US20150018646A1 - Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof - Google Patents
Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof Download PDFInfo
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Abstract
A noninvasive analyzer apparatus and method of use thereof is described using a sample mapping phase to establish one or more analyzer/software parameters used in a subsequent individual and/or group specific data collection phase. For example, in the sample mapping phase distance between incident and collected light is varied as a function of time for collected noninvasive spectra. Spectra collected in the sample mapping phase are analyzed to determine a physiological property of the subject, such as dermal thickness, hydration, collagen density, epidermal thickness, and/or subcutaneous fat depth. Using the physiological property or measure thereof, the analyzer is optically reconfigured for the individual to yield subsequent spectra having enhanced features for noninvasive analyte property determination. Similarly, in the mapping and/or collection phase, the incident light is varied in time in terms of any of: sample probe position, incident light solid angle, incident light angle, depth of focus, energy, and/or intensity.
Description
- This application is:
-
- a continuation-in-part of U.S. patent application Ser. No. 13/941,389 filed Jul. 12, 2013, which:
- is a continuation-in-part of U.S. patent application Ser. No. 13/941,369 filed Jul. 12, 2013, which claims the benefit of U.S. provisional patent application No. 61/672,195 filed Jul. 16, 2012; and
- claims the benefit of U.S. provisional patent application No. 61/700,291 filed Sep. 12, 2012; and
- claims the benefit of 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.
- a continuation-in-part of U.S. patent application Ser. No. 13/941,389 filed Jul. 12, 2013, which:
- The present invention relates to a noninvasive analyzer using a sample mapping phase to generate instrumentation setup parameters followed by a subject specific data collection phase using the configured instrument.
- 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.
- 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.
- The structure of skin varies widely among individuals as well as between different skin sites on a single individual. The skin has layers, including: (1) a stratum corneum of flat, dehydrated, biologically inactive cell about 10 to 20 micrometers thick; (2) a stratified epidermis, of about 10 to 150 micrometers thickness, formed and continuously replenished by slow upward migration of keratinocyte cells from the germinative basal layer of the epidermis; (3) an underlying dermis of connective fibrous protein, such as collagen, and a blood supply, which form a layer of 0.5 to 4.0 millimeters in thickness with an average thickness of about 1.2 millimeters; and (4) a underlying fatty subcutaneous layer or adipose tissue.
- Garside, J., et. al., “Fiber Optic Illumination and Detection Patterns, Shapes, and Locations for use in Spectroscopic Analysis”, U.S. Pat. No. 6,411,373 (Jun. 25, 2002) describe software and algorithms to design fiber optic excitation and/or collection patterns in a sample probe.
- Maruo, K., et. al., “Device for Non-Invasive Determination of Glucose Concentration in Blood”, European patent application no. EP 0843986 B1 (Mar. 24, 2004) described the use of light projecting fiber optics in the range of 0.1 to 2 millimeters from light receiving fiber optics at the contacted fiber optic bundle/sample interface.
- Rennert, J., et. al., “Non-Invasive Method of Determining Skin Thickness and Characterizing Layers of Skin Tissue In Vivo”, U.S. Pat. No. 6,456,870 B1 (Sep. 24, 2002) described the use of near-infrared absorbance spectra to determine overall thickness of skin tissue and layer-by-layer thickness of skin tissue.
- Ruchti, T. L., et. al., “Classification System for Sex Determination and Tissue Characterization”, U.S. Pat. No. 6,493,566 B1 (Dec. 10, 2002) describe the near-infrared tissue measurements to yield predictions consisting of gender and one or more of thickness of a dermis, collagen content, and amount of subcutaneous fat.
- Mattu, M., et. al., “Classification and Screening of Test Subjects According to Optical Thickness of Skin”, U.S. Pat. No. 6,738,652 B2 (May 18, 2004) describe the use of near-infrared reflectance measurements of skin to determine the optical thickness of skin through analysis of water, fat, and protein marker bands.
- Abul-Haj, A., et. al., “Method and Apparatus for Noninvasive Targeting”, U.S. patent application no. US 2006/0217602 A1 (Sep. 28, 2006) describe a sample probe interface method and apparatus for targeting a tissue depth and/or pathlength that is used in conjunction with a noninvasive analyzer to control spectral variation.
- Welch, J. M., et. al., “Method and Apparatus for Noninvasive Probe/Skin Tissue Contact Sensing”, WIPO International publication no. WO 2008/058014 A2 (May 15, 2008) describe a method and apparatus for determining proximity and/or contact of an optical probe with skin tissue.
- What is needed is a noninvasive glucose concentration analyzer having precision and accuracy suitable for treatment of diabetes mellitus.
- The invention comprises a noninvasive analyzer apparatus having dynamic control of distance between a plurality of irradiation zones and a detection zone and a method of use thereof.
- 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; -
FIG. 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 ; -
FIG. 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 ; -
FIG. 8A illustrates a third example sample interface end of the fiber optic bundle andFIG. 8B illustrates a mask; -
FIG. 9 illustrates a mask selection wheel; -
FIG. 10A illustrates a position selection optic;FIG. 10B illustrates the position selection optic selecting position;FIG. 10C illustrates solid angle selection using the position selection optic; andFIG. 10D illustrates radial control of incident light relative to a detection zone; -
FIG. 11(A-B) illustrate a pathlength resolved sample interface for (1) a first subject,FIG. 11A and (2) a second subject,FIG. 11B ; -
FIG. 12 provides a method of use of a data processing system; and -
FIG. 13 provides a method of using a sample mapping phase and a subsequent subject specific data collection phase. - 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.
- The invention comprises an apparatus and method of use thereof for acquisition of noninvasive mapping spectra of skin and to reconfigure the apparatus based upon the mapping spectra for subsequent subject specific data collection.
