NON-INVASIVE MEASUREMENT OF ANALYTES
First Claim
1. A sensor composition comprising at least one small molecule metabolic reporter (SMMR), wherein the composition is applied to at least one surface of living tissue, organs, interstitial fluid, and whole organisms and transported into the tissue at an effective concentration, wherein when the at least one small molecule metabolic reporter is brought in contact with one or more specific metabolites, a change in fluorescence or absorption of the at least one small molecule metabolic reporter occurs, thereby allowing quantification of the change in fluorescence or absorption, thereby providing detailed in vivo information regarding picomolar through millimolar levels of cellular metabolites and metabolic precursors in the living tissue, organs, interstitial fluid, and whole organisms.
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Abstract
This invention provides devices, compositions and methods for determining the concentration of one or more metabolites or analytes in a biological sample, including cells, tissues, organs, organisms, and biological fluids. In particular, this invention provides materials, apparatuses, and methods for several non-invasive techniques for the determination of in vivo blood glucose concentration levels based upon the in vivo measurement of one or more biologically active molecules found in skin.
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Citations
71 Claims
- 1. A sensor composition comprising at least one small molecule metabolic reporter (SMMR), wherein the composition is applied to at least one surface of living tissue, organs, interstitial fluid, and whole organisms and transported into the tissue at an effective concentration, wherein when the at least one small molecule metabolic reporter is brought in contact with one or more specific metabolites, a change in fluorescence or absorption of the at least one small molecule metabolic reporter occurs, thereby allowing quantification of the change in fluorescence or absorption, thereby providing detailed in vivo information regarding picomolar through millimolar levels of cellular metabolites and metabolic precursors in the living tissue, organs, interstitial fluid, and whole organisms.
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18. A method for identifying a small molecule metabolic reporter (SMMR) suitable for use in a sensor composition, the method comprising:
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delineating the one or more metabolites required to characterize a selected metabolic pathway in a living system; determining a basic mechanism of action for the SMMR; selecting one or more wavelength choices for excitation and emission of the SMMR for analysis of absorption and fluorescence measurements; selecting a molecular structure to meet quantum efficiency and yield requirements; selecting location, diffusion rate, and duration or lifetime of the SMMR within a tissue or organ layers; selecting toxicity requirements and limitations; and optionally relating measured real-time metabolic conditions to disease state for diagnostics or patient care, thereby identifying a small molecule metabolic reporter for use in a sensor composition.
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19. An in vivo method for determining the metabolic health and well-being in living organisms, the method comprising:
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applying at least one small molecule metabolic reporter (SMMR) to a surface of an organ for a predetermined period of time; causing penetration of the SMMR to a depth of about 10 μ
m to about 300 μ
m;monitoring a change in the fluorescence or absorption based upon peripheral or epithelial tissue metabolite levels; and correlating the metabolite levels within peripheral or epithelial tissue with cellular metabolite levels, thereby determining the metabolic health and well-being in living organisms.
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20. An in vivo method for monitoring and controlling disease states that affect metabolic processes in living organisms, the method comprising:
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applying at least one small molecule metabolic reporter (SMMR) to at least one surface of a living tissue, organs, and/or whole organisms for a predetermined period of time; causing penetration of the SMMR to a depth of about 10 μ
m to about 300 μ
m;monitoring a change in the fluorescence or absorption based upon peripheral or epithelial tissue metabolite levels; and correlating the metabolite levels within peripheral or epithelial tissue with cellular metabolite levels, thereby monitoring and controlling disease states that affect metabolic processes in living organisms. - View Dependent Claims (21)
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22. An in vivo method for monitoring the concentration of one or more metabolites or analytes, the method comprising:
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applying at least one small molecule metabolic reporter (SMMR) to at least one surface of a living tissue, organs, and/or whole organisms for a predetermined period of time; causing penetration of the SMMR to a depth of about 10 μ
m, wherein said depth corresponds with the bottom of the dead stratum corneum layer, to about 175 μ
m, wherein said depth corresponds with the top of the dermal layer, into the epidermis; andmonitoring a change in the concentration of the one or more metabolites or analytes in a metabolic pathway by detecting changes in the at least one SMMR at one or more time points using an optical reader. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 71)
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- 36. An in vivo method for measuring metabolite levels, said method comprising monitoring in a population of cells one or more relevant metabolites, parameters or analytes in at least one metabolic pathway, wherein the monitoring comprises measuring the fluorescence spectrum emitted by at least one small molecule metabolic reporter (SMMR), wherein at least one fluorescence spectrum emitted by the SMMR is stoichiometrically related to the metabolite, parameter or analyte concentration in the population of cells, whereby analyzing the relatedness provides the in vivo metabolite level.
