# US 7,066,884 B2 · System, method, and device for non-invasive body fluid sampling and analysis > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,066,884 B2 - Document ID: US7066884B2 - Status: Granted - Kind: B2 - Application number: 09/979,096 - Filed: 2001-03-16 - Published: 2003-05-29 - Granted: 2006-06-27 - Earliest claimed: 2000-03-17 - Assignees: Sontra Medical, Inc. - Inventors: Linda Custer; Tuan A. Elstrom; Scott C. Kellogg; Joseph Kost; Nicholas F. Warner - Web page: https://patentgrep.com/patent/US7066884B2 ## CPC - A61B 10/0045: {Devices for taking samples of body liquids} - A61B 5/14514: {using means for aiding extraction of interstitial fluid, e.g. microneedles or suction} - A61B 5/14532: {for measuring glucose, e.g. by tissue impedance measurement} - A61B 5/150022: {for capillary blood or interstitial fluid} - A61B 5/150083: {by vibration, e.g. ultrasound} - A61B 5/150358: {Strips for collecting blood, e.g. absorbent} - A61B 5/150755: {Blood sample preparation for further analysis, e.g. by separating blood components or by mixing} - A61B 5/15087: {short range, e.g. between console and disposable (using implanted devices A61B5/150877)} - A61B 5/150969: {Low-profile devices which resemble patches or plasters, e.g. also allowing collection of blood samples for testing} - A61B 5/15134: {Bladeless capillary blood sampling devices, i.e. devices for perforating the skin in order to obtain a blood sample but not using a blade, needle, canula, or lancet, e.g. by laser perforation, suction or pressurized fluids} - A61B 5/157: {Devices} characterised by integrated means for measuring characteristics of blood - A61B 8/00: Diagnosis using ultrasonic, sonic or infrasonic waves - A61B 2010/008: {Interstitial fluid} - A61M 25/02: Holding devices, e.g. on the body - A61M 37/0092: {using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis} - A61M 2025/0206: {where the catheter is secured by using devices worn by the patient, e.g. belts or harnesses} - A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D) - A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)} ## Abstract A system, method, and device for non-invasive body fluid sampling is provided. According to one embodiment of the present invention, the system includes a controller that controls the generation of ultrasound; an ultrasonic applicator that applies the ultrasound to an area of biological membrane; a receiver that contacts the area of biological membrane and receives body fluid through and out of the area of biological membrane; and a meter that interacts with the receiver and detects the presence of at least one analyte in the body fluid in the receiver. The receiver may include a membrane and a medium, such as a hydrogel, a fluid, or a liquid, that is contained in the membrane. According to one embodiment of the present invention, the method includes the steps of (1) identifying an area of biological membrane having a permeability level; (2) increasing the permeability level of the area of biological membrane; (3) contacting the area of biological membrane with a receiver; (4) extracting body fluid through and out of the area of biological membrane; (5) providing an external force to enhance the body fluid extraction; (6) collecting the body fluid in the receiver; (7) analyzing the collected body fluid for the presence of at least one analyte; and (8) providing the results of the step of analyzing the body fluid. ## Claims ### Claim 1 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane by applying ultrasound having a frequency range of from about 10 kHz to about 500 kHz to the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing an external force to enhance the extraction of the at least one analyte; continuously analyzing the at least one analyte; and providing the results of the step of continuously analyzing the at least one analyte. ### Claim 2 (depends on 1) The method of claim 1, wherein the step of increasing the permeability level of the area of biological membrane comprises: applying ultrasound having a frequency range of from about 20 kHz to about 150 kHz to the area of biological membrane. ### Claim 3 (depends on 1) The method of claim 1, wherein the step of increasing the permeability level of the area of biological membrane comprises: applying ultrasound having a frequency of about 50 kHz to the area of biological membrane. ### Claim 4 (depends on 1) The method of claim 1, wherein the step of increasing the permeability level of the area of biological membrane comprises: increasing the permeability level of the area of biological membrane to a predetermined level. ### Claim 5 (depends on 1) The method of claim 1, wherein the step of increasing the permeability level of the area of biological membrane comprises: increasing the permeability