- For example, a near-infrared noninvasive analyzer is configured with a first optical configuration used to map an individual and/or group of individuals through use of mapping spectra. The mapping spectra are analyzed and used to reconfigure the optical setup of the analyzer to a second optical configuration suited to the individual and/or group of individuals. Subsequently, collection of noninvasive spectra of the individual and/or group of individuals is performed using the second optical configuration, which is preferably optimized to yield additional information based on the skin of the individual and/or group of individuals.
- In another embodiment, a data processing system analyzes data from an analyzer to estimate and/or determine an analyte property, such as concentration using multiple types of data, such as from an external sensor, from two or more radial positions, and/or with two of more focusing depths.
- In still another embodiment, an analyzer using light interrogates the sample using one or more of:
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- a spatially resolved system;
- an incident light radial distance resolved system;
- a controllable and variable incident light solid angle system; and
- a controllable and variable incident light angle 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;
- collection of spectra with varying radial distances between incident light entering skin and detected light exiting the skin;
- an incident angle resolved system; and
- a collection angle resolved system.
- a spatially 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 yet 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 still yet another embodiment, a data processing system uses information related to contact pressure on a tissue sample site.
- In 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.
- In still yet another 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.
- 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. If necessary, 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.
- Referring now to
FIG. 1 , ananalyzer 100 is illustrated. The analyzer comprises at least: alight source system 110, aphoton transport system 120, adetector system 130, and adata processing system 140. In use theanalyzer 100 estimates and/or determines a physical property, a sample state, a constituent property, and/or a concentration of an analyte. - Still referring to
FIG. 1 , an example of theanalyzer 100 is presented. In this example, theanalyzer 100 includes asample interface 150, which interfaces to areference 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, theanalyzer 100 is used by a user to analyze the user, referred to as the subject 170, the subject 170 and is used by a medical professional to analyze a patient. - Still referring to
FIG. 1 , theanalyzer 100 optionally includes asystem controller 180. Thesystem controller 180 is used to control one or more of: thelight source system 110 or alight source 112 thereof, thephoton transport system 120, thedetector system 130 or adetector 132 thereof, thesample interface 150, position of thereference 160 relative to thesample interface 150, position of the subject 170 relative to thesample interface 150, and communication to anoutside system 190, such as asmart phone 192, and/or aremote system 194 using awireless communication system 196 and/or hardwired 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 , theoptional system controller 180 operates in any of a predetermined manner or in communication with thedata processing system 140. In the case of operation in communication with thedata processing system 140, the controller generates control statements using data and/or information about the current state of theanalyzer 100, current state of a surroundingenvironment 162 outside of theanalyzer 100, information generated by thedata processing system 140, and/or input from a sensor, such as asample interface sensor 152 or anauxiliary system 10 or anauxiliary sensor 12 thereof. Herein, theauxiliary system 10 is any system providing input to theanalyzer 100. - Still referring to
FIG. 1 , theoptional system controller 180 is used to control: photon intensity of photons from the source using anintensity controller 122, wavelength distribution of photons from thesource 110 using awavelength controller 124, and/or physical routing of photons from thesource 110 using aposition controller 126. - Still referring to
FIG. 1 , for clarity of presentation the optionaloutside system 190 is illustrated as using asmart phone 192. However, thesmart phone 192 is optionally a cell phone, a tablet computer, a computer network, and/or a personal computer. Similarly, thesmart phone 192 also refers to a feature phone, a mobile phone, a portable phone, and/or a cell phone. Generally, thesmart phone 192 includes hardware, software, and/or communication features carried by an individual that is optionally used to offload requirements of theanalyzer 100. For example, thesmart phone 192 includes a user interface system, a memory system, a communication system, and/or a global positioning system. Further, thesmart phone 192 is optionally used to link to theremote 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 thesmart phone 192. In yet another example, the analyzer gathers information from at least oneauxiliary sensor 12 and relays that information and/or a processed form of that information to thesmart phone 192, where the auxiliary sensor is not integrated into theanalyzer 100. - 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. - 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 , aphoton transit system 200 through skin layers of the subject 170 is illustrated. In this example, thephoton transport system 120 guides light from asource 112 of thesource system 110 to the subject 170, optionally with anair gap 210 between a last optic of an illumination system and skin of the subject 170. Further, in this example, thephoton 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 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 system 130 gathers the traversing or diffusely reflected photons. Various photons traversing or diffusely scattering through the skin encounter anepidermis 173 or epidermis layer, adermis 174 or dermis layer, andsubcutaneous fat 176 or a subcutaneous fat layer. As depicted inFIG. 2 , the diffuse reflectance of the various photons through the skin detected by thedetection system 130 follow a variety of optical paths through the tissue, such as shallow paths through theepidermis 173, deeper paths through theepidermis 173 anddermis 174, and still deeper paths through theepidermis 173,dermis 174, andsubcutaneous 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 thedetection system 130. - 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: -
AαbC (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.
