theanalyzer100, information generated by thedata processing system140, and/or input from a sensor, such as asample interface sensor152 or anauxiliary system10 or anauxiliary sensor12 thereof. Herein, theauxiliary system10 is any system providing input to theanalyzer100.
• Still referring toFIG. 1, theoptional system controller180 is used to control: photon intensity of photons from the source using anintensity controller122, wavelength distribution of photons from thesource110 using awavelength controller124, and/or physical routing of photons from thesource110 using aposition controller126.
• Still referring toFIG. 1, for clarity of presentation the optionaloutside system190 is illustrated as using asmart phone192. However, thesmart phone192 is optionally a cell phone, a tablet computer, a computer network, and/or a personal computer. Similarly, thesmart phone192 also refers to a feature phone, a mobile phone, a portable phone, and/or a cell phone. Generally, thesmart phone192 includes hardware, software, and/or communication features carried by an individual that is optionally used to offload requirements of theanalyzer100. For example, thesmart phone192 includes a user interface system, a memory system, a communication system, and/or a global positioning system. Further, thesmart phone192 is optionally used to link to theremote system194, 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 subject170 is performed using thesmart phone192. In yet another example, the analyzer gathers information from at least oneauxiliary sensor12 and relays that information and/or a processed form of that information to thesmart phone192, where the auxiliary sensor is not integrated into theanalyzer100.
Source
• Herein, thesource system110 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 toFIG. 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 toFIG. 2, aphoton transit system200 through skin layers of the subject170 is illustrated. In this example, thephoton transport system120 guides light from asource112 of thesource system110 to the subject170. Optionally, acontact gap210 is present between a last optic of thephoton transport system120 and skin of the subject170. Further, in this example, thephoton transport system120 irradiates skin of the subject170 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 subject170 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 subject170 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 thedetector system130 gathers the traversing or diffusely reflected photons. Various photons traversing or diffusely scattering through the skin encounter anepidermis173 or epidermis layer, adermis174 or dermis layer, andsubcutaneous fat176 or a subcutaneous fat layer. As depicted inFIG. 2, the diffuse reflectance of the various photons through the skin detected by thedetection system130 follow a variety of optical paths through the tissue, such as shallow paths through theepidermis173, deeper paths through theepidermis173 anddermis174, and still deeper paths through theepidermis173,dermis174, andsubcutaneous fat176. However, for a large number of photons, there exists a mean photon path for photons from entering the skin that are detected by thedetection system130.
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 theanalyzer100.
• 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 thedata processing system140. 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 toFIG. 3, thephoton transit system200 ofFIG. 2 is illustrated where thephoton transport system110 irradiates the skin of the subject170 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 toFIG. 4, thephoton transit system200 uses a vector or array ofillumination sources400, of thesource system110, 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 sevenfiber optics401,402,403,404,405,406,407 are positioned, radially along the x,y plane of the subject170 to provide a set of illuminations zones, relative to a detection fiber at a detection zone. As illustrated the thirdillumination fiber optic403/detector132 combination yields a mean photon path having a third depth of penetration, d₃, for a third fiber optic-to-detector radial distance, r₃; the fifthillumination fiber optic405/detector132 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 seventhillumination fiber optic407/detector132 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 toFIG. 5, thephoton transit system200 uses a vector or array ofdetectors500 in thedetection system130. 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 sevendetectors501,502,503,504,505,506,507 are positioned, radially along the x,y plane to provide a set of detection zones, relative to an illumination zone. As illustrated thesource112/second detector502 combination yields a mean photon path having a second depth of penetration, d₂, for a second source-to-detector radial distance, r₂; thesource112/fourth detector504 combination yields a mean photon path having a fourth depth of penetration, d₄, for a fourth source-to-detector radial distance, r₄; and thesource112/sixth detector506 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 toFIGS. 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 toFIGS. 6A-D, an example of a temporally resolvedgating system600 is illustrated. Generally, in thetemporal gating system600 the time of flight of a photon is used to determine the pathlength, b. Referring now toFIG. 6A, at an initial time, t₀, aninterrogation pulse610 of one or more photons is introduced to the sample, which herein is skin of the subject170. Theinterrogation pulse610 is also referred to as a pump pulse or as a flash of light. At one or more subsequentgated detection times620, after passing through the sample theinterrogation pulse610 is detected. As illustrated, the gated detection times are at afirst time622, t₁; asecond time624, t₂; athird time626, t₃; and at an n^thtime628, t_n, where n is a positive number. Optionally, thegated detection times620 overlap. For the near-infrared spectral region, the elapsed time used to detect theinterrogation photons610 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:
