TISSUE PATHLENGTH RESOLVED NONINVASIVE ANALYZER APPARATUS AND METHOD OF USE THEREOF
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.
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 INVENTIONThe present invention relates to a temporal resolution gating noninvasive analyzer for use in analyte concentration estimation.
DESCRIPTION OF THE RELATED ARTPatents and literature related to the current invention are summarized herein.
DiabetesDiabetes 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 StatementWhat is needed is a noninvasive glucose concentration analyzer having precision and accuracy suitable for treatment of diabetes mellitus.
SUMMARY OF THE INVENTIONThe invention comprises a temporal resolution gating noninvasive analyzer apparatus and 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.
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 EMBODIMENTSThe 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.
- 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 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.
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.
AnalyzerReferring now to
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Herein, the source system 110 generates photons in any of the visible, infrared, near-infrared, mid-infrared, and/or far-infrared spectral regions. In one case, the source system generates photons in the near-infrared region from 1100 to 2500 nm or any range therein, such as within the range of about 1200 to 1800 nm; at wavelength longer than any of 800, 900, 1000, and 1100 nm; and/or at wavelengths shorter than any of 2600, 2500, 2000, or 1900 nm.
Photon/Skin InteractionLight interacts with skin through laws of physics to scatter and transmit through skin voxels.
Referring now to
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Herein, for clarity, without loss of generality, and without limitation, Beer's Law is used to described photon interaction with skin, though those skilled in the art understand deviation from Beer's Law result from sample scattering, index of refraction variation, inhomogeneity, turbidity, and/or absorbance out of a linear range of the analyzer 100.
Beer's Law, equation 1, states that:
A a bC (eq. 1)
where A is absorbance, b is pathlength, and C is concentration. Typically, spectral absorbance is used to determine concentration. However, the absorbance is additionally related to pathlength. Hence, determination of the optical pathlength traveled by the photons is useful in reducing error in the determined concentration. Two methods, described infra, are optionally used to estimate pathlength: (1) spatial resolution of pathlength and (2) temporal resolution of pathlength.
AlgorithmThe data and/or derived information from each of the spatial resolution method and temporal resolution method are each usable with the data processing system 140. Examples provide, infra, illustrate: (1) both cases of the spatial resolution method and (2) the temporal resolution method. However, for clarity of presentation and without limitation, the photons in most examples are depicted as radially traversing from a range of input zones to a detection zone. Similarly, photons are optionally controlled from an input zone to a range of detection zones. Still further, photons are optionally directed to a series of input zones, as a function of time, and for each input zone or set of input zones one or more detection zones are used.
Spatial ResolutionThe first method of spatial resolution contains two cases. Herein, in a first case photons are depicted traversing from a range of input points on the skin to a radially located detector to derive photon interrogated sample path and/or depth information. However, in a second case, equivalent systems optionally use a single input zone of the photons to the skin and a plurality of radially located detector zones to determine optical sample photons paths and/or depth information. Still further, a combination of the first two cases, such as multiple sources and multiple detectors, is optionally used to derive photon path information in the skin.
In the first system, Referring now to
In the first case of the spatial resolution method, referring now to
In the second case of the spatial resolution method, referring now to
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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
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.
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Hence, both the spatial resolution method and temporal resolution method yield information on pathlength, b, which is optionally used by the data processing system 140 to reduce error in the determined concentration, C.
Analyzer and Subject VariationAs described, supra, Beer's Law states that absorbance, A, is proportional to pathlength, b, times concentration, C. More precisely, Beer's Law includes a molar absorbance, ε, term, as shown in equation 3:
A=εbC (eq. 3)
Typically, spectroscopists consider the molar absorbance as a constant due to the difficulties in determination of the molar absorbance for a complex sample, such as skin of the subject 170. However, information related to the combined molar absorbance and pathlength product for skin tissue of individuals is optionally determined using one or both of the spatially resolved method and time resolved method, described supra. In the field of noninvasive glucose concentration determination, the product of molar absorbance and pathlength relates at least to the dermal thickness of the particular individual or subject 170 being analyzed. Examples of spatially resolved analyzer methods used to provide information on the molar absorbance and/or pathlength usable in reduction of analyte property estimation or determination are provided infra.
