WO2016009228A1 - Réseaux microstructurés à sondes multiples - Google Patents

Réseaux microstructurés à sondes multiples Download PDF

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Publication number
WO2016009228A1
WO2016009228A1 PCT/GB2015/052090 GB2015052090W WO2016009228A1 WO 2016009228 A1 WO2016009228 A1 WO 2016009228A1 GB 2015052090 W GB2015052090 W GB 2015052090W WO 2016009228 A1 WO2016009228 A1 WO 2016009228A1
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WO
WIPO (PCT)
Prior art keywords
electrodes
electrode
functionalized
signals
sensor according
Prior art date
Application number
PCT/GB2015/052090
Other languages
English (en)
Inventor
Tony CASS
Sanjiv Sharma
Original Assignee
Imperial Innovations Limited
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 Imperial Innovations Limited filed Critical Imperial Innovations Limited
Priority to EP15741293.3A priority Critical patent/EP3169234A1/fr
Publication of WO2016009228A1 publication Critical patent/WO2016009228A1/fr

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685Microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/04Arrangements of multiple sensors of the same type
    • A61B2562/046Arrangements of multiple sensors of the same type in a matrix array
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes

Definitions

  • This invention relates to microstructured arrays, in particular electrode arrays, which may be used in sensors, such as biosensor arrays arranged to be placed in contact with the skin to sense analyte(s) in or under the skin, in particular in the dermal interstitial fluid, or may be used in stimulation devices arranged to apply electrical stimulation signals to the tissue or specialized cells such as neural cells.
  • sensors such as biosensor arrays arranged to be placed in contact with the skin to sense analyte(s) in or under the skin, in particular in the dermal interstitial fluid, or may be used in stimulation devices arranged to apply electrical stimulation signals to the tissue or specialized cells such as neural cells.
  • CGM continuous glucose monitoring
  • the present invention provides an electrode array, which may be a micro-structured electrode array, comprising a base with a plurality of groups of probes formed thereon, each group of probes having a conductive layer formed thereon so that the group forms a single electrode, wherein the electrodes are electrically isolated from each other.
  • the conductive layer may be formed, for example, of platinum, gold, silver, or a carbon based material such as carbon nanotubes or graphite.
  • the present invention further provides a sensor device, which may be a biosensor device, comprising a base with a plurality of groups of probes formed thereon, each group of probes having a conductive layer formed thereon so that the group forms a single electrode, wherein the electrodes are electrically isolated from each other, and processing means having an input connected to each of the electrodes to receive a signal therefrom, and arranged to process the signals to generate a sensor output, which may be in the form of an output signal .
  • Each probe may be a single functional device or formation. It may be tapered to a point, for example so that it can pierce the surface of the skin.
  • the tip diameter of the probe may be in the range of 10-50 microns and the height of the microprobe may be in the range of 100 to 1000 microns.
  • the group of probes may form an array, in which each probe may be an independent entity in respect of its functional properties.
  • the sensor device may be arranged to convert a physical or chemical parameter to an electrical signal.
  • the sensor device may be a biosensor, and may be arranged to measure a biological signal or to use biological materials for its function.
  • One of the electrodes may be arranged to form a reference electrode . At least one of the electrodes is arranged to form a sensing electrode .
  • the at least one sensing electrode may be functionalized, and may be arranged to produce a signal indicative of the presence of an analyte .
  • the reference electrode may not be functionalized, or may be functionalized differently from the sensing electrodes.
  • the sensing electrode may comprise a probe or array of probes, which makes contact with the analyte .
  • it should be arranged to apply the desired potential in a controlled way and facilitate the transfer of charge to or from the analyte.
  • the reference electrode may be a probe or array of probes controlling the sensing electrode's potential and it may be arranged to pass no current at any point.
  • Two of the electrodes may be functionalized in different ways.
  • the two electrodes may be arranged to detect the presence of different analytes.
  • At least two of the electrodes may be functionalized in the same way.
  • the processing means may be arranged to generate an average of the signals from the at least two electrodes.
  • At least three of the electrodes may be functionalized in the same way.
