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WO2000014535A1 - Procede et dispositif utilisant les fluides interstitiels pour la determination d'un analysat corporel - Google Patents

Procede et dispositif utilisant les fluides interstitiels pour la determination d'un analysat corporel Download PDF

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Publication number
WO2000014535A1
WO2000014535A1 PCT/US1999/020915 US9920915W WO0014535A1 WO 2000014535 A1 WO2000014535 A1 WO 2000014535A1 US 9920915 W US9920915 W US 9920915W WO 0014535 A1 WO0014535 A1 WO 0014535A1
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WO
WIPO (PCT)
Prior art keywords
test
skin
body fluid
patient
matrix material
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Application number
PCT/US1999/020915
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English (en)
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WO2000014535A9 (fr
Inventor
Su I. Yum
Jeffrey N. Roe
Joel S. Douglas
John H. Priest
Original Assignee
Amira Medical
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amira Medical filed Critical Amira Medical
Priority to AU60352/99A priority Critical patent/AU6035299A/en
Publication of WO2000014535A1 publication Critical patent/WO2000014535A1/fr
Publication of WO2000014535A9 publication Critical patent/WO2000014535A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/525—Multi-layer analytical elements

Definitions

  • the present invention relates to a test device and method for the colorimetric determination of a chemical or biochemical component (analyte) in interstitial body fluid.
  • the present invention relates to a dry reagent test strip from which an analyte presence and/or concentration is determined by visual interpretation or by the use of an instrument.
  • Such test strips are commonly used for determination of glucose level in blood by diabetics.
  • a dry chemistry reagent system is a system in which the wet chemistries are imbibed into an absorbent or bibulous medium, dried, and later reconstituted by fluid from the test sample.
  • the reagent strips contain an indicator which changes color, depending on the presence or concentration of a particular analyte in a biological fluid applied to the strip. These strips may be read visually by reference to a color standard or colorimetrically by an instrument calibrated or programmed to detect a certain color.
  • strips use reduction chemistries, more commonly they involve an oxidizable dye or dye couple.
  • Some of the strips include an enzyme, such as glucose oxidase, which is capable of oxidizing glucose to gluconic acid and hydrogen peroxide. They also contain an oxidizable dye and a substance having peroxidative activity, which is capable of selectively catalyzing oxidation of the oxidizable dye in the presence of hydrogen peroxide. (See, for example, U.S. Patent No. 5,306,623, to Kiser et al.). Examples of these devices, in addition to those used to test blood glucose, include tests for cholesterol, triglycerides, calcium or albumin in whole blood, and for protein, ketones, albumin or glucose in urine.
  • Dry chemistry reagent strips incorporating enzyme-based compositions are used daily by millions of diabetics to determine blood glucose concentrations.
  • Most diabetics must test themselves periodically in order to make appropriate adjustments to their diet or medication. It is thus especially important for diabetics to have rapid, low pain, and accurate reagent strips for glucose determination.
  • the embodiment of dry chemistry reagent systems in test strips enable simple yet effective analytical protocols.
  • current blood base devices require the patient to lance their fingers with a lancing device which cause considerable initial and residual pain. This process has caused many patients to reduce the amount of testing they do because of the pain associated with testing.
  • U.S. Patent No. 3,607,093 to Stone discloses a membrane for testing blood where the membrane has a skin permeable to solutions but impermeable to solids such as red blood cells and to macromolecules such as proteins. This membrane is disclosed as being used by applying a blood sample then wiping away the red blood cells from the skin in order to reach the test indication through the skin.
  • U.S. Patent No. 3,552,928, issued to Fetter discloses the use of certain water soluble salts and amino acids in reagent formulations as separation agents to provide blood separation. With solids such as red blood cells substantially removed from the biological fluid, there is less background color at the test site to obscure a change in coloration produced by a testing reagent. Phillips et al., U.S.
  • Patent No. 4,935,346, discloses a system wherein a whole blood sample is applied to the device and indicator development occurs in the presence of the colored components of the sample. Measurements of the color change in indicator are made at two distinct wavelengths to eliminate the interferences from the presence of colored blood components.
  • Kiser et al. U.S. Patent Nos. 5,306,623 and 5,418,142, disclose a visual meter device which incorporates various coatings on a matrix material to filter red blood cells from fluids. Similar devices for visual indication are disclosed by Hochstrasser in U.S. Patent Nos. 3,964,871 and 4,059,407.
  • Terminello et al. U.S. Patent No. 4,774,192, disclose a system in which the matrix is formed of an asymmetric material used to filter the red blood cells in the sample.
  • the asymmetric material has a density gradient from one side to the other to progressively separate red blood cells from the fluids.
  • U.S. Patent No. 4,994,2308 disclose a test device that comprises an asymmetric reagent layer that has progressively finer filtration with increased distance from one surface toward the other surface.
  • Castino et al. U.S. Patent No. 5,456,835, disclose the use of filters formed of ligand modified polymeric film such as polypropylene fibers and polyethersulfone fibers.
  • Macho et al. U.S. Patent No. 5,451,350, disclose the use of absorbent channels to distribute sample fluid in multi-zone test devices.
  • Charlton et al., U.S. Patent No. 5,208,163 also disclose the use of capillary channels to distribute blood to various chambers in the device.
  • Gerstel et al. U.S. Patent No. 3,964,482 disclose the use of a drug delivery device for precutaneous administration of a drug comprising of a plurality of projections.
  • Japanese Patent No. JP 2551743-B2 assigned to Sansei Denki KK describes a skin damage forming device for medicine delivery. This device causes small holes formed by tiny needles in the device.
  • Fendrock, U.S. Patent No. 5,305,746, describes a patch for reducing skin impedance by using an array of flexible tines.