- 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 delivered, simultaneously and/or as a function of time, 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 one or more detection zones are used to detect the photons directed to the series of input zones, simultaneously and/or as a function of time. - 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, similar 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 , thephoton transit system 200 ofFIG. 2 is illustrated where thephoton 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 , thephoton transit system 200 uses a vector or array ofillumination sources 400, of thesource 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 sevenfiber optics 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 fifthillumination 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 seventhillumination 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 , thephoton transit system 200 uses a vector or array ofdetectors 500 in thedetection 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 sevendetectors 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; thesource 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 thesource 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, where light enters skin of the subject 170, from one or more source elements, is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100 or more and the number of detection zones, where light exiting the skin of the subject 170 is detected by one or more detection elements and/or systems, is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100, 500, 1000, 5000, 10,000, 50,000 or more. - 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 resolvedgating system 600 is illustrated. Generally, in thetemporal gating system 600 the time of flight of a photon is used to determine the pathlength, b. Referring now toFIG. 6A , at an initial time, t0, aninterrogation pulse 610 of one or more photons is introduced to the sample, which herein is skin of the subject 170. Theinterrogation pulse 610 is also referred to as a pump pulse or as a flash of light. At one or more subsequentgated detection times 620, after passing through the sample theinterrogation pulse 610 is detected. As illustrated, the gated detection times are at afirst time 622, t1; asecond time 624, t2; athird time 626, t3; and at an nth time 628, tn, where n is a positive number. Optionally, thegated detection times 620 overlap. For the near-infrared spectral region, the elapsed time used to detect theinterrogation 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: -
- 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 between photon launch and photon detection where the pathlength of photons in the sample is related to elapsed time, optionally with one or more additional variables related to one or more refractive indices.
- Referring now to
FIG. 6B , illustrative paths of the photons for the firstgated 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 secondgated 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 secondgated detection time 624 is twice as long as the firstgated detection time 622, then the second pathlength, p2, for the secondgated detection time 624 is twice as long as the first pathlength, p1, for the firstgated 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, elapsed times between a pulse of incident photon delivery and time gated detection are in a range between 100 nanoseconds and 100 picoseconds, such as about 1, 5, 10, and 50 picoseconds. - 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. - 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.
- 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 thedata 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 fiberoptic interface system 700 of theanalyzer 100 to the subject 170 is provided, which is an example of thesample interface system 150. Light from thesource system 110 of theanalyzer 100 is coupled into a fiberoptic illumination bundle 714 of afiber optic bundle 710. The fiberoptic illumination bundle 714 guides light to asample site 178 of the subject 170. Thesample site 178 has a surface area and a sample volume. In a first case, asample interface tip 716 of thefiber optic bundle 710 contacts the subject 170 at thesample site 178. In a second case, thesample interface tip 716 of thefiber optic bundle 710 proximately contacts the subject 170 at thesample site 178, but leaves agap 720 between thesample interface tip 716 of thefiber optic bundle 710 and the subject 170. In one instance, thegap 720 is filled with a contact fluid and/or an optical contact fluid. In a second instance, thegap 720 is filled with air, such as atmospheric air. Light transported by thefiber optic bundle 710 to the subject 170 interacts with tissue of the subject 170 at thesample site 178. A portion of the light interacting with the sample site is collected with one or more fiberoptic collection fibers 718, which is optionally and preferably integrated into thefiber optic bundle 710. As illustrated, asingle collection fiber 718 is used. Thecollection fiber 718 transports collected light to thedetector 132 of thedetection system 130. - Referring now to
FIG. 7B , a first example of a sample sidelight collection end 716 of thefiber optic bundle 710 is illustrated. In this example, thesingle collection fiber 718 is circumferentially surrounded by anoptional spacer 730, where the spacer has an average radial width of less than about 200, 150, 100, 50, or 25 micrometers. Theoptional spacer 730 is circumferentially surrounded by a set of fiberoptic elements 713. As illustrated, the set of fiberoptic elements 713 are arranged into a set of radial dispersed fiber optic rings, such as afirst ring 741, asecond ring 742, athird ring 743, afourth 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 fiberoptic elements 713 are in any configuration, such as in a close-packed configuration about thecollection fiber 718 or in an about close-packed configuration about thecollection fiber 718. The distance of each individual fiber optic of the set of fiberoptic elements 713, or light collection element, from the center of thecollection fiber 718 is preferably known. - Referring now to
FIG. 7C , a second example of the sample sidelight collection end 716 of thefiber optic bundle 710 is provided. In this example, the centrally positionedcollection fiber 718 is circumferentially surrounded by a set ofspacer 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. Thespacer fibers 750 are circumferentially surrounded by the radially dispersed fiber optic rings, such as thefirst ring 741, thesecond ring 742, thethird ring 743, thefourth ring 744, and the nth ring 745. Optionally, fiber diameters of thespacer fibers 750 are at least ten, twenty, or thirty percent larger or smaller than fiber diameters of the set of fiberoptic elements 713. Further, optionally the fiberoptic elements 713 are arranged in any spatial configuration radially outward from thespacer fibers 750. More generally, the set of fiberoptic elements 713 and/orspacer 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. - Referring now to
FIG. 8A ,FIG. 8B andFIG. 9 , andFIGS. 10 A-D a system forspatial illumination 800 of thesample site 178 of the subject 170 is provided. Thespatial illumination system 800 is used to control distances between illumination zones and detection zones as a function of time. In a first case, light is distributed radially relative to a detection zone using a fiber optic bundle. In a second case, light is distributed radially relative to a detection zone using a reflective optic system and/or a lens system. Generally, the first case and second case are non-limiting examples of radial distribution of light about one or more detection zones as a function of time. - Referring now to