Spatially Resolved AnalyzerHerein, an analyzer 100 using fiber optics is used to describe obtaining spatially resolved information, such as pathlength and/or molar absorbance, of skin of an individual, which is subsequently used by the data processing system 140. The use of fiber optics in the examples is used without limitation, without loss of generality, and for clarity of presentation. More generally, photons are delivered in quantities of one or more through free space, through optics, and/or off of reflectors to the skin of the subject 170 as a function of distance from a detection zone.
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In practice, the mask wheel 830 contains an integral number of n positions, where the n positions selectively illuminate and/or block any combination of: (1) the individual fibers of the set of fiber optics 713 and/or (2) bundlets 810 of the set of fiber optic optics 713. Further, the filter wheel is optionally of any shape and uses any number of motors to position mask position openings relative to selected fiber optics. Still further, in practice the filter wheel is optionally any electro-mechanical and/or electro-optical system used to selectively illuminate the individual fibers of the set of fiber optics 713. Yet still further, in practice the filter wheel is optionally any illumination system that selectively passes light to any illumination optic or illumination zone, where various illumination zones illuminate various regions of the subject 170 as a function of time. The various illumination zones alter the effectively probed sample site 178 or region of the subject 170.
Adaptive Subject MeasurementReferring now to
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In yet another example, light is delivered with known radial distance to the detection zone, such as with optics of the analyzer, without use of a fiber optic bundle and/or without the use of a filter wheel. Just as the illumination ring determines the deepest tissue layer probed, control of the irradiation zone/detection zone distance determines the deepest tissue layer probed.
In still yet another example, referring again to time resolved spectroscopy, instead of delivering light through the filter wheel to force radial distance, photons are optionally delivered to the skin and the time resolved gating system is used to determine probably photon penetration depth. For example, Table 3 shows that at greater elapsed time to the nth gated detection period, the probability of the deepest penetration depth reaching deeper tissue layers increases.
Still referring to
In a first example, a first spectral marker is optionally related to the absorbance of the subcutaneous fat 176 for the first subject 171. During the first sample mapping phase, the fifth and sixth radial positions of the fiber probe illustrated in
In a second example, the first sample mapping phase of the previous example is repeated for the second subject 172. The first sample mapping phase indicates that for the second subject, the sixth radial illumination ring of the fiber bundle illustrated in
Generally, a particular subject is optionally probed in a sample mapping phase and results from the sample mapping phase are optionally used to configure analyzer parameters in a subsequent data collection phase. Optionally, the mapping phase and data collection phase occur within thirty seconds of each other. Optionally, the subject 170 does not move away from the sample interface 150 between the mapping phase and the data collection phase.
Further, generally each of the spatial and temporal methods yield information on pathlength, b, and/or a product of the molar absorptivity and pathlength, which is not achieved using a standard spectrometer.
In yet another embodiment, the sample interface tip 716 of the fiber optic bundle 710 includes optics that change the mean incident light angle of individual fibers of the fiber optic bundle 716 as they first hit the subject 170. For example, a first optic at the end of a fiber in the first ring 741 aims light away from the collection fiber optic 718; a second optic at the end of a fiber in the second ring 742 aims light nominally straight into the sample; and a third optic at the end of a fiber in the third ring 742 aims light toward the collection fiber 718. Generally, the mean direction of the incident light varies by greater than 5, 10, 15, 20, or 25 degrees.
Still yet another embodiment includes any combination and/or permutation of any of the analyzer and/or sensor elements described herein.
The particular implementations shown and described are illustrative of the invention and its best mode and are not intended to otherwise limit the scope of the present invention in any way. Indeed, for the sake of brevity, conventional manufacturing, connection, preparation, and other functional aspects of the system may not be described in detail. Furthermore, the connecting lines shown in the various figures are intended to represent exemplary functional relationships and/or physical couplings between the various elements. Many alternative or additional functional relationships or physical connections may be present in a practical system.