  • Whitney et al. U.S. Patent No. 4,235,234, discloses a subcutaneous injection system which uses projections to inject a drug into the tissue.
  • Azimi World Patent WO 95/02357, discloses a noninvasive glucose monitor that does not rely on heat, electricity or chemicals to collect glucose from interstitial fluid across a patient's skin.
  • Liplovker U.S. Patent No. 5,617,851 discloses a noninvasive method and apparatus for withdrawing fluid from an organism and determining the concentration of a substance in the fluid.
  • Liplovker U.S. Patent No. 5,421,816, discloses a method of using ultrasound to move a drug across the skin of a patient.
  • Halili et al. U.S. Patent No. 5,586,553, discloses a transcutaneous sensor placed at a selected site within a patient's body to determine the concentration of analyte in a patient.
  • Eppstein et al. U.S. Patent No. 5,458,140, discloses a method of enhancing the permeability of the skin using ultrasound either in the presence or absence of chemical skin permeation enhancers to permit analytes to cross the skin to an analyte collection site.
  • Schroeder et al. U.S. Patent No. 5,140,985, discloses a device which measures the blood glucose of a patient via the concentration of glucose in sweat.
  • the glucose receiving medium includes a glucose permeation enhancer capable of increasing the permeability of glucose across the epithelial membrane.
  • the disclosures of the above-discussed documents are incorporated herein by reference.
  • the devices and methods discussed above provide varying degrees of effectiveness of blood analysis at varying degrees of complexity and pain. It is an object of the present invention to provide improved devices and methods to improve the performance and minimize the pain and complexity compared to the prior art devices.
  • this invention provides a device for testing a body for the presence or concentration of an analyte, such as glucose.
  • the device can be described as a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising: (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; (b) a substantially non-porous material separating each test area from adjacent test areas; (c) an attachment means for attaching the device to the skin of a patient; and (d) an extraction means for extracting interstitial body fluid through the skin of the patient; wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the
  • Another aspect of the present invention includes a method for testing the interstitial body fluid of a patient for the presence or concentration of an analyte comprising: providing a device comprising (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; (b) a substantially non-porous material separating each test area from adjacent test areas; (c) an attachment means for attaching the device to the skin of a patient; and (d) an extraction means for extracting interstitial body fluid through the skin of the patient; wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid
  • Another aspect of the present invention includes a process for preparing a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising: (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; (b) a substantially non-porous material separating each test area from adjacent test areas; (c) an attachment means for attaching the device to the skin of a patient; and (d) an extraction means for extracting interstitial body fluid through the skin of the patient; wherein each test area is oriented so that the absorption side of the test area is positioned to contact the inter
  • Another aspect of the present invention includes a process for preparing a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising: (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; (b) a substantially non-porous material separating each test area from adjacent test areas; (c) an attachment means for attaching the device to the skin of a patient; and (d) an extraction means for extracting interstitial body fluid through the skin of the patient; wherein each test area is oriented so that the absorption side of the test area is positioned to contact the inter
  • kits for use by a patient to determine the presence or concentration of an analyte in the interstitial body fluid of the patient comprising: (1) a device comprising: (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; (b) a substantially non-porous material separating each test area from adjacent test areas; (c) an attachment means for attaching the device to the skin of a patient; and (d) an extraction means for extracting interstitial body fluid through the skin of the patient; wherein each test area is oriented so that the absorption side of the test area is
  • a further aspect of the present invention includes a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising: a substantially impermeable backing; a semipermeable membrane secured to the backing to form at least one pocket; a gel including an indicator reagent capable of indicating the presence of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid; an absorption side matrix in communication with the semipermeable membrane; and an adhesive located on the absorption side of the matrix, the adhesive capable of securing a device to a patient.
  • FIG. 1 is a top plan view of a first embodiment of a patch in accordance with the present invention showing result indications in a matrix member;
  • FIG. 2 is a sectional view of the device shown in FIG. 1;
  • FIG. 3 is a perspective exploded view of the device shown in FIG. 1;
  • FIG. 4 shows a bottom plan view of the device shown in FIG. 1 showing the skin interface zones under each result indicator area;
  • FIG. 5 is a sectional view of a second embodiment of a patch in accordance with the present invention impregnated isolation and skin interface zones under each result indicator area;
  • FIG. 6 is a sectional view of a third embodiment of a patch in accordance to the present invention.
  • FIG. 7 is a perspective exploded view of a fourth embodiment of a patch according to the present invention.
  • FIG. 8 a perspective view of a kit according to the present invention.
  • the devices of the present invention are simpler to use and are easier and less painful than most devices previously available. This is especially important for diabetics who rely on blood glucose testing multiple times per day to keep their disease under control. For many diabetics, the pain associated with blood glucose monitoring is prohibitive and prevents the patient from testing.
  • Devices of various configurations and various uses based on the embodiments of the invention disclosed herein can be delivered to the diabetic and do not cause pain from finger tip lancing. The ease of use and portability of these devices, coupled with the painless operation of these devices will facilitate increased patient compliance with recommended testing routines and will result in improved overall health of diabetic patients.
  • this invention uses an intrinsically hydrophilic membrane.
  • the hydrophilic nature of the membrane encourages absorption of the sample, provides a suitable matrix for testing the sample and provides a substrate for applying the indicating reagent and subsequently drying it to the matrix fibers.
  • the invention can be used with various membranes including fiber, polyethersulfone, polyamide, and other polymeric membranes.
  • membranes such as the Whatman 41 and Pall Gelman Sciences Supor 200 are preferable for this application.
  • microporous membranes are polyethersulfone polymeric membrane (Pall Gelman Sciences Supor 200 is an example) which is formed with a microporous skin side which acts as a reflectance surface for the test side of the membrane and a matrix side which has uniform pore size for wicking in the sample.