• $\begin{array}{cc}\mathrm{OPD}=\frac{c}{n}\left(b\right)& \left(\mathrm{eq}.2\right)\end{array}$
• 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 toFIG. 6B, illustrative paths of the photons for the firstgated detection time622 are provided. A first path, p_1a; second path, p_1b; and third path, p_1c, 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 toFIG. 6C, illustrative paths of the photons for the secondgated detection time624 are provided. A first path, p_2a; second path, p_2b; and third path, p_2c, 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 secondgated detection time624 is twice as long as the firstgated detection time622, then the second pathlength, p₂, for the secondgated detection time624 is twice as long as the first pathlength, p₁, for the firstgated detection time622. 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. 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 toFIG. 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, 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. 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 thedata processing system140 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 subject170. 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 subject170 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, ananalyzer100 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 thedata processing system140. 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 subject170 as a function of distance from a detection zone.
• Referring now toFIG. 7A, an example of a fiberoptic interface system700 of theanalyzer100 to the subject170 is provided, which is an example of thesample interface system150. Light from thesource system110 of theanalyzer100 is coupled into a fiberoptic illumination bundle714 of afiber optic bundle710. The fiberoptic illumination bundle714 guides light to asample site178 of the subject170. Thesample site178 has a surface area and a sample volume. In a first case, asample interface tip716 of thefiber optic bundle710 contacts the subject170 at thesample site178. In a second case, thesample interface tip716 of thefiber optic bundle710 proximately contacts the subject170 at thesample site178, but leaves agap720 between thesample interface tip716 of thefiber optic bundle710 and the subject170. In one instance, thegap720 is filled with a contact fluid and/or an optical contact fluid. In a second instance, thegap720 is filled with air, such as atmospheric air. Light transported by thefiber optic bundle710 to the subject170 interacts with tissue of the subject170 at thesample site178. A portion of the light interacting with the sample site is collected with one or more fiberoptic collection fibers718, which is optionally and preferably integrated into thefiber optic bundle710. As illustrated, asingle collection fiber718 is used. Thecollection fiber718 transports collected light to thedetector132 of thedetection system130.
• Referring now toFIG. 7B, a first example of a sample sidelight collection end716 of thefiber optic bundle710 is illustrated. In this example, thesingle collection fiber718 is circumferentially surrounded by anoptional spacer730, where the spacer has an average radial width of less than about 200, 150, 100, 50, or 25 micrometers. Theoptional spacer730 is circumferentially surrounded by a set of fiberoptic elements713. As illustrated, the set of fiberoptic elements713 are arranged into a set of radial dispersed fiber optic rings, such as afirst ring741, asecond ring742, athird ring743, afourth ring744, and an n^thring745, where n comprises a positive integer of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the fiberoptic elements713 are in any configuration, such as in a close-packed configuration about thecollection fiber718 or in an about close-packed configuration about thecollection fiber718. The distance of each individual fiber optic of the set of fiberoptic elements713, or light collection element, from the center of thecollection fiber718 is preferably known.
• Referring now toFIG. 7C, a second example of the sample sidelight collection end716 of thefiber optic bundle710 is provided. In this example, the centrally positionedcollection fiber718 is circumferentially surrounded by a set ofspacer fibers750. 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. Thespacer fibers750 are circumferentially surrounded by the radially dispersed fiber optic rings, such as thefirst ring741, thesecond ring742, thethird ring743, thefourth ring744, and the n^thring745. Optionally, fiber diameters of thespacer fibers750 are at least ten, twenty, or thirty percent larger or smaller than fiber diameters of the set of fiberoptic elements713. Further, optionally the fiberoptic elements713 are arranged in any spatial configuration radially outward from thespacer fibers750. More generally, the set of fiberoptic elements713 and/orspacer fibers750 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 toFIG. 8A-8C, a system forspatial illumination800 of thesample site178 of the subject170 is provided. Thespatial illumination system800 is used to control distances between illumination zones and detection zones as a function of time.