In the foregoing description, the invention has been described with reference to specific exemplary embodiments; however, it will be appreciated that various modifications and changes may be made without departing from the scope of the present invention as set forth herein. The description and figures are to be regarded in an illustrative manner, rather than a restrictive one and all such modifications are intended to be included within the scope of the present invention. Accordingly, the scope of the invention should be determined by the generic embodiments described herein and their legal equivalents rather than by merely the specific examples described above. For example, the steps recited in any method or process embodiment may be executed in any order and are not limited to the explicit order presented in the specific examples. Additionally, the components and/or elements recited in any apparatus embodiment may be assembled or otherwise operationally configured in a variety of permutations to produce substantially the same result as the present invention and are accordingly not limited to the specific configuration recited in the specific examples.
Benefits, other advantages and solutions to problems have been described above with regard to particular embodiments; however, any benefit, advantage, solution to problems or any element that may cause any particular benefit, advantage or solution to occur or to become more pronounced are not to be construed as critical, required or essential features or components.
As used herein, the terms “comprises”, “comprising”, or any variation thereof, are intended to reference a non-exclusive inclusion, such that a process, method, article, composition or apparatus that comprises a list of elements does not include only those elements recited, but may also include other elements not expressly listed or inherent to such process, method, article, composition or apparatus. Other combinations and/or modifications of the above-described structures, arrangements, applications, proportions, elements, materials or components used in the practice of the present invention, in addition to those not specifically recited, may be varied or otherwise particularly adapted to specific environments, manufacturing specifications, design parameters or other operating requirements without departing from the general principles of the same.
Although the invention has been described herein with reference to certain preferred embodiments, one skilled in the art will readily appreciate that other applications may be substituted for those set forth herein without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below.
Claims
1. An apparatus for determination of an analyte property of a subject, comprising:
- a near-infrared analyzer, comprising: a source configured to deliver a sub-microsecond burst of near-infrared light in the range of 1000 to 2500 nanometers; a temporal resolution gating system configured to collect signal from the burst of near-infrared light during a time period of at least one time delayed gated window, the time period comprising a period greater than one femtosecond and less than one nanosecond after a midpoint of the burst of the near-infrared light; and a data processing system configured to use the signal and the time period of the at least one delayed gated window in determination of a glucose concentration.
2. The apparatus of claim 1, said data processing system configured to resolve a pathlength of the near-infrared light in the subject using the signal from the burst of near-infrared light in the at least one time delayed gated window, the pathlength used in said data processing system in the determination of the glucose concentration.
3. The apparatus of claim 1, said data processing system configured to use the time period of the at least one time delayed gated window in determination of a product of pathlength and molar absorptivity.
4. The apparatus of claim 1, wherein said analyzer further comprises:
- at least one optic configured to vary radial distance, by at least one millimeter as a function of time, between a middle of an illumination zone of the burst of near-infrared light on the subject and a middle of a detection zone of a detection optic of said analyzer.
5. The apparatus of claim 4, wherein the radial distance comprises a set of at least four mean distances as a function of scan number, wherein the signal comprises a set of at least ten sub-signals correlating to said set of four mean distances.
6. The apparatus of claim 1, wherein said data processing system uses a database, said database configured to store at least one physiology parameter, said physiology parameter comprising at least one of an epidermal thickness and a dermal thickness, said data processing system configured to use at least one of the epidermal thickness and the dermal thickness in the determination of the glucose concentration.
7. The apparatus of claim 1, in the determination of the glucose concentration, said data processing system configured to use at least one of:
- an anisotropy value; and
- an index of refraction.
8. The apparatus of claim 1, in the determination of the glucose concentration, said data processing system configured to use at least one of:
- a scattering coefficient; and
- an absorbance of any of water, protein, and fat.