  • the membranes are treated with test reagents which are designed to react with the analyte being tested.
  • membranes having a matrix layer having uniform porosity but no reflectance skin are also within the scope of this invention.
  • a second preferred type of membranes includes cellulose fiber or polymer based membranes or matrix products which facilitate wicking (Whatman 41 is an example).
  • Membranes of the second type are preferably cellulose fiber or polymer based membranes and can also be treated with test reagents. During use, clear interstitial fluid moves from the absorbent side into the test zone and reacts with the indicator reagents to indicate the presence and concentration of analyte.
  • test or reaction zones must be positioned such that clear interstitial fluid migrates into the zones and such that each reaction zone is isolated from other reaction zones.
  • the reaction zones are isolated by either embossing the matrix to restrict the flow between zones or imbibing the area between zones with a hydrophobic barrier such as hot melt adhesive, or a silicone and fluorocarbon coating. These isolated zones are microtitration areas. Providing a uniform and adequate sample volume for the test or reaction zones assures a uniform test at each test site.
  • the invention provides different mechanisms for using the dry chemistry reagent systems with and without microtitration volume control. The dry chemistry components and microtitration principles are described below, independent of the embodiments which follow.
  • microtitration concept employed in some aspects of this invention can be explained as a method of controlling the sample volume and the reagent amount to give a consistent titration and therefore consistent and reliable results. This concept is described in Douglas et al. , WO 97/38126.
  • the first step is to create a test zone which is bounded.
  • the traditional wet chemistry analysis uses a fixed (pre-measured) volume of sample and titrates a quantity of test reagent against that sample.
  • the quantity of the test reagent has to be impregnated into the matrix in a ratio proportional to the void volume of the matrix.
  • the ratio SV/TRV must be constant to provide an accurate titration.
  • the device of this invention creates a fixed control geometry which does not permit significant fluid flow between test zones and the sample delivery channel.
  • the membrane has a tendency to wick laterally, which the device in this aspect of the invention prevents.
  • the fluid is delivered so that it enters the test area matrix from the absorbent side of the matrix.
  • the test reagent can either be applied to the matrix by the technique described in U.S. Patent No. 5,547,702, issued to Gleisner, or by discretely applying it in the reaction zones. To discretely apply the reagent only in the reaction zones a syringe or needle is used to apply the reagents in the test area.
  • the most effective way to do this is to preassemble the device and coat the reagents while the membrane is supported by the test device construction.
  • the other materials can be impregnated into the matrix either locally or by a generally controlled application.
  • the most preferred method is to apply the test reagent as described in U.S. Patent No. 5,547,702. This system can be modified for discrete reagent application and is further elaborated in Douglas et al., U.S. Patent 5,876,957, which is incorporated herein by reference.
  • the preferred method for controlling the test area geometry is to emboss the membrane into the a gasket mask or molded part, deforming a portion of the membrane into openings in the gasket or molded part and leaving the test areas uncompressed and compressing a portion of the membrane.
  • the compressed areas are preferably fastened to the gasket with an adhesive such as 3M grade 415 acrylic pressure sensitive adhesive, to create test areas which are completely bounded on the sides, thus preventing any flow between the test areas. In this way, the only entry into each opening is through the absorbent side of the matrix.
  • the membrane is embossed into the gasket or mask by bringing both pieces together between two platens of a hydraulic press. A portion of the membrane is pushed into the gasket openings and deforms the material outside of the openings by compressing that material so that the thickness is reduced by 80% to 95 % in the compressed area.
  • the embossed material can be die cut and the compressed area can be removed (in a process similar to creating a label on a printing press) to further eliminate any chance for cross-talk or flow between test zones.
  • the test zones are held to the device by a small ring of adhesive because the majority of the embossed or compressed material has been removed.
  • the adhesive seals the die-cut matrix inserts to the gasket member, thereby preventing any leakage of fluid between test zones or areas.
  • the indicating reagent mix must be capable of detecting the presence of the analyte.
  • the analyte reacts with a specific oxidase enzyme and produces hydrogen peroxide. This strongly oxidative substance reacts with the indicator(s) present to produce a colored end product.
  • the oxidase enzyme may be one of the following: glucose oxidase, cholesterol oxidase, uricase, alcohol oxidase, aldehyde oxidase or glycerophosphate oxidase. While the examples and preferred embodiments herein comprise glucose oxidase in the formulations, formulation changes required to utilize other oxidase enzymes are evident to one who is skilled in the art.
  • the indicator chemistries which provide acceptable color generation when coated on the microporous membrane from Pall Gelman (polyethersulfone), or Whatman 41 cellulose fiber matrix include 3-methyl-2-benzothiazolinone hydrazone hydrachloride (MBTH) combined with 3,3-dimethylaminobenzoic acid (DMAB), MBTH combined with 3,5-dichloro-2-hydroxybenzenc-sulfonic acid (DCHBS); 4-aminoantipyrene (4-AAP) (at 4mg/ml) and 5-Oxo- 1 -(p-sulfophenyl)- 2-pyrazoline-3-carboxylic acid (OPSP); 4-AAP (at 4mg/ml) and n-(m-tolyl)- diethanolamine (NDA); 2,2 '-azino-di (3-ethylbenzthiazoline) sulfonic acid (ABTS); 4AAP (at 4mg/ml) and 4-methoxyna
  • a preferred dye system is disclosed in U.S. Patent 5,776,719, which is incorporated herein by reference. Klose et al., U.S. Patent No. 4,101,381, also describes a MBTH-S formulation. This preferred dye system is based on the sulfonated form of MBTH, 3-Methyl-6-(M sulfonate)benzothiazolinone-(2)- hydrazone (MBTH-S) where M is sodium, potassium, ammonium or other equivalent ion, but is preferably sodium.