• Referring now toFIG. 8A, a third example of the sample sidelight collection end716 of thefiber optic bundle710 is provided. In this example, thecollection fiber718 or collection optic is circumferentially surrounded by the set of fiberoptic elements713 or irradiation points on the skin of the subject170. For clarity of presentation and without loss of generality, the fiberoptic elements713 are depicted in a set of rings radially distributed from thecollection fiber718. However, it is understood that the set offiber optics713 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 fiberoptic elements713 from thecollection fiber718 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 toFIG. 8B, an example of alight input end712 of thefiber optic bundle710 is provided. In this example, individual fibers of the set offiber optics713 having the same or closely spaced radial distances from thecollection fiber718 are grouped into a set of fiber optic bundles or a set offiber optic bundlets810. As illustrated, the seven fibers in the first ring circumferentially surrounding thecollection fiber718 are grouped into afirst bundlet811. Similarly, the sixteen fibers in the second ring circumferentially surrounding thecollection fiber718 are grouped into asecond bundlet812. Similarly, the fibers from the third, fourth, fifth, and sixth rings about thecollection fiber718 at the sampleside illumination end716 of thefiber bundle710 are grouped into athird bundlet813, afourth bundlet814, afifth bundlet815, and asixth bundlet816, respectively. For clarity of presentation, the individual fibers are not illustrated in the second, third, fourth, fifth, andsixth bundlets812,813,814,815,816. Individual bundles and/or individual fibers of the set of fiberoptic bundlets810 are optionally selectively illuminated using amask820, described infra.
• Referring now toFIG. 8C andFIG. 7A, amask wheel830 is illustrated. Generally, themask wheel830 rotates, such as through use of awheel motor820. As a function of mask wheel rotation position, holes or apertures through themask wheel830 selectively pass light from thesource system110 to the fiberoptic input end712 of thefiber optic bundle710. 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 theinput end712 of the fiber optic bundle or (2) individual bundlets of the set offiber optic bundlets810. Optionally an encoder ormarker section840 of themask wheel830 is used for tracking, determining, and/or validating wheel position in use.
• Still referring toFIG. 80, an example of use of themask wheel830 to selectively illuminate individual bundlets of the set offiber optic bundlets810 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. Thefirst mask position821 figuratively illustrates an aperture passing light from thesource system110 to thefirst bundlet811 while blocking light to the second through sixth bundlets812-816. At a second point in time, themask wheel830 is rotated such that a second mask position, p₂,822 is aligned with theinput end712 of thefiber optic bundle710. As illustrated, at the second point in time, themask wheel830 passes light from theillumination system110 to thesecond bundlet812, while blocking light to thefirst bundlet811 and blocking light to the third through six bundlets813-816. Similarly, at a third point in time the mask wheel uses a third mask position, p₃,823 to selectively pass light into only thefifth bundlet815. Similarly, at a fourth point in time the mask wheel uses a fourth mask position, p₄,824 to selectively pass light into only thesixth bundlet816.
• Still referring toFIG. 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, themask wheel830 is rotated such that a fifth mask position, p₅,825 is aligned with theinput end712 of thefiber optic bundle710. As illustrated, at the fifth point in time, themask wheel830 passes light from theillumination system110 to all of (1) thesecond bundlet812, (2) thethird bundlet813, and (3) thefourth bundlet814, while blocking light to all of (1) thefirst bundlet811, (2) thefifth bundlet815, and (3) thesixth bundlet816. Similarly, at a sixth point in time a sixth mask position, p₆,826 of themask wheel830 passes light to the second through fifth bundlets812-815 while blocking light to both thefirst bundlet811 andsixth bundlet816.