  • the processing means may be arranged to identify the signal from at least two of the at least three electrodes as being most similar to each other.
  • the processing means may be arranged to base the output at least predominantly on the signals from those two electrodes.
  • One or more of the sensing electrodes may be functionalized with alternative enzyme to respond to the presence of a second or multiple other analytes.
  • the processing means may then be arranged to compare the signals so as to generate a sensing output indicative of the presence of the other of the analytes.
  • At least one of the electrodes may be functionalized so as to act as a compensation electrode to measure the contributions from interfering species present in the matrix. For example in one of the example of continuous glucose monitoring, the presence of electro-active analytes present in the skin compartment to compensate for the interference . As another example one of the working electrodes may be used to measure the oxygen tension in the analyte matrix under examination.
  • the processing means may be arranged to correct the signal values obtained from sensing electrode, using the signal from the compensation electrode, to nullify the interference effect or to take into account the effect of oxygen concentration in the biological matrix.
  • the compensation electrode may therefore be an electrode that corrects for the other interferants present in the matrix under investigation.
  • One of the electrodes may be arranged to form a counter electrode, which may be arranged to pass all the current needed to balance the current observed, or flowing, at the sensing electrode.
  • the processing means may be arranged to analyse the signals and detect the occurrence of a predetermined change in the signals over time.
  • the sensor/ biosensor may comprise several electrodes that are monolithically integrated on the same structure.
  • the sensor may be arranged to enable continuous monitoring of glucose and/or other analytes such as lactate, for example in the dermal interstitial fluid, and preferably in a minimally invasive and pain free manner.
  • the array may be sub-divided into a reference electrode/counter electrode, a background correction electrode and other sensing electrodes that are functionalized to measure glucose and other analytes simultaneously.
  • the multielectrode arrays add redundancy to the platform thus enabling voting methods (either hardware or software) to improve the accuracy and precision of the device .
  • the functionalization may comprise electro-polymerisation of phenol, for example on the platinum microprobe array electrodes, optionally with glucose oxidase entrapped in the electro-polymerised polyphenol.
  • the functionalization for example of a gold electrode, may comprise forming a self-assembled monolayer of thiols, optionally followed by immobilisation of glucose oxidase enzyme.
  • a membrane may be deposited on the microprobe array electrodes.
  • the invention further provides a stimulation device comprising an electrode array according to the invention, a power source, and control means arranged to generate a stimulation signal from the power source and control the application of the stimulating signal to each of the electrodes.
  • the invention further provides a method of producing a probe according to the invention.
  • the method may comprise making a master, for example a metal master, e.g. of aluminium, making a mould, for example a PDMS mould from the master, and then forming a sensor array, for example from epoxy, in the mould.
  • the electrodes may then be formed on the sensors by forming a mask on the sensor body that defines a number of openings corresponding to the areas to be covered by the electrodes, and then applying the conductive coating to the areas exposed by the mask to form the electrodes.
  • the processor may then mounted on the back of the sensor body and electrically connected to the electrodes.
  • the device may further comprise, in any combination, any one or more features of the preferred embodiments of the invention, which will now be described by way of example only with reference to the accompanying drawings.
  • Figure 1 is a sectional view of a biosensor device according to an embodiment of the invention.
  • Figure 2 is a front view of the biosensor device of Figure 1 ;
  • Figure 3 is a SEM image of part of the device of Figure 1 ;
  • Figure 4 is a set of cyclic voltammograms obtained from the three bare working electrodes against an integrated Ag/AgCl reference electrode with FCA as the redox mediator;
  • Figure Si is a set of dose-response curves obtained after functionalization of a single working electrode.
  • a biosensor device comprises a main sensor body 10 made up of a square base 12 with four groups 13 of microstructures, which in this case take the form of microprobes 14 formed on its front surface 15.
  • the base 12 and microstructures are formed as a single epoxy moulding.
  • Each of the groups of microstructures 14 is arranged in a 4x4 square pattern.