  • MBTH-S formed as a dye couple with DMAB, ANS or N-(3-sulfopropyl)aniline provides an indicator system which provides a stable color end point in a short period of time. This dye system enables visual reading on a reliable basis without the use of meters or complex timing sequences.
  • both components require an acid pH of approximately 4.0, which is indicated enhances enzyme activity and requires the use of higher levels of oxidase or peroxidase enzymes than desired in the chemistry system.
  • a near neutral pH system is more preferred.
  • MBTH-S and ANS dye system referred to above can exist at approximately a pH of 6 and has the advantages of being easier to formulate and enhanced enzyme activity.
  • MBTH-S coupled with ANS provides good spectral abso ⁇ tion, is water soluble and does not sublime under dry chemistry storage conditions.
  • a preferred dye system of the MBTH-S and ANS dye couple can be used in the device of present invention because of the clear fluid absorbed into the reaction site provided by the devices and methods of present invention.
  • the spectral abso ⁇ tion in the range of 580-650 nm of the dye system is acceptable due to the clear color of the absorbed fluid. This range produces colors which are purple to blue.
  • One who is skilled in the art can formulate an acceptable chemistry based on the components disclosed herein and in the prior art.
  • the above reagents will create a chemistry which can be read with either a meter or by visual color comparison.
  • a visual strip which can be read in binary fashion as described in U.S. Patent No. 3,964,871, issued to Hochstrasser, a plurality of test areas must be designed into the test device.
  • an antioxidant is used to inhibit or intercept the reaction in visual test zones which only change color if the analyte is present in a greater quantity than the inhibition chemistry in that zone. They participate in a noncompetitive reaction and are consumed first by the hydrogen peroxide. If the antioxidant is fully consumed by the reaction the dye indicator or indicators are oxidized and color is developed in the test matrix.
  • Antioxidants may also be used to delay the onset of the desired reaction sequence.
  • Another aspect of this invention is the use of antioxidants such as ascorbic acid to consume possible contaminants (such as intracellular fluid, which may be present upon penetrating the stratum corneum and which could dilute the interstitial fluid and analytes measured therein) before the preferred reaction sequence is triggered.
  • the reaction is delayed by applying ascorbic acid or another antioxidant to the device in an amount sufficient to delay the conversion of the indicator (damping antioxidant).
  • the antioxidant is used in the reaction to convert the glucose in the initial sample and as it is consumed the glucose found in the initial sample is no longer available to convert the indicator.
  • the amount of antioxidant would be in addition to any antioxidant needed to create a multi-zone reading device.
  • skin permeation enhancers such as those described in Stanley et al., U.S. Patent No. 5,139,023, are used.
  • the skin permeation enhancers include natural bile salt, sodium cholate, sodium dodecyl sulfate, sodium deoxycholate, taurodeoxycholate or sodium glycocholate.
  • Various fatty acids can also be used as a skin permeation enhancers.
  • the most preferred embodiment uses one or more combinations of skin permeation enhancers in conjunction with other mechanical means such as ultrasound, iontophoresis and tape stripping.
  • Such permeation enhancers can be selected from, but are not limited to C 2 _ 4 alcohols such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, esters of fatty acids having from about 10 to about 20 carbon atoms, and monoglycerides or mixtures of monoglycerides of fatty acids having a total monoesters content of at least 51 % where the monoesters are those with from 10- 20 carbon atoms. Diglycerides and triglycerides of fatty acids, or mixtures thereof, are also included.
  • Fatty acids are, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid.
  • Monoglyceride permeation enhancers include glyceral monooleate, glycerol monolaurate and glycerol monolinoleate, for example.
  • the permeation enhancer is a polyethelene glycol-3-lauramide (PEG- 3-LR), glycerol monooleate (GMO), glycerol monolinoleate or glycerol monolaurate (GML), more preferably, glycerol monooleate.
  • permeation enhancers include, but are not limited to; diethylene glycol monoethyl ether, dodecyl acetate, propylene glycol, methyl laurate, ethyl acetate, isopropyl myristrate, ethyl palmitate, isopropyl palmitate glycerol monocaprylate isopropyl oleate, ethyl oleate, lauryl pidolate, lauryl lactate, propylene glycol monolaurate, n-decyl methyl sulfucide.
  • the multi-zone test systems can use various indicating reagent technologies including: indicating dyes and an antioxidant system to provide threshold readings which can be utilized in multizone nonmetered test formats as described above; indicating dyes which are consumed by the reaction, i.e. a test zone with more dye will turn off at higher concentrations of analyte than a test zone with less dye; and indicating dyes which are generated in proportion to the concentration of an analyte, which may be used in a color match system or in conjunction with a meter such as a spectrophotometer.
  • a three level sample device can be used in the present invention based on the chemistry systems described below.
  • the indicator reagents, oxidase enzymes, peroxidase enzymes, buffers, and antioxidants together with the dye system are impregnated in a membrane matrix selected from polyethersulfone, polysulfone, polyamide, and cellulose.
  • An alternate means of utilizing the antioxidant damping system is to apply the damping antioxidant solution to a separate absorbent layer which is placed in primary communication with the skin.
  • the indicating reagents and secondary antioxidant reagent is placed in a second absorbent layer in communication with the first layer.
  • This embodiment provides a secondary barrier which prevents the indicating reagent from being transferred back into the patient.
  • FIGS. 1-4 show a first embodiment of a patch device 1 according to the present invention.
  • a frame or support member 2 includes six result zones and a mask 3.
  • the result zones include five test zones 10 and one reaction complete timer 11. Exemplary reaction complete timers are described in U.S. Patent No. 5,843,691.