FIG. 8A , a third example of the sample sidelight collection end 716 of thefiber optic bundle 710 is provided. In this example, thecollection fiber 718 or collection optic is circumferentially surrounded by the set of fiberoptic elements 713 or irradiation points on the skin of the subject 170. For clarity of presentation and without loss of generality, the fiberoptic elements 713 are depicted in a set of rings radially distributed from thecollection fiber 718. However, it is understood that the set offiber 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 fiberoptic elements 713 from thecollection 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 alight input end 712 of thefiber optic bundle 710 is provided. In this example, individual fibers of the set offiber optics 713 having the same or closely spaced radial distances from thecollection fiber 718 are grouped into a set of fiber optic bundles or a set offiber optic bundlets 810. As illustrated, the seven fibers in the first ring circumferentially surrounding thecollection fiber 718 are grouped into afirst bundlet 811. Similarly, the sixteen fibers in the second ring circumferentially surrounding thecollection fiber 718 are grouped into asecond bundlet 812. Similarly, the fibers from the third, fourth, fifth, and sixth rings about thecollection fiber 718 at the sampleside illumination end 716 of thefiber bundle 710 are grouped into athird bundlet 813, afourth bundlet 814, afifth bundlet 815, and asixth bundlet 816, respectively. For clarity of presentation, the individual fibers are not illustrated in the second, third, fourth, fifth, andsixth bundlets optic bundlets 810 are optionally selectively illuminated using amask 820, described infra. - Referring now to
FIG. 9 andFIG. 7A , amask wheel 830 is illustrated. Generally, themask wheel 830 rotates, such as through use of awheel motor 820. As a function of mask wheel rotation position, holes or apertures through themask wheel 830 selectively pass light from thesource system 110 to the fiberoptic input end 712 of thefiber 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 theinput end 712 of the fiber optic bundle or (2) individual bundlets of the set offiber optic bundlets 810. Optionally an encoder ormarker section 840 of themask wheel 830 is used for tracking, determining, and/or validating wheel position in use. - Still referring to
FIG. 9 , an example of use of themask wheel 830 to selectively illuminate individual bundlets of the set offiber 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. Thefirst mask position 821 figuratively illustrates an aperture passing light from thesource system 110 to thefirst bundlet 811 while blocking light to the second through sixth bundlets 812-816. At a second point in time, themask wheel 830 is rotated such that a second mask position, p2, 822 is aligned with theinput end 712 of thefiber optic bundle 710. As illustrated, at the second point in time, themask wheel 830 passes light from theillumination system 110 to thesecond bundlet 812, while blocking light to thefirst 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 thefifth 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 thesixth bundlet 816. - Still referring to
FIG. 9 , 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 wheel 830 is rotated such that a fifth mask position, p5, 825 is aligned with theinput end 712 of thefiber optic bundle 710. As illustrated, at the fifth point in time, themask wheel 830 passes light from theillumination system 110 to all of (1) thesecond bundlet 812, (2) thethird bundlet 813, and (3) thefourth bundlet 814, while blocking light to all of (1) thefirst bundlet 811, (2) thefifth bundlet 815, and (3) thesixth bundlet 816. Similarly, at a sixth point in time a sixth mask position, p6, 826 of themask wheel 830 passes light to the second through fifth bundlets 812-815 while blocking light to both thefirst bundlet 811 andsixth 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 offiber optics 713 and/or (2) bundlets 810 of the set offiber 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 offiber 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 probedsample site 178 or region of the subject 170. - Radial Position Using a Mirror and/or Lens System
- Referring now to
FIG. 10 , a dynamically positionedoptic system 1000 for directing incident light to a radially changing position about a collection zone is provided. - Referring now to
FIG. 10A , amirror 1010 is illustrative of any mirror, lens, mirror system, and/or lens system used to dynamically and positionally direct incident light to one or more illumination zones of the subject 170 relative to one or more detection zones and/or volumes monitored by thephoton transport system 120 and/or thedetector system 130. - Still more generally, the
data processing system 140 and/or thesystem controller 180 optionally control one or more optics, figuratively illustrated as themirror 1010, to dynamically control incident light 711 on the subject 170 relative to a detection zone on the subject 170 that combine to form thesample site 178 through control of one or more of: -
- x-axis position of the incident light on the subject 170;
- y-axis position of the incident light on the subject 170;
- solid angle of the incident light on a single fiber of the
fiber bundle 710; - solid angle of incident light on a set of fibers of the
fiber bundle 710; - a cross-sectional diameter or width of the incident light;
- an incident angle of the incident light on the subject 170 relative to an axis perpendicular to skin of the subject 170 where the incident light interfaces to the subject 170;
- focusing of the incident light; and/or
- depth of focus of the incident light on the subject 170.
- Several examples are provided, infra, to further illustrate the use of the
system controller 180 to control shape, position, and/or angle of theincident light 711 reaching a fiber optic bundle, skin of the subject 170, and/or an element of thephoton transport system 120. - Referring again to
FIG. 10A , an example is provided of light directed by thephoton transport system 120 from thesource system 110 to the subject directly, through one or more fiber optic of thefiber optic bundle 710, and/or through thephoton transport system 120. However, orientation of themirror 1010 is varied as a function of time relative to an incident set of photons pathway. For example, themirror 1010 is translated along the x-axis of the mean optical path, is rotated about the y-axis of the mean optical path, and/or is rotated about the z-axis of the mean optical path of theanalyzer 100. For example, a firstmirror movement element 1022, such as a first spring, and a secondmirror movement element 1024, such as a second spring, combine to rotate the mirror about the y-axis as illustrated. Similarly, a thirdmirror movement element 1026, such as a third spring, and a fourthmirror movement element 1028, such as a fourth spring, combine to rotate the mirror about the z-axis as illustrated in the second time position, t2, relative to a first time position, t1. - Referring now to