level of the biological membrane with a method selected from the group consisting of: creating physical micropores in the area of biological membrane; physically disrupting lipid bilayers in the area of biological membrane; chemically modifying lipid bilayers in the area of biological membrane; physically disrupting the stratum corneum in the area of biological membrane; and chemically modifying the stratum corneum in the area of biological membrane. ### Claim 6 (depends on 1) The method of claim 1, wherein the step of providing an external force to enhance the extraction of the at least one analyte comprises: generating at least one osmotic force to enhance the extraction of the at least one analyte. ### Claim 7 (depends on 6) The method of claim 6, wherein the step of generating at least one osmotic force to enhance the extraction of the at least one analyte comprises: generating the at least one osmotic force by applying at least one osmotic agent to the area of biological membrane. ### Claim 8 (depends on 1) The method of claim 1, wherein the step of continuously analyzing the at least one analyte comprises: providing the receiver with at least one reagent that facilitates the measurement of analyte flux for the at least one analyte. ### Claim 9 (depends on 1) The method of claim 1, wherein the step of continuously analyzing the at least one analyte comprises: using a method selected from the group consisting of electrochemical, biochemical, optical, fluorescence, absorbance, reflectance, Raman, magnetic, mass spectrometry, IR spectroscopy measurement methods, and combinations thereof to measure analyte flux for the at least one analyte. ### Claim 10 (depends on 1) The method of claim 1, wherein the step of continuously analyzing the at least one analyte comprises: providing a meter to analyze the at least one analyte using a method selected from the group consisting of electrochemical, optical, fluorescence, absorbance, reflectance, Raman, magnetic mass spectrometry, IR spectroscopy measurement methods, and combinations therof. ### Claim 11 (depends on 1) The method of claim 1, wherein the step of continuously analyzing the at least one analyte at least comprises: determining an analyte flux for the at least one analyte from the body fluid. ### Claim 12 (depends on 1) The method of claim 1, wherein the step of providing the results of the step of analyzing the at least one analyte comprises: displaying the results of the step of analyzing the at least one analyte. ### Claim 13 (depends on 1) The method of claim 1, wherein said analyte is glucose. ### Claim 14 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing an external force to enhance the extraction of the at least ne analyte; analyzing the at least one analyte; and providing the results of the step of analyzing the at least one analyte; wherein the step of identifying an area of biological membrane having a permeability level comprises: providing a target identifying device to the area of biological membrane. ### Claim 15 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing an external force to enhance the extraction of the at least one analyte; analyzing the at least one analyte; providing the results of the step of analyzing the at least one analyte; providing the receiver with a second receiver, the second receiver having a concentration of the at least one analyte; and maintaining the concentration of the at least one analyte in the second receiver at a level that is lower than a concentration of the extracted at least one analyte. ### Claim 16 (depends on 15) The method of claim 15, further comprising the step of: providing a second external force to the second receiver. ### Claim 17 (depends on 16) The method of claim 16, wherein the first external force and the second external force differ in at least one of a type, duration, and an intensity. ### Claim 18 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeabiligy level of the area of biologial membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of area of biological membrane and into the receiver; providing a first external force by generating at least one osmotic force to enhance the extraction of the at least one analyte; analyzing the at least one analyte; and providing the results of the step of analyzing the at least one analyte; wherein the step of generating at least one osmotic force to enhance the extraction of the at least one analyte comprises: regulating the at least one osmotic force with a second external force selected from the group consisting of heat, a temperature force, a pressure force, an electromotive force, mechanical agitation, ultrasound, iontophoresis, an electromagnetic force, a magnetic force, a photothermal force, a photoacoustic force, and combinations thereof. ### Claim 