  • the device 1 which includes an embossed matrix 5 having isolated reaction or test zones 10.
  • the device 1 utilizes a porous matrix member 5 having a test side 30 and a absorbent side 31.
  • the matrix member 5 is attached to the mask 3 by an adhesive layer 21 which contains openings 23 which correspond to the result zones.
  • the matrix member 5 is preferably an intrinsically hydrophilic material and is optionally impregnated or coated with reagents to facilitate testing. A sample of body fluid is absorbed in the matrix member 5 from the absorbent side 31.
  • the body fluid then wicks to the test side 30 where the body fluid interacts with the testing reagents to create a spectrophotometric change.
  • the matrix member 5 and mask 3 are fitted within the frame or support member 2.
  • a second adhesive layer 33 is located adjacent the absorbent side 31 of the matrix member 5 and preferably overlaps matrix member 5.
  • a skin interface layer 7 is located next to the second adhesive layer 33 and includes skin permeation enhancers at locations 8. The skin permeation enhancers preferably protrude through openings 34 in the second adhesive layer 33.
  • a third adhesive layer 6 secures the device to a test area and is protected by a guard 9.
  • the permeation enhancers can comprise chemical means, mechanical means, or one or more combinations thereof.
  • Indicator reagents are present in the matrix member 5, as well as enzymes, buffers, antioxidants and chelators, which are useful in providing a test device which is capable of determining the level of an analyte in the body fluid sample.
  • the various indicator reagents are known in the art and are conventionally formulated into reagent cocktails with solvents and applied to the matrix member 5.
  • the reagent cocktails for each analyte to be detected are formulated into groups which can coexist at the same pH and solvent solution conditions.
  • the indicator in the test side 30 of the matrix changes color to provide the desired indication of the analyte, e.g., glucose, in the sample.
  • the assembly of the first embodiment or device according to the present invention is shown schematically in FIG. 3.
  • the mask 3 is preferably covered by adhesive 21. Openings 25 are punched in the mask 3 to correspond with the test zones 10 and reaction complete timer 11.
  • the matrix 5 is the applied to the mask 3 so that the adhesive 21 adheres to the matrix 5 on the mask 3.
  • the matrix 5 is then embossed into the mask 5 to form uncompressed areas 4 and compressed areas 12.
  • This composite is then attached to a skin interface layer 7 which is treated with one or more skin permeation enhancers in locations 8 which correspond to the uncompressed areas 4 in the matrix member 12.
  • the mask, adhesive and matrix composite is secured to the skin interface layer 7 by the second adhesive layer 33.
  • the third adhesive layer 6 is attached to the frame 2.
  • the third adhesive layer 6 is adjacent the second adhesive layer 33.
  • the adhesive layer 6 acts to secure the patch or device to the patient's skin.
  • the second adhesive layer 33 preferably overlaps an opening in the third adhesive layer 6 in order to add to the overall thickness of the device 1.
  • the guard 9 protects the adhesive layer 6 and the skin interface layer 7 (which optionally contains an antioxidant) until the patch is applied to the patient's skin.
  • FIG. 5 shows a cross section of a second embodiment of the device 1 ' which uses adhesive to segregate the reaction zones 100 without using a mask. Instead, adhesive 102 is imbibed into the matrix 104 to form a hydrophobic barrier which forms reaction zones 100. Otherwise the second embodiment is assembled in the same way as the first embodiment.
  • FIG. 6 shows a sectional view of a third embodiment in accordance with the present invention.
  • the device 1 " of the third embodiment includes a matrix gel 200, and an impermeable backing 202, which is transparent so as not to obscure indicator colors.
  • a pocket 204 to hold gel 200 is formed between backing 202 and a semipermeable membrane 206.
  • the semi-permeable membrane 206 is in communication with gel 200 and is secured to the impermeable backing 202 by heat sealing the membrane 206 and the backing 202 together at their periphery. Multiple pockets may be formed by heat sealing the membrane 206 and backing 202 together to segregate one pocket from another.
  • An absorption side matrix 208 is in communication with semipermeable membrane 206 and acts to wick interstitial body fluid toward the gel matrix 200.
  • a contact adhesive 210 applied to the semipermeable membrane 206 is protected by a release liner 212.
  • the adhesive is connected to a skin compromising system such as those discussed earlier (e.g., a sheet of tiny tines).
  • the adhesive 210 is semipermeable to allow interstitial body fluid pass through the adhesive 210 and ultimately into the gel matrix 200.
  • Advantages of the embodiment shown in FIG. 6 include the safe containment of potentially harmful components of the indicating reagent in the test side matrix and improved adhesion or contact between the patch and skin surface.
  • the strips can either be heat sealed or bonded using hot melt or pressure sensitive adhesive material .
  • the matrix gel 200 preferably includes an osmotic agent (NaCI) along with indicator reagents to greatly improve the kinetics of interstitial fluid flow.
  • NaCI osmotic agent
  • indicator reagents to greatly improve the flow rate of interstitial fluid over the flow rates obtained through the use of skin permeation enhancing means such as chemical adjuvants, electrical potential, ultrasound, mechanical penetration, etc.
  • the visual glucose test strip is applied to the skin surface following removal of the release liner 212.
  • the skin may be pre-treated chemically, mechanically, ultrasonically, or electrically prior to applying the strip or patch.
  • the interstitial fluid will then migrate through the layers of contact adhesive 210, abso ⁇ tion matrix 208, semipermeable membrane 206 and then into the test matrix gel 200.
  • the indicator dye will then develop color at some preprogrammed temporal sequences and/or glucose concentrations.
  • the transparent impermeable backing 202 keeps the interstitial fluid from rising to the surface of the device.