FIG. 10B , an example of the dynamically positionedoptic system 1000 directing the incident light 711 to a plurality of positions as a function of time is provided. As illustrated, themirror 1010 directs light to thelight input end 712 of thefiber bundle 710. Particularly, theincident light 711 is directed at a first time, t1, to afirst fiber optic 751 and theincident light 711 is directed at a second time, t2, to asecond fiber optic 752 of a set offiber optics 750. However, more generally, the dynamically positionedoptic system 1000 directs the incident light using themirror 1000 to any y-, z-axis position along the x-axis of the incident light as a function of time, such as to any optic and/or to a controlled position of skin of the subject 170. - Referring now to
FIG. 10C , an example of the dynamically positionedoptic system 1000 directing the incident light to a plurality of positions with a controllable and varying as a function of time solid angle is provided. Optionally, the solid angle is fixed as a function of time and the position of the incident light 711 onto thelight input end 712 of thefiber bundle 710 is varied as a function of time. As illustrated, themirror 1010 directs light to thelight input end 712 of thefiber bundle 710 where thefiber bundle 710 includes one or more bundlets, such as the set offiber optic bundlets 810. In this example, the incident light is directed at a first time, t1, with a first solid angle to a first fiber optic bunch or group, such as thefirst bundlet 811, described supra, and at a second time, t2, with a second solid angle to a second fiber optic bunch, such as thesecond bundlet 812, described supra. However, more generally, the dynamically positionedoptic system 1000 directs the incident light to any y-, z-axis position along the x-axis of the incident light as a function of time at any solid angle or with any focusing angle, such as to any optic, any group of optics, and/or to a controlled position and/or size of skin of the subject 170 relative to a detection zone. - Referring now to
FIG. 10D , an example is provided of the dynamically positionedoptic system 1000 directing the incident light to a plurality of positions with a varying incident angle onto skin of the subject 170. As illustrated, themirror 1010 directs light directly to the subject 170 without an optic touching the subject 170 or without touching a coupling fluid on the subject 170. However, alternatively the light is redirected after themirror 1010, such as with a grins lens on a fiber optic element of thefiber optic bundle 710. In this example, the incident light is directed at a first time, t1, with a first incident angle, θ1, and at a second time, t2, with a second incident angle, θ2. However, more generally, the dynamically positionedoptic system 1000 directs the incident light to any y-, z-axis position along the x-axis of the incident light as a function of time at any solid angle, with any focusing depth, and/or an any incident angle, such as to any optic and/or to a controlled position and/or size of skin of the subject 170 relative to a detection zone. In this example, the detection zone is a volume of the subject monitored by thephoton transport system 120 and/or an lens or mirror of thephoton transport system 120 as interacting with thedetector system 130 and a detector therein. - Delivery of the incident light 711 to the subject 170 is optionally varied in time in terms of position, radial position relative to a point of the skin of the subject 170, solid angle, incident angle, depth of focus, energy, and/or intensity. Herein, without limitation a spatial illumination system is used to illustrate the controlled and variable use of incident light.
- Referring now to
FIG. 11A andFIG. 11B , examples of use of aspatial illumination system 1100 are illustrated for afirst subject 171 and asecond subject 172. However, while the examples provided in this section use a fiber optic bundle to illustrate radially controlled irradiation of the sample, the examples are also illustrative of use of the dynamically positionedoptic system 1000 for directing incident light to a radially changing position about a collection zone. Still more generally thephoton transport system 120 inFIGS. 11A and 11B 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. 11A andFIG. 9 , an example of application of thespatial illumination system 800 to thefirst subject 171 is provided. At a first point in time, the first position, p1, 821 of thefilter wheel 830 is aligned with thelight input end 712 of thefiber bundle 710, which results in the light from thefirst bundlet 811, which corresponds to thefirst ring 741, irradiating thesample site 178 at a first radial distance, r1, and a first depth, d1, which as illustrated inFIG. 11A has a mean optical path through the epidermis. Similarly, at a second point in time, thefilter wheel 830 at thesecond position 822 passes light to thesecond bundlet 812, which corresponds to the second ring, irradiating thesample site 178 at a second increased distance and a second increased depth, which as illustrated inFIG. 11A has a mean optical path through the epidermis and dermis. The dynamically positionedoptic system 1000 is optionally used to direct light as a function of time to thefirst position 821 and subsequently to thesecond position 822. Similarly, results of interrogation of the subject 170 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 1Illumination Ring Deepest Tissue Layer Probed 1 Epidermis 2 Dermis 3 Dermis 4 Dermis 5 Subcutaneous Fat 6 Subcutaneous Fat - Referring now to
FIG. 11B andFIG. 8A , an example of application of thespatial illumination system 800 to thesecond subject 172 is provided. Again, the dynamically positionedoptic system 1000 is optionally used to deliver light to thespatial illumination system 800. Results of interrogation of the subject 170 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 subject 172 has a deepest penetration depth into thedermis 174. Hence, the fifth radial fiber ring, f5, yields photons probing thesubcutaneous fat 176 for thefirst subject 171 and yields photons probing thedermis 174 of thesecond subject 172. Hence, for a water soluble analyte and/or a blood borne analyte, such as glucose, theanalyzer 100 is more optimally configured to not use both the fifth fiber ring, f5, and the sixth fiber ring, f6, for thefirst subject 171. However,analyzer 100 is more optimally configured to not use only the sixth fiber ring, f6, for thesecond subject 172, as described infra. -
TABLE 2 Subject 2Illumination 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.
- Referring again to
FIGS. 10A-D , the dynamically positionedoptic system 1000 is optionally used as a function of time to control one or more of: -
- delivery of the incident light 711 to a single selected fiber optic of the
fiber optic bundle 710; - delivery of the incident light 711 to a selected bundlet of the set of
fiber optic bundlets 810, such as to thefirst bundlet 811 at a first point in time and to thesecond bundlet 812 at a second point in time; - variation of solid angle of the incident light 711 to an optic and/or to the subject 170;
- variation of radial position of delivery of the
incident light 711 relative to a fixed location, such as a center of an optic, a target point on skin of the subject 170, or a center of thesample site 178; - incident angle of the
incident light 711 relative to a plane tangential to the skin of the subject 170 and/or an axis normal to the skin of the subject 170 at thesample site 178; - apparent focus depth of the incident light 711 into the skin of the subject 170;
- energy; and
- intensity, such as number of photon per second varying from one point in time to another by greater than 1, 10, 50, 100, 500, 1000, or 5000 percent.