19 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing a first external force by generating at least one osmotic force to enhance the extraction of the at least one analyte; analyzing the at least one analyte; and providing the results of the step of analyzing the at least one analyte; wherein the step of generating at least one osmotic force to enhance the extraction of the at least one analyte comprises: manipulating at least one of an intensity of the at least one osmotic force, a duration of the at least one osmotic force, and a frequency of the at least one osmotic force with a second external force. ### Claim 20 (depends on 19) The method of claim 19, wherein the second external force is generated by a method selected from the group consisting of: applying an electric field force, applying a magnetic field force; applying an electromagnetic field force; applying a chemical; adjusting a molarity of the at least one osmotic agent; adjusting a pH level of the at least one osmotic agent; applying an ultrasonic field force; applying an electro-osmotic field force; applying a iontophoretic field force; applying an electroporatic field force; and combinations thereof. ### Claim 21 A method for non-invasive body fluid samling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing an external force to enhance the extraction of the at least one analyte; analyzing the at least one analyte; and providing the results of the step of analyzing the at least one analyte; wherein the step of analyzing the at least one analyte comprises: determining an analyte flux for the at least one analyte from the body fluid based on an analyte flux for a plurality of analytes from the body fluid. ### Claim 22 A method for non-invasive body fluid sampling and analysis, comprising: identifying an area of biological membrane having a permeability level; increasing the permeability level of the area of biological membrane; contacting the area of biological membrane with a receiver; extracting at least one analyte of the body fluid through and out of the area of biological membrane and into the receiver; providing an external force to enhance the extraction of the at least one analyte; analyzing the at least one analyte; and providing the results of the step of analyzing the at least one analyte; and removing the receiver from the area of biological membrane after a predetermined condition. ### Claim 23 (depends on 22) The method of claim 22, wherein the step of removing the receiver from the area of biological membrane after a predetermined condition comprises: removing the receiver from the area of biological membrane after an amount of the at least one analyte sufficient for analysis is received in the receiver. ### Claim 24 (depends on 23) The method of claim 23, wherein the step of removing the receiver from the area of biological membrane after a predetermined condition comprises: removing the receiver from the area of biological membrane within 15 minutes after the receiver contacts the area of biological membrane. ### Claim 25 (depends on 23) The method of claim 23, wherein the step of removing the receiver from the area of biological membrane after a predetermined condition comprises: removing the receiver from the area of biological membrane within 10 minutes after the receiver contacts the area of biological membrane. ### Claim 26 (depends on 23) The method of claim 23, wherein the step of removing the receiver from the area of biological membrane after a predetermined condition comprises: removing the receiver from the area of biological membrane within 5 minutes after the receiver contacts the area of biological membrane. ### Claim 27 A system for non-invasive body fluid sampling and analysis comprising: a device for measuring a permeability level of an area of biological membrane; an ultrasonic applicator that applies the ultrasound to the area of biological membrane; a controller that controls the generation of ultrasound in response to permeability measurements; a receiver that contacts the area of biological membrane and receivers at least one analyte of the body fluid through and out the area of biological membrane, the receiver comprising: a medium; and a meter that interacts with thge receiver and detects the analyte flux for the at least one analyte entering the receiver. ### Claim 28 (depends on 27) The system of claim 27, further comprising: a cartridge containing an ultrasonic coupling solution that is inserted into the ultrasound applicator. ### Claim 29 (depends on 27) The system of claim 27, wherein the ultrasonic applicator comprises: a cartridge chamber that receives the cartridge; and a solution chamber that receives the ultrasonic coupling solution from the cartridge. ### Claim 30 (depends on 27) The system of claim 