  • the semi-permeable membrane 206 is permeable to glucose but impermeable to the indicator reagent components. Therefore, the embodiment illustrated in FIG. 6 renders improved safety to users by containing indicator reagent components away from the patient's skin.
  • the device 1 '" includes an absorbent or wicking layer 75 is placed between the skin interface layer 7 and matrix 5 to dampen out an analyte signal from contaminants.
  • the wicking or absorbent layer 75 is imbibed with antioxidant.
  • An adhesive 76 is imbibed into those areas of the absorbent layer 75 not corresponding to test zones 30 to make it hydrophobic in those areas.
  • the wicking layer 75 preferably made of a non- woven fibrous sheet such as Accuwik ® 14-12 or Whatman 541. Except for the wicking layer 75, the fourth embodiment can be structurally similar to the first embodiment shown in FIGS. 1-4, thus corresponding features have been labeled using the same reference numerals previously used .
  • All embodiments of this invention can include skin interface layer 7 having tiny tines to replace skin permeation enhancers in locations 8 to compromise the skin so that body fluid can be extracted through the skin.
  • the literature documents these members such as chemical enhancers, tiny tines to roughen the skin to extract interstitial fluid, reverse iontophores, electroporation, and ultrasonic devices.
  • all embodiments can be designed to be completely disposable or have a reusable skin compromising system.
  • the thickness of the skin will be about 0.5 mil or less.
  • the mask member such as 3 in FIG. 2 will preferably be a polymeric strip having a thickness preferably from about 3 mils to about 12 mils in most applications. However, depending on the type of polymeric strip employed a thickness of about 2 to 4 mils may be more preferred for the mask member.
  • the skin interface layer 7 in FIG. 2 preferably has a thickness of from about 0.5 mils to about 5 mils with about 1 to 2 mils in thickness being most preferred.
  • Certain members of the devices of this invention which provide fixed volumetric openings into which the matrix material is compressed will preferably be in the range of 4 to 12 mils in thickness and more preferably about 4 to 5 mils in thickness. It will also be recognized that these members providing the volumetric fixed size openings will preferably be injection molder materials but can be sufficiently rigid in noncompressable polymeric strips from which the desired volumetric opening has been punched or dye cut.
  • the overall thickness of the assembled test strip or patch devices according to the present invention may vary according to the desired use.
  • the overall thickness of the assembled devices preferably range from about 8 to about 40 mils. Due to the strength provided by laminating the various layers, thinner layered materials may be used and provide sufficient strength.
  • the overall thickness of a test device according to this invention will be determined also by the necessary and desired thickness of the matrix member to provide color separation and sufficient volume abso ⁇ tion.
  • the embodiments of this invention providing the fixed volumetric openings will dictate the thickness of the layers providing the volumetric openings of desired volume for the titration tests enabled by the devices of this invention.
  • the typical matrix material When the matrix member is compressed into the adjacent member, the typical matrix material preferably has a thickness of about 5 mils to about 12 mils will preferably be compressed in the compressed area to a thickness of about 1 mil or less and more preferably less than about 0.5 mil. At the same time the portion of the matrix layer which protrudes into the volumetric opening will remain at or near its full original thickness.
  • the methods of assembling the devices according to the present invention will be apparent to one skilled in the art following the teaching contained herein together with conventional laminating techniques for application of adhesive to the various layers, heat bonding various layers and similar techniques for assembly of the devices disclosed herein.
  • the devices according to the invention are conveniently made into test patches of convenient size and configuration for individual use.
  • the devices according to the invention are also configured for visual inspection or for use with instruments or meters which are adapted to measure the color or other indicator provided by the test strips. It is desirable to have a system, or kit, which contains all the necessary supplies for performing a test.
  • a kit is particularly advantageous for diabetic patients, many of whom are highly mobile.
  • the patch can be designed to be completely disposable or have a reusable skin compromising system.
  • the presentation of a complete testing kit is also extremely useful for individuals as well as for clinics or visiting nurse groups where complete segregation of all testing supplies from patient to patient is advantageous.
  • kits 300 An example of a kit 300 according to the present invention is shown schematically in FIG 8.
  • Individually foil wrapped patches 302 coupled with an applicator 304 provides the minimum supplies required to perform a glucose test.
  • the kit 300 includes a prepackaged towlette 306 to clean and/or numb the test area of the patient's skin and a measuring device or chart 308 to facilitate accurate reading of the color change or other indicators of analyte level in the test patch. Measuring devices are described in U.S. Patent No. 5,585,790. By grouping all of the necessary components to perform analyte testing together in a kit, proper and consistent use of the test device is encouraged.
  • Gantrez AN-139 dissolved in water 30 mg horseradish peroxidase, 100 units/mg, and 3.0 glucose oxidase, 2000 units/mi Stir until dissolved.
  • Reagent 3a Damping antioxidant solution of 50:50 ethanol and ascorbic acid at a pH of 4.0, in varying amounts.
  • Test A Polyethersulfone Matrix A piece of polyethersulfone membrane is uniformly coated with reagent la; the excess is squeegeed off and the material is dried. The membrane is then coated with reagent 2a in the same fashion and dried. The antioxidant solution reagent 3a is directly applied to the test areas in varying concentrations using a syringe. The membrane is then assembled into a test device as shown in FIG. 2. The patch is firmly applied to the patients skin opening tiny micro pores in the skin and the glucose level is read from the front based on the indicator response in each of the test zones.
  • a piece of cellulose fiber matrix is discretely coated with reagent la and dried. It is then discretely coated with reagent 2a and dried.
  • the antioxidant solution reagent 3a is applied to each test area in varying concentrations using a syringe.
  • the membrane is then assembled into a test device as shown in FIG. 2. The device is test similar to the polyethersulfone device.