- delivery of the incident light 711 to a single selected fiber optic of the
- 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 - Referring now to
FIG. 12 , thedata processing system 140 is further described. Thedata processing system 140 is optionally uses a step of post-processing 1120 to process a set of collecteddata 1210. The post-processing step 1120 optionally operates on data collected as a function of any of: radial distance of the incident light 711 to a reference point, such as a detector; solid angle of theincident light 711 relative to the subject 170; angle of theincident light 711 relative to skin of the subject 170; and/or depth of focus of theincident light 711 relative to a surface of the skin of the subject 170. - Referring now to
FIG. 13 , in another embodiment, theanalyzer 100 is used in two phase system 1300: (1) asample mapping phase 1310, such as a subject or group mapping phase and (2) a subject specificdata collection phase 1330. In one example, in thefirst mapping phase 1310, skin of the subject 170 is analyzed with theanalyzer 100 using a first optical configuration. Subsequently, the mapping phase spectra are analyzed 1320. In the second subject specificdata collection phase 1330, theanalyzer 100 is setup in a second optical configuration based upon data collected in thesample mapping phase 1310. The second optical configuration is preferably configured to enhance performance of theanalyzer 100 in terms of accuracy and/or precision of estimation and/or determination of an analyte property, such as a noninvasive glucose concentration. Examples provided, infra, use asingle subject 170. However, more generally thesample mapping phase 1310 is optionally used to classify the subject into a group or cluster and theanalyzer 100 is subsequently setup in a second optical configuration for the group or cluster, which represents a subset of the human population, such as by gender, age, skin thickness, water absorbance, fat absorbance, protein absorbance, epidermal thickness, dermal thickness, depth of a subcutaneous fat layer, and/or a model fit parameter. For clarity of presentation, several examples are provided infra describing use of asample mapping phase 1310 and a subsequent subject specificdata collection phase 1330. - In a first example, referring again to
FIG. 11A andFIG. 11B , a first optional two-phase measurement approach is herein described. Optionally, during the firstsample mapping phase 1310, thephoton transport system 120 provides interrogation photons to a particular test subject at controlled, but varying, radial distances from thedetection 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 thedata processing system 140 selecting how to illuminate/irradiate the subject 170. Subsequently, during the second subject specificdata collection phase 130, thesystem controller 180 controls thephoton transport system 120 to deliver photons over selected conditions and/or optical configuration to the subject 170. - In a second example, a first spectral marker is optionally related to the absorbance of the
subcutaneous fat 176 for thefirst subject 171. During the firstsample mapping phase 1310, the fifth and sixth radial positions of the fiber probe illustrated inFIG. 8A , yield collected signals for thefirst 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, which more generally establishes an outer radial distance for subsequent illumination. Still in the firstsample mapping phase 130, 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 thedermis 174, such as a protein absorbance band or an algorithmic/mathematical representation thereof. Hence, thedata processing system 140 yields a result that the fifth and sixth radial fiber optic rings or distance of thefiber bundle 170 should not be used in the second subject specificdata collection phase 1330 and that the fourth radial fiber optic ring or distance should be used in the second subject specificdata collection phase 1330. Subsequently, in the second subject specificdata collection phase 1330, 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 third example, the first
sample mapping phase 1310 of the previous example is repeated for thesecond subject 172. The firstsample mapping phase 1310 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. - In a fourth example, the
first mapping phase 1310 determines positions on the skin where papillary dermis ridges are closest to the skin surface and positions on the skin where the papillary dermis valleys are furthest from the skin surface. In the subsequent subject specificdata collection phase 1330, the incident light is optionally targeted at the papillary dermis valleys, such as greater than 50, 60, or 70 percent of the incident light is targeted at the papillary dermis valley and less than 30, 40, or 50 percent of the incident light is targeted at the papillary dermis ridge. The increased percentage of the incident light striking the papillary dermis valley increases the number of photons sampling the underlying dermis layer, where blood borne analytes reside, which increases the signal-to-noise ratio of collected data and lowers resultant errors in blood borne analyte property determination. - Generally, a particular subject is optionally probed in a
sample mapping phase 1310 and results from thesample mapping phase 1310 are optionally used to configure analyzer parameters in a subsequent subject specificdata collection phase 1330. While for clarity of presentation, and without loss of generality, radial distance was varied in the provided examples, any optical parameter of the analyzer is optionally varied in thesample mapping phase 1310, such as sample probe position, incident light solid angle, incident light angle, focal length of an optic, position of an optic, energy of incident light, and/or intensity of incident light. Optionally, thesample mapping phase 1310 and sample specificdata collection phase 1330 occur within thirty seconds of each other. Optionally, the subject 170 does not move away from thesample interface 150 between thesample mapping phase 1310 and the subject specificdata collection phase 130. 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 thefiber optic bundle 710 includes optics that change the mean incident light angle of individual fibers of thefiber optic bundle 716 as they first hit the subject 170. For example, a first optic at the end of a fiber in thefirst ring 741 aims light away from thecollection fiber optic 718; a second optic at the end of a fiber in thesecond ring 742 aims light nominally straight into the sample; and a third optic at the end of a fiber in thethird ring 742 aims light toward thecollection fiber 718. Generally, the mean direction of the incident light varies by greater than 5, 10, 15, 20, or 25 degrees. - The
data processing system 140 is further described herein. Generally, the data processing system uses an instrumentconfiguration analysis system 1340 to determine an optical configuration of theanalyzer 100 and/or a software configuration of theanalyzer 100 while the sampleproperty analysis system 1350 is used to determine a chemical, a physical, and/or a medical property, such as an analyte concentration, measured or represented by collected spectra. Further, thedata processing system 140 optionally uses a preprocessing step and a processing step to determine an instrument configuration and/or to determine an analyte property. - In one embodiment, the