  • Each of the microstructures is in the form of a four-sided pyramid whose height is approximately equal to the width of its base, both of which are very approximately 0.5mm in this embodiment, though of course the exact size and shape will vary depending on the application of the sensors.
  • Each group 13 of microstructures 14, together with the area of the base 12 between the microstructures in the group, is coated with a conductive coating so that together they form a single electrode 16.
  • the area of the base 12 between the groups is not so coated, and the four groups 13 therefore form four electrodes 16 which are all electrically isolated from each other.
  • Three of the electrodes 16 are also functionalized to make them responsive to the presence of a particular analyte, which generally includes applying a substance to the surface of the microstructures 14 that will react with the analyte to produce a detectable signal on the electrode.
  • One of the electrodes is not so functionalized and forms a reference electrode .
  • a processor 20 is mounted on the back of the base 12, i.e. on the opposite side to the microprobes 14, and each of the functionalized electrodes and reference electrode 16 is connected to a respective input of the processor by a respective conductor 22. Although shown schematically, the conductors 22 are most easily formed on the surface of the base 12.
  • the processor 20 is arranged to detect the signals of the functionalized electrodes, and process them to generate an output at an output 24 of the processor. Fabrication of the device can be carried out in a variety of ways such as injection moulding, hot embossing, laser micromachining, 3D printing and micromoulding.
  • the process comprises making moulds, for example PDMS moulds, from metal masters, for example aluminium masters, and then forming epoxy microstructured sensor arrays in the moulds.
  • the electrodes are then formed on the sensors by forming a mask on the sensor body that defines a number of openings corresponding to the areas to be covered by the electrodes, and then applying the conductive coating to the areas exposed by the mask to form the electrodes.
  • the processor is then mounted on the back of the sensor body and electrically connected to the electrodes.
  • the aluminium master is produced by electric discharge milling of aluminium blocks.
  • the master corresponds in shape to the final probe which is described in more detail below.
  • microprobe array structures can be manufactured in each batch. Each batch takes approximately 3 hours to manufacture.
  • microprobe array structures one from each batch.
  • the first is for producing a microprobe electrode array with platinum working and counter electrodes and a Ag/AgCl reference electrode .
  • the second is for producing an array with gold working and counter electrodes and a Ag/AgCl reference electrode. Many of the steps are common to both methods.
  • the chamber in which the device is metallised is controlled and subjected to inert gases such as nitrogen and argon.
  • the metallisation is done at low pressure (2xl 0 ⁇ 6 Bar).
  • the silver microprobe array electrode can be modified to a silver/silver chloride reference electrode by treating the electrode with a saturated solution of Ferric chloride or by electrochemical modification.
  • spin photoresists such as the AZ photoresist or the SU 8 epoxy material.
  • Functionalization of the metallised microprobe arrays can be done in many different ways depending on what the sensor is to be used for. We describe here two different methods for functionalization of the microprobe array electrodes, each of which can be used to make them suitable for use as amperometric glucose biosensors.
  • the first method involves electropolymerisation of phenol on the platinum microprobe array electrodes with glucose oxidase entrapped in the electropolymerised polyphenol.
  • the second method is for functionalization of gold microprobe array electrodes using self- assembled monolayer of thiols followed by immobilisation of glucose oxidase enzyme and depositing a membrane conformally on the microprobe array electrodes. The membrane can also be deposited on the electrodes functionalized by the first method. Electropolymerisation of platinum microprobe array electrodes
  • the platinum working electrodes should be poised at 0V for 20 seconds and then biased at 0.9V for 15 minutes using a potentiostat, this cycle can then be repeated six times.
  • Cyclic voltammetry (CV) showing multielectrode system showing integrated reference electrode The monolithically integrated microprobe arrays were tested by performing cyclic voltammetry using ferrocene carboxylic acid (FCA) as a redox species.
  • FCA ferrocene carboxylic acid
  • the metallised microprobe arrays comprised four 4X4 sub-arrays. One of these sub-arrays was metallized with silver, and the other four were conformally sputtered with 150 nm gold.
  • Figure 5 is a set of dose-response curves obtained after functionalization of a single working electrode