  • Test B Polyethersulfone Matrix A piece of polyethersulfone membrane is uniformly coated with reagent la, the excess is squeegeed off and the material is dried. It is then coated with reagent 2a in the same fashion and dried. The antioxidant solution reagent 3a is applied to the test areas in varying concentrations using a syringe. The membrane is then assembled into a test device as shown in FIGS. 2 and 3. The device is tested similarly to the above test where the highest reacted reaction zone is read.
  • a piece of cellulose and glass fiber matrix is discretely coated with reagent la and dried. It is then discretely coated with reagent 2a and dried.
  • the antioxidant solution reagent 3a is applied to each test area in varying concentrations using a syringe.
  • the membrane is then assembled into a test device as shown in FIGS. 2 and 3. The device is tested similarly to the above test where the highest reacted reaction zone is read.
  • the dry chemistry reagent system can be used with the identified membranes in many different ways.
  • the system can be used to develop a visual patch for multiple analytes or for varying concentrations of the same analyte.
  • the system can be used for meter read or color match tests. Additional enhancements can be developed by interfacing the patch with a meter and providing novel interface systems for the test device and meter.

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Abstract

La présente invention concerne des dispositifs et des procédés permettant d'utiliser les systèmes de réactifs colorés de la chimie sèche pour l'analyse de fluides corporels tels que la glycémie. A cet effet, on utilise un patch jetable pourvu d'une membrane poreuse. Les dispositifs permettent également un microtitrage des échantillons de fluides dans des orifices volumétriques fixes contenant des réactifs. Les dispositifs de l'invention sont bon marché en raison de procédés efficaces utilisés pour la fabrication.
PCT/US1999/020915 1998-09-09 1999-09-09 Procede et dispositif utilisant les fluides interstitiels pour la determination d'un analysat corporel WO2000014535A1 (fr)

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AU60352/99A AU6035299A (en) 1998-09-09 1999-09-09 Interstitial fluid methods and devices for determination of an analyte in the body

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US9964098P 1998-09-09 1998-09-09
US60/099,640 1998-09-09
US9977598P 1998-09-10 1998-09-10
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ES2229915A1 (es) * 2003-07-14 2005-04-16 Ascott Llc Parche para la toma de muestras de fluido corporal.
EP2206462A1 (fr) * 2009-01-13 2010-07-14 Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO Capteur chimique non invasif, timbre cutané, matériaux de conditionnement et système de surveillance l'utilisant
US8919605B2 (en) 2009-11-30 2014-12-30 Intuity Medical, Inc. Calibration material delivery devices and methods
US8969097B2 (en) 2005-06-13 2015-03-03 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit-volume correction and feedback control
US9060723B2 (en) 2005-09-30 2015-06-23 Intuity Medical, Inc. Body fluid sampling arrangements
US9095292B2 (en) 2003-03-24 2015-08-04 Intuity Medical, Inc. Analyte concentration detection devices and methods
CN105916433A (zh) * 2013-10-18 2016-08-31 辛辛那提大学 以确保时间顺序方式的汗液感测
US9603562B2 (en) 2002-02-08 2017-03-28 Intuity Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
US9636051B2 (en) 2008-06-06 2017-05-02 Intuity Medical, Inc. Detection meter and mode of operation
CN106793969A (zh) * 2014-05-28 2017-05-31 辛辛那提大学 具有在传感器和汗腺之间的减小的汗液体积的装置
US9782114B2 (en) 2011-08-03 2017-10-10 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US9833183B2 (en) 2008-05-30 2017-12-05 Intuity Medical, Inc. Body fluid sampling device—sampling site interface
WO2017209688A1 (fr) * 2016-05-31 2017-12-07 Cell Id Pte Ltd Trousse d'analyse
GB2559627A (en) * 2017-02-14 2018-08-15 Ndm Tech Ltd Device
WO2018165180A1 (fr) * 2017-03-06 2018-09-13 Medtronic Minimed, Inc. Capteur colorimétrique pour la détection non invasive du glucose dans la sueur dans le pre-diabète et diabète de type 2
WO2018202922A1 (fr) * 2017-05-05 2018-11-08 University Of Ulster Dispositif de diagnostic minimalement effractif
US10182795B2 (en) 2013-10-18 2019-01-22 University Of Cincinnati Devices for integrated, repeated, prolonged, and/or reliable sweat stimulation and biosensing
US10330667B2 (en) 2010-06-25 2019-06-25 Intuity Medical, Inc. Analyte monitoring methods and systems
US10383556B2 (en) 2008-06-06 2019-08-20 Intuity Medical, Inc. Medical diagnostic devices and methods
US10405794B2 (en) 2016-07-19 2019-09-10 Eccrine Systems, Inc. Sweat conductivity, volumetric sweat rate, and galvanic skin response devices and applications
US10433780B2 (en) 2005-09-30 2019-10-08 Intuity Medical, Inc. Devices and methods for facilitating fluid transport
US10471249B2 (en) 2016-06-08 2019-11-12 University Of Cincinnati Enhanced analyte access through epithelial tissue
US10485460B2 (en) 2015-02-13 2019-11-26 University Of Cincinnati Devices for integrated indirect sweat stimulation and sensing
CN110573063A (zh) * 2017-03-06 2019-12-13 美敦力泌力美公司 用于前驱和2型糖尿病人的汗液中的葡萄糖的非创性筛查的比色传感器
US10506968B2 (en) 2015-10-23 2019-12-17 Eccrine Systems, Inc. Devices capable of fluid sample concentration for extended sensing of analytes
US10646142B2 (en) 2015-06-29 2020-05-12 Eccrine Systems, Inc. Smart sweat stimulation and sensing devices
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US10736565B2 (en) 2016-10-14 2020-08-11 Eccrine Systems, Inc. Sweat electrolyte loss monitoring devices
US10888244B2 (en) 2013-10-18 2021-01-12 University Of Cincinnati Sweat sensing with chronological assurance
US10932761B2 (en) 2014-05-28 2021-03-02 University Of Cincinnati Advanced sweat sensor adhesion, sealing, and fluidic strategies
CN113194814A (zh) * 2018-11-13 2021-07-30 辛辛那提大学 所采集的间质液样本的质量保证
US11129554B2 (en) 2014-05-28 2021-09-28 University Of Cincinnati Sweat monitoring and control of drug delivery
US11253190B2 (en) 2016-07-01 2022-02-22 University Of Cincinnati Devices with reduced microfluidic volume between sensors and sweat glands
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US9603562B2 (en) 2002-02-08 2017-03-28 Intuity Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
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ES2229915B2 (es) * 2003-07-14 2005-11-16 Ascott Llc Parche para la toma de muestras de fluido corporal.