• In practice, themask wheel830 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 offiber optics713 and/or (2) bundlets810 of the set offiber optic optics713. 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 offiber optics713. 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 subject170 as a function of time. The various illumination zones alter the effectively probedsample site178 or region of the subject170.
Adaptive Subject Measurement
• Referring now toFIG. 9A andFIG. 9B, examples of use of thespatial illumination system800 is illustrated for afirst subject171 and asecond subject172. However, more generally thephoton transport system120 inFIGS. 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 toFIG. 9A,FIG. 8A, andFIG. 8C, an example of application of thespatial illumination system800 to thefirst subject171 is provided. At a first point in time, the first position, p₁,821 of thefilter wheel830 is aligned with thelight input end712 of the fiber bundle, which results in the light from thefirst bundlet811, which corresponds to thefirst ring741, irradiating thesample site178 at a first radial distance, r₁, and a first depth, d₁, which as illustrated inFIG. 9A has a mean optical path through the epidermis. Similarly, at a second point in time, thefilter wheel830 at thesecond position822 passes light to thesecond bundlet812, which corresponds to the second ring, irradiating thesample site178 at a second increased distance and a second increased depth, which as illustrated inFIG. 9A has a mean optical path through the epidermis and dermis. Similarly, results of interrogation of the subject170 with light passed through the six illustrative fiber illumination rings inFIG. 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 toFIG. 9B andFIG. 8A, an example of application of thespatial illumination system800 to thesecond subject172 is provided. Results of interrogation of the subject170 with light passed through the six illustrative fiber illumination rings inFIG. 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 thesecond subject172 has a deepest penetration depth into thedermis174. Hence, the fifth radial fiber ring, f₅, yields photons probing thesubcutaneous fat176 for thefirst subject171 and yields photons probing thedermis174 of thesecond subject172. Hence, for a water soluble analyte and/or a blood borne analyte, such as glucose, theanalyzer100 is more optimally configured to not use both the fifth fiber ring, f₅, and the sixth fiber ring, f₆, for thefirst subject171. However,analyzer100 is more optimally configured to not use only the sixth fiber ring, f₆, for thesecond subject172, 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 n^thgated 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 toFIG. 9A andFIG. 9B, a first optional two-phase measurement approach is herein described. Optionally, during a first sample mapping phase, thephoton transport system120 provides interrogation photons to a particular test subject at controlled, but varying, radial distances from thedetection system130. 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 thedata processing system140 selecting how to illuminate/irradiate the subject170. Subsequently, during a second data collection phase, thesystem controller180 controls thephoton transport system120 to deliver photons over selected conditions to the subject170. For clarity, several illustrative examples are provided, infra.
• In a first example, a first spectral marker is optionally related to the absorbance of thesubcutaneous fat176 for thefirst subject171. During the first sample mapping phase, the fifth and sixth radial positions of the fiber probe illustrated inFIG. 8A, yield collected signals for thefirst subject171 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 thedermis174, such as a protein absorbance band or an algorithmic/mathematical representation thereof. Hence, thedata processing system140 yields a result that the fifth and sixth radial fiber optic rings or distance of thefiber bundle170 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 thesecond subject172. The first sample mapping phase indicates that for the second subject, the sixth radial illumination ring of the fiber bundle illustrated inFIG. 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 subject170 does not move away from thesample interface150 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, thesample interface tip716 of thefiber optic bundle710 includes optics that change the mean incident light angle of individual fibers of thefiber optic bundle716 as they first hit the subject170. For example, a first optic at the end of a fiber in thefirst ring741 aims light away from thecollection fiber optic718; a second optic at the end of a fiber in thesecond ring742 aims light nominally straight into the sample; and a third optic at the end of a fiber in thethird ring742 aims light toward thecollection fiber718. 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 1, wherein said analyzer further comprises:

a sample interface configured to not contact the subject during collection of the signal.

10. The apparatus ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 14, wherein said step of processing estimates a molar absorptivity of the subject.

17. The method ofclaim 14, further comprising the step of:

adapting an optical configuration of the analyzer using the molar absorptivity.

18. The method ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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 ofclaim 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.

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