27, wherein the medium comprises at least one osmotic agent and at least one of a hydrogel layer, a fluid, and a liquid. ### Claim 31 (depends on 30) The system of claim 30, wherein the osmotic agent comprises: at least one of sodium chloride, lactate and magnesium sulfate. ### Claim 32 (depends on 31) The system of claim 31, wherein the medium further comprises: at least one agent. ### Claim 33 (depends on 27) The system of claim 27, wherein the meter comprises: a processor; and a device that detects the analyte flux selected from the group consisting of: an electrochemical detector; a biochemical detector; a fluorescence detector; a reflectance detector; a Raman detector; a magnetic detector; a mass spectrometryt detector; an IR spectroscopy detector; and combinations thereof. ### Claim 34 (depends on 27) The system of claim 27, wherein the meter comprises a display that displays an analayte flux. ### Claim 35 (depends on 27) The system of claim 27, further comprising: a device that provides a first additional energy/force to the area of biological membrane. ### Claim 36 (depends on 27) The system of claim 27, further comprising: a target ring that is attached to the area of biological membrane. ### Claim 37 (depends on 36) The system of claim 36, wherein the target ring is preapplied with an adhesive. ### Claim 38 (depends on 29) The system of claim 29, wherein the meter is wearable. ### Claim 39 A system for non-invasive body fluid sampling and analysis comprising: a controller that controls the generation of ultrasound; an ultrasonic applicator that applies the ultrasound to an area of biological membrane; a receiver that contracts the area of biological membrane and receives at least one analyte of the body fluid through and out of the area biological membrane, the receiver comprising: a medium; and a meter that interacts with the receiver and detects analyte flux for the at least one analyte entering the receiver; a device that provides a first additional energy/force to the area of biological membrane, and a second receiver in communication with the receiver and having a concentration of the at least one analyte; wherein the concentration of the at least one analyte in the second receiver is maintained at a level that is lover than a concentration of the at least one analyte received in the receiver. ### Claim 40 (depends on 39) The system of claim 39, further comprising: a device that provides a second additional energy/force to the receiver. ### Claim 41 (depends on 40) The system of claim 40, wherein the first additional energy/force and the second additional energy/force differ in at least one of a type, a duraton, and an intensity. ### Claim 42 A method for noninvasive body fluid sampling and analysis, comprising: enhancing a permeability level of an area of biological membrane; attaching a receiver to the area of biological membrane; extracting at least one analyte through and out of the area biological membrane; receiving the at least one analyte in the receiver; and determining a flux of at least one analyte from the body fluid, based on the flux of a plurality of analaytes from the body fluid. ### Claim 43 (depends on 42) The method of claim 42, wherein the step attaching a receiver to the area of biological membrane comprises: using an adhesive to contact the receiver to the area of biological membrane. ### Claim 44 (depends on 42) The method of claim 42, wherein the step of determining a flux of at least one analyte from the body fluid comprises: using a method selected from the group consisting of electrochemical, biochemical, optical, fluorescence, absorbance, reflectance, Raman, magnetic, mass spectrometry, IR spectroscopy measurement methods, and combinations thereof to measure the flux of the at least one analyte. ### Claim 45 (depends on 42) The method of claim 42, wherein the step of determining a flux of at least one analyte from the body fluid comprises: providing a meter to analyze the at least one analyte using a method selected from the group consisting of electrochemical, biochemical, optical, fluorescence, absorbance, reflectance, Raman, magnetic, mass spectrometry, IR spectroscopy measurement methods, and combinations thereof. ### Claim 46 (depends on 43) The method of claim 43, further comprising the step of: wearing the meter. ### Claim 47 (depends on 42) The method of claim 42, wherein the step of determining a flux of at least one analyte from the body fluid comprises: continuously determining the flux for at least one analyte from the body fluid. ### Claim 48 (depends on 42) The method of claim 42, wherein the step of determining a flux of at least one analyte from the body fluid comprises: periodically determining the flux of at least one analyte from the body fluid. ### Claim 49 (depends on 42) The