data processing system 140 uses a preprocessing step to achieve any of: lower noise and/or higher signal. Representative and non-limiting forms of preprocessing include any of: use of a digital filter, use of a convolution function, use of a derivative, use of a smoothing function, use of a resampling algorithm, and/or a form of assigning one or more spectra to a cluster of a whole. The data processing system subsequently uses any multivariate technique, such as a form of principal components regression, a form of partial least squares, and/or a form of a neural network to further process the pre-processed data. - In another embodiment, the
data processing system 140 and/or the sampleproperty analysis system 1350 operates on spectra collected by theanalyzer 100, such as in the subject specificdata collection phase 1330, using a first step of defining finite width channels and a second step of feature extraction, which are each further described, infra. - In one example, the sample
property analysis system 1350 defines a plurality of finite width channels, where the channels relate to changes in an optical parameter, software setting of theanalyzer 100, a chemical condition, a physical property, a distance, and/or time. Still further, the channels optionally relate to radial distance between the incident light from theanalyzer 100 entering skin of the subject 170 and detected light exiting the skin of the subject 170 and detected by thedetector system 130, a focal length of an optic, a solid-angle of a photon beam from thesource system 110, an incident angle of light onto skin of the subject, and/or a software setting, such as control over spectral resolution. For clarity of presentation, the channels are described herein in terms of wavelength channels. For example, a spectrum is collected over a range of wavelengths and the finite width channels represent finite width wavelength channels within the spectrum. Generally, the channels are processed to enhance localized signal, to decrease localized noise, and/or are processed using a cross-wavelet transform. - In one case, the sample
property analysis system 1350 defines a plurality of finite width wavelength channels, such as more than 3, 5, 10, 15, 20, 30, 40, or 50 wavelength channels contained in a broader spectral region, such as within a spectrum from 900 to 2500 nanometers or within a sub-range therein, such as within 1100 to 1800 nanometers. The plurality of multiple finite width wavelength channels enhance accessibility to content related to: (1) a target analyte, such as a glucose concentration, and (2) a measurement context, such as the state of skin of the subject 170, which is used as information in a self-correcting background. - In one case, feature extraction determines and/or calculates coherence between channels, which is referred to herein as cross-coherence, to identify and/or enhance information common to the analytical signal, such as frequency, wavelength, shift, and/or phase information. Subsequently, cross-coherence terms are selected using a metric, such as to provide maximum contrast between: (1) the target analyte or signal and (2) the measurement context or background. Examples of background include, but are not limited to: spectral interference, instrument drift impacting the acquired signal, spectral variation resultant from physiology and/or tissue variation, temperature impact on the analyzer, mechanical variations in the analyzer as a function of time, and the like. Generally, the cross-coherence terms function to reduce toward or to monotonicity detected variation as a function of analyte concentration. In a particular instance, an N×N grid is generated per spectrum, which is symmetric about the diagonal of the N×N grid, with each grid element representing an M term coherence estimate versus frequency, where N is a positive integer of at least three.
- Typically, a model, such as a nonlinear model, is constructed to map the extracted features to the analyte property, such as a glucose concentration. For example, the total differential power of the cross-coherence estimate is determined between features related to the analyte versus the background and a separate nonlinear function is calculated for multiple analyte ranges.
- The
data processing system 140 optionally uses absorbance spectra of skin and/or blood constituents, such as water absorbance peaks at about 1450 nm or in the range of 1350 to 1500 nm. - In one example, a method for determining a concentration of a blood borne analyte of a subject, includes the steps of: (1) collecting a plurality of mapping spectra of the subject using a noninvasive analyzer setup in a first set of optical configurations, (2) calculating a metric related to skin tissue physiology of the subject using the mapping spectra, (3) based on the metric, setting up the analyzer in a second set of optical configurations, the first set of optical configurations is configured to deliver light to the subject in a manner different than the second set of optical configurations, (4) collecting subject specific noninvasive spectra of the subject using the second set of optical configurations; and (5) post-processing the subject specific noninvasive spectra to determine the concentration.
- 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. A method for determining a concentration of a blood borne analyte of a subject, comprising the steps of:
collecting a plurality of mapping spectra of the subject using a noninvasive analyzer setup in a first set of optical configurations;
calculating a metric related to skin tissue physiology of the subject using the mapping spectra;
based on the metric, setting up said analyzer in a second set of optical configurations, the first set of optical configurations configured to deliver light to the subject in a manner different than the second set of optical configurations;
collecting subject specific noninvasive spectra of the subject using the second set of optical configurations; and
post-processing the subject specific noninvasive spectra to determine the concentration.
2. The method of claim 1 , wherein said step of collecting a plurality of mapping spectra comprises the step of:
tilting an optic of said analyzer to at least three orientations and collecting the mapping spectra sequentially at each of the at least three orientations of the optic.
3. The method of claim 1 , wherein said step of collecting a plurality of mapping spectra comprises the step of:
sequentially collecting a set of spectra using at least three different mean radial distances between incident light from said analyzer entering skin of the subject and a detection zone of detected light exiting the skin of the subject to a detector system of said analyzer, wherein the three different mean radial distances differ from each other by at least ten micrometers, wherein the three mean radial distances are each less than one millimeter.
4. The method of claim 1 , wherein said step of collecting a plurality of mapping spectra comprises the step of:
sequentially collecting a set of spectra using at least three different mean radial distances between incident light from said analyzer entering skin of the subject and a detection zone of detected light exiting the skin of the subject to a detector system of said analyzer, wherein the three different mean radial distances differ from each other by at least one-fifth of a millimeter, wherein the three mean radial distances are each less than four millimeters.