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48. A noninvasive method for monitoring in vivo blood glucose levels, the method comprising:
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applying at least one small molecule metabolic reporter (SMMR) to at least one surface of skin for a predetermined period of time; causing penetration of the one or more SMMR to a depth of about 10 μ
m, wherein said depth corresponds with the bottom of the dead stratum corneum layer, to about 175 μ
m, wherein said depth corresponds with the top of the dermal layer, into the epidermis;contacting the one or more SMMR with one or more metabolites or analytes; monitoring a change in the concentration of the one or more metabolites or analytes by detecting changes in the SMMR using an optical reader, and correlating the change in the concentration of the one or more metabolites or analytes with in vivo blood glucose levels. - View Dependent Claims (49, 50, 51, 52, 53, 54)
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55. A reagent strip for use in a glucose measuring instrument comprising:
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a polymer strip; and a known concentration of at least one small molecule metabolic reporter (SMMR), wherein when a sample of a biological fluid containing an amount of glucose is interacted with the reagent strip, a change in fluorescence or absorption of the at least one SMMR occurs, wherein said change is measured by the glucose measuring instrument, thereby detecting the glucose concentration of the biological fluid. - View Dependent Claims (56, 57)
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58. A reagent strip for use in calibrating a glucose measuring instrument comprising:
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a polymer strip; a known concentration of at least one small molecule metabolic reporter (SMMR); and at least one sample containing a known concentration of glucose, wherein when the at least one sample is interacted with the reagent strip, a change in fluorescence or absorption of the at least one SMMR occurs, wherein said change is measured by the glucose measuring instrument and wherein the calculated glucose is compared to the known concentration, thereby calibrating the instrument. - View Dependent Claims (59, 60)
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64. A method for determining in vivo blood glucose concentration, comprising the steps of:
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performing an instrument response measurement on a calibration target and recording the response data; applying at least one SMMR mixture to the skin in a first controlled area such that the SMMR resides in the epidermal layer of the skin; applying a second SMMR mixture to the skin in a second controlled area; perturbing the second area such that one or more extreme changes that the mixture may undergo are achieved; performing a calibration measurement on the perturbed area and recording the calibration data; performing a background measurement on an area of skin that has no SMMR and recording this background data; illuminating the first area with light and performing a first measurement on the first area; detecting at least one wavelength spectrum of light reflected back from the first area; performing at least a second measurement on the first area at wavelengths suitable for each SMMR present; calculating at least one parameter from the response data to normalize the background data, calibration data and measurement data for the response using a spectrometer; calculating at least one parameter from the background data to correct the calibration data and measurement data for emission, absorption and scattering properties of the tissue; and calculating at least one metabolite parameter from the calibration data to relate the measurement data to the blood glucose concentration; thereby determining in vivo blood glucose concentration. - View Dependent Claims (65)
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66. A method of calculating a blood glucose concentration, said method comprising:
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measuring at least one background response and at least one autofluorescence tissue response from a calibration target comprising an epidermal layer of skin; providing a first SMMR mixture to a first skin location and causing portions of the first SMMR mixture to transfer into the epidermal layer of the skin; providing a second SMMR mixture to a second skin location and causing and recording at least one extreme change in the mixture; illuminating the first skin location with a radiative emission; detecting at least one resulting wavelength spectrum reflected from the first skin location; optionally repeating the illuminating and detecting steps using at least one irradiation and wavelength spectrum associated with each SMMR provided; and detecting at least one physico-chemical parameter that is related to the glycolytic pathway, wherein said parameter comprises a stoichiometric or highly correlated relationship with glucose concentration; thereby determining the blood glucose concentration. - View Dependent Claims (67, 68)
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69. A method for determining the concentration of at least one metabolite or analyte in skin tissue, the method comprising:
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administering to the skin tissue at least one small molecule metabolite reporter (SMMR) agent; causing penetration of the at least one SMMR agent to a region of the skin at a depth between the dermis and the epidermis, wherein the depth from the surface of the skin is from about 10 μ
m, wherein said depth corresponds with the bottom of the dead stratum corneum layer, to about 175 μ
m, wherein said depth corresponds with the top of the dermal layer;irradiating the at least one SMMR agent in the skin tissue with a source of electromagnetic radiation; measuring at least one fluorescence spectrum emitted from the at least one SMMR agent; and analyzing the emitted fluorescence spectra; wherein the analysis results in a determination of the concentration of the metabolite or analyte.
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Specification