method of claim 42, further comprising: displaying the flux of the at least one analyte. ### Claim 50 (depends on 42) The method of claim 42, wherein the step of attaching a receiver to the area of biological comprises: attaching the receiver to the area of biological membrane for at least 24 hours. ### Claim 51 (depends on 42) The method of claim 42, wherein the step of attaching a receiver to the area of biological membrane comprises: attaching the receiver to the area of biological membrane for at least 12 hours. ### Claim 52 (depends on 42) The method of claim 42, wherein the step of attaching a receiver to the area of biological membrane comprises: attaching the receiver to the area of biological membrane for at least 6 hours. ### Claim 53 (depends on 42) The method of claim 42, wherein the step of attaching a receiver to the area of biological membrane comprises: attaching the receiver to the area of biological membrane for at least 2 hours. ### Claim 54 A device for noninvasive body fluid sampling and analysis, comprising: a receiver that is adapted to be attached to an area of biological membrane with an enhanced permeability and adapted to receiver at least one analyte through and out of the area of biological membrane, the receiver comprising: a medium; and a wearable meter that measures the flux of the at least one analyte in a continuous manner, the wearable meter comprising: a processor; and a device that detects the flux of the analyte selected from the group consisting of: an electrochemcial detector, a biochemical detector; a fluorescence detector, a absorbance detector, a reflectance detector, a Raman detector; a magnetic detector; a mass spectrometry detector, IR spectroscopy detector; and combinations thereof. ### Claim 55 (depends on 54) The device of claim 54, wherein the medium comprises: at least one osmotic agent and at least one of a hydrogel layer, a fluid, and a liquid ### Claim 56 (depends on 55) The device of claim 55, wherein the osmotic agent comprises: at least one of sodium chloride, lactate, and magnesium sulfate. ### Claim 57 (depends on 55) The device of claim 55, wherein the medium further comprises: at least one agent. ### Claim 58 (depends on 54) The device of claim 54, wherein the wearable meter further comprises: a display that displays the analyte concentration in body fluid. ### Claim 59 (depends on 54) The device of claim 54, wherein the wearable meter further comprises: a display that displays an analyte concentration. ### Claim 60 A receiver that is adapted to be attached to an area of biological membrane with an enhanced permeability and adapted to receive at least one analyte through and out of the area of biological membrane, the receiver comprising: a first grid; a medium layer comprising at least one agent; a membrane that induces a concentration gradient barrier for the at least one agent; a counter grid; an oxidase layer; a detection layer; and a voltage source that provides a potential difference between the first grid and the counter grid; wherein the at least one analyte flows out of or through the biological membrane to the detector layer via the first grid, the counter grid, and the oxidase layer. ### Claim 61 (depends on 60) The receiver of claim 60, wherein the medium layer comprises at least one of a hydrogel and a liquid. ### Claim 62 (depends on 60) The receiver of claim 60, wherein the at least one agent comprises an osmotic agent. ### Claim 63 (depends on 62) The receiver of claim 62, wherein the osmotic agent comprises negative and positive charged species. ### Claim 64 (depends on 63) The receiver of claim 63, wherein a concentration of the charged species can be changed with the voltage source. ### Claim 65 (depends on 61) The receiver of claim 61, wherein the oxidase layer comprises: at least one catalyst or enzyme that detect at least one analyte. ### Claim 66 (depends on 60) The receiver of claim 60, wherein the detection layer further comprises: at least one working electrode; and at least one reference electrode; wherein the at least one working electrode and the at least one reference electrode allow for the detection of the by-products of the oxidase layer to quantify a concentration of the desired analyte of detection. ### Claim 67 A method for non-invasive body fluid sampling and analysis, comprising: a) identifying an area of biological membrane having a permeability level; b) increasing the permeability level of said area by applying low frequency ultrasound; c) providing a transport force to said area to extract an analyte from a body fluid through said area into a sensing zone in communication therewith; and d) continuously analyzing said analyte in said sensing zone. ### Claim 68 (depends on 67) The method of claim 67, wherein said analyte is glucose.