US11419532B2 (en) 2005-06-13 2022-08-23 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
US8969097B2 (en) 2005-06-13 2015-03-03 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit-volume correction and feedback control
US10226208B2 (en) 2005-06-13 2019-03-12 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
US9366636B2 (en) 2005-06-13 2016-06-14 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
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US9380974B2 (en) 2005-09-30 2016-07-05 Intuity Medical, Inc. Multi-site body fluid sampling and analysis cartridge
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US11986293B2 (en) 2008-06-06 2024-05-21 Intuity Medical, Inc. Medical diagnostic devices and methods
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US10383556B2 (en) 2008-06-06 2019-08-20 Intuity Medical, Inc. Medical diagnostic devices and methods
WO2010082820A3 (fr) * 2009-01-13 2010-12-02 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Capteur chimique non invasif, timbre transdermique, matériau de conditionnement et système de surveillance associé
EP2206462A1 (fr) * 2009-01-13 2010-07-14 Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO Capteur chimique non invasif, timbre cutané, matériaux de conditionnement et système de surveillance l'utilisant
US11002743B2 (en) 2009-11-30 2021-05-11 Intuity Medical, Inc. Calibration material delivery devices and methods
US8919605B2 (en) 2009-11-30 2014-12-30 Intuity Medical, Inc. Calibration material delivery devices and methods
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US10639015B2 (en) 2014-05-28 2020-05-05 University Of Cincinnati Devices with reduced sweat volumes between sensors and sweat glands
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US11129554B2 (en) 2014-05-28 2021-09-28 University Of Cincinnati Sweat monitoring and control of drug delivery
US10932761B2 (en) 2014-05-28 2021-03-02 University Of Cincinnati Advanced sweat sensor adhesion, sealing, and fluidic strategies
EP3148416A4 (fr) * 2014-05-28 2018-01-10 University of Cincinnati Dispositifs à volumes de sueur réduits entre capteurs et glandes sudoripares
US11317835B2 (en) 2014-09-22 2022-05-03 University Of Cincinnati Sweat sensing with analytical assurance
US10485460B2 (en) 2015-02-13 2019-11-26 University Of Cincinnati Devices for integrated indirect sweat stimulation and sensing
US10646142B2 (en) 2015-06-29 2020-05-12 Eccrine Systems, Inc. Smart sweat stimulation and sensing devices
US10506968B2 (en) 2015-10-23 2019-12-17 Eccrine Systems, Inc. Devices capable of fluid sample concentration for extended sensing of analytes
US10674946B2 (en) 2015-12-18 2020-06-09 Eccrine Systems, Inc. Sweat sensing devices with sensor abrasion protection
WO2017209688A1 (fr) * 2016-05-31 2017-12-07 Cell Id Pte Ltd Trousse d'analyse
US10471249B2 (en) 2016-06-08 2019-11-12 University Of Cincinnati Enhanced analyte access through epithelial tissue
US11253190B2 (en) 2016-07-01 2022-02-22 University Of Cincinnati Devices with reduced microfluidic volume between sensors and sweat glands
US10405794B2 (en) 2016-07-19 2019-09-10 Eccrine Systems, Inc. Sweat conductivity, volumetric sweat rate, and galvanic skin response devices and applications
US12262990B2 (en) 2016-08-19 2025-04-01 University Of Cincinnati Methods and materials for prolonged sweat stimulation
US10736565B2 (en) 2016-10-14 2020-08-11 Eccrine Systems, Inc. Sweat electrolyte loss monitoring devices
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CN110573063A (zh) * 2017-03-06 2019-12-13 美敦力泌力美公司 用于前驱和2型糖尿病人的汗液中的葡萄糖的非创性筛查的比色传感器
WO2018165180A1 (fr) * 2017-03-06 2018-09-13 Medtronic Minimed, Inc. Capteur colorimétrique pour la détection non invasive du glucose dans la sueur dans le pre-diabète et diabète de type 2
US11986288B2 (en) 2017-03-06 2024-05-21 Medtronic Minimed, Inc. Colorometric sensor for the non-invasive screening of glucose in sweat in pre and type 2 diabetes
EP4361631A3 (fr) * 2017-03-06 2024-07-17 Medtronic MiniMed, Inc. Capteur colorimétrique pour le criblage non invasif de glucose dans la sueur dans le diabète pré et de type 2
WO2018202922A1 (fr) * 2017-05-05 2018-11-08 University Of Ulster Dispositif de diagnostic minimalement effractif
EP3880063A4 (fr) * 2018-11-13 2022-08-24 University of Cincinnati Assurance qualité d'échantillons de fluide interstitiel collectés
CN113194814A (zh) * 2018-11-13 2021-07-30 辛辛那提大学 所采集的间质液样本的质量保证

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