9. The apparatus of claim 1, wherein said analyzer further comprises:
- a sample interface configured to not contact the subject during collection of the signal.
10. The apparatus of claim 1, wherein said analyzer further comprises:
- a sample interface configured to contact at least one of the subject and a coupling fluid during collection of the signal.
11. The apparatus of claim 1, wherein said analyzer further comprises:
- a fiber optic bundle comprising: a first fiber optic configured to deliver the burst of the near-infrared light to the subject, said first fiber optic comprising a first cross-sectional area; and a second fiber optic configured to deliver the burst of the near-infrared light to the subject, said second fiber optic comprising a second cross-sectional area, said second cross-sectional area at least ten percent larger than said first cross-sectional area.
12. The apparatus of claim 1, wherein said analyzer further comprises:
- a vibration reduction system, wherein said vibration reduction system maintains a gap between a sample interface of said analyzer and the subject by monitoring shaking of the subject and adjusting physical position of said sample interface relative to the subject.
13. The apparatus of claim 1, wherein said analyzer further comprises:
- a first sample side optic configured to deliver the burst of light to the subject at a first mean incident angle relative to an axis normal to a sample site of the subject,
- a second sample side optic configured to deliver the burst of light to the subject at a second mean incident angle relative to the axis normal to the sample site of the subject, the first mean incident angle at least ten degrees larger than the second mean incident angle.
14. A method for determination of an analyte property of a subject having skin, comprising the steps of:
- delivering a spectral burst of near-infrared light at least within the range of 1000 to 2500 nanometers from a source of an analyzer to an illumination region of the skin of the subject;
- generating a signal during at least one time period using a temporal resolution gating system to detect the burst of light in at least one time delayed gated window between one hundred picoseconds and one hundred nanoseconds after origination of the burst of the near-infrared light; and
- processing the signal using the at least one time period and the signal to generate a glucose concentration of the subject.
15. The method of claim 14, wherein said step of processing uses the time of said at least one time delayed gated window and the signal to generate an optical pathlength of the burst of the near-infrared light in the subject.
16. The method of claim 14, wherein said step of processing estimates a molar absorptivity of the subject.
17. The method of claim 14, further comprising the step of:
- adapting an optical configuration of the analyzer using the molar absorptivity.
18. The method of claim 14, wherein said step of processing further comprises the steps of:
- sending a form of the signal to a smart phone;
- analyzing the form of the signal using the smart phone to generate a result; and
- using said smart phone to convey the result to the subject.
19. The method of claim 14, further comprising the steps of:
- using said analyzer to gather information from a sensor external to said analyzer; and
- relaying a form of the information to a cell phone.
20. The method of claim 14, further comprising the step of:
- varying radial distance of the burst of light onto the subject relative to a zone monitored by a detector of said analyzer by at least one millimeter in a ten second time period.
21. A method for determination of a glucose concentration of a subject, comprising the steps of:
- using a temporal resolution analyzer to time near-infrared photon traversal through skin using a time resolved gating system and to gather a signal at a detection time period of the time resolved gating system; and
- using the detection time period and the signal to noninvasively determine a glucose concentration of the subject.
22. The method of claim 21, wherein said detection time comprises a time period greater than one femtosecond and less than one nanosecond after generation of a burst of light by said analyzer, wherein the signal is collected during said time period.
23. The method of claim 21, wherein said detection time comprises a time period greater than ten microseconds and less than one-tenth of a second after generation of a burst of light by said analyzer, wherein the signal is collected during said time period.
Type: Application
Filed: Jul 12, 2013
Publication Date: Jan 15, 2015
Inventors: Sandeep Gulati (La Canada, CA), Thomas George (La Canada, CA), Timothy Ruchti (Gurnee, IL), Alan Abul-Haj (Mesa, AZ), Kevin H. Hazen (Gilbert, AZ)
Application Number: 13/941,369
International Classification: A61B 5/1455 (20060101); A61B 5/00 (20060101); A61B 5/145 (20060101);