5. The method of claim 4 , wherein said step of calculating a metric related to skin tissue physiology comprises any of the steps of:
generating an epidermal thickness measure of the skin tissue physiology;
generating a dermis thickness measure of the skin tissue physiology; and
generating a subcutaneous fat depth measure of the skin tissue physiology.
6. The method of claim 4 , wherein said step of calculating a metric related to skin tissue physiology comprises any of the steps of:
calculating a measure of pathlength through an aqueous medium;
calculating a measure of pathlength through a fat medium; and
calculating a measure of signal-to-noise ratio for any of the set of spectra at the at least three different mean radial distances.
7. The method of claim 4 , wherein said step of setting up said analyzer in the second set of optical configurations increases mean absorbance of spectra with any of: (1) a range of 1325 to 1375 nm, (2) a range of 1375 to 1425 nm, (3) a range of 1425 to 1475, and (4) a range of 1475 to 1525 nanometers by at least ten percent relative to absorbance collected using the first set of optical configurations.
8. The method of claim 4 , wherein said step of setting up said analyzer in the second set of optical configurations increases an average absorbance ratio of spectra at 1450 nanometers to that at 1720 nanometers relative to the mapping spectra using the first set of optical configurations.
9. The method of claim 4 , wherein a mean range of radial distance between the incident light entering the skin and the collected light exiting the skin is greater for said plurality of mapping spectra than for the subject specific noninvasive spectra.
10. The method of claim 1 , wherein the plurality of mapping spectra comprise spectra collected in more optical configurations of said analyzer than used to collect the subject specific noninvasive spectra.
11. The method of claim 1 , said step of post-processing further comprising the step of:
determining correlation between two non-overlapping wavelength ranges of the subject specific noninvasive spectra.
12. The method of claim 1 , said step of post-processing further comprising the steps of:
defining finite width channels for the noninvasive spectra;
calculating coherence between the channels to form a set of cross-coherence values; and
selecting a subset of the set of cross-coherence values for subsequent multivariate analysis.
13. The method of claim 1 , said step of post-processing further comprising the step of:
generating a N×N grid of at least one spectrum of the subject specific noninvasive spectra, symmetrical about a diagonal of the N×N grid, wherein elements of the N×N grid represent a coherence estimate versus frequency, wherein N comprises a positive integer of at least ten.
14. The method of claim 1 , further comprising the step of:
using a model and said metric in said step of setting up said analyzer.
15. An apparatus for determining a concentration of a blood borne analyte of a subject, comprising:
a noninvasive analyzer, comprising:
a source configured to provide photons;
a photon transport system configured to deliver the photons to the subject; and
a detector system configured to receive the photons from the subject,
said analyzer configured to collect a plurality of mapping spectra of the subject using said analyzer in a first set of optical configurations; and
a data processing system, said data processing system configured to:
calculate a metric related to skin tissue physiology of the subject using the mapping spectra; and
set up said analyzer in a second set of optical configurations, the first set of optical configurations configured to deliver light to the subject in a manner different than the second set of optical configurations,
said analyzer configured to collect subject specific noninvasive spectra of the subject using the second optical configuration, and
said data processing system configured to post-process the subject specific noninvasive spectra to determine the concentration.
16. The apparatus of claim 15 , said analyzer further comprising:
a tiltable optic, said tiltable optic configured in at least three distinct orientations during collection of the mapping spectra.
17. The apparatus of claim 15 , said analyzer further comprising:
means for sequentially collecting a set of spectra using at least three different mean radial distances between incident light from said source entering skin of the subject and a detection zone of detected light exiting the skin of the subject to said detector system, wherein the three different mean radial distances differ from each other by at least one-half millimeter, wherein the three mean radial distances are each less than four millimeters.
18. The apparatus of claim 15 , said analyzer comprising:
a set of at least three fiber optics at at least three radial positions from a mean position of photons exiting the subject into said detector system; and
a photon delivery system configured to individually and sequentially illuminate each of said set of at least three fiber optics with the photons from said source.
19. The apparatus of claim 15 , said photon transport system comprising:
at least one optic configured to deliver a mean path of the photons to the subject at at least three positions separated from each other by at least one-twentieth of a millimeter as a function of time.
20. The apparatus of claim 15 , said photon transport system comprising:
at least one optic configurable to at least three focal lengths as a function of time.
21. The apparatus of claim 15 , said analyzer further comprising:
a time resolved gating system configured to detect the photons in a pulse mode from the source in time periods greater than one femtosecond and less than one hundred milliseconds after the photons leave the source.
22. The apparatus of claim 15 , said photon transport system comprising:
at least one optic configurable to deliver the photons to the subject, during a single sampling period of less than one minute, at at least three mean incident angles relative to a plane normal to the subject, wherein the at least three mean incident angles differ from each other by greater than five degrees as a function of time.
23. The apparatus of claim 15 , said data processing system configured to:
calculate a set of coherence values between finite width channels of elements of the noninvasive spectra; and
use said set of coherence values in determination of the concentration of the blood borne analyte of the subject.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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US13/963,933 US20150041656A1 (en) | 2013-07-12 | 2013-08-09 | Multiplexed 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 |
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 |
US14/493,234 US9351671B2 (en) | 2012-07-16 | 2014-09-22 | Multiplexed pathlength resolved 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 |
US14/504,065 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 |
US14/965,807 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 |
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US20150041656A1 (en) | 2015-02-12 |
US20150015888A1 (en) | 2015-01-15 |
US9766126B2 (en) | 2017-09-19 |
US20150018642A1 (en) | 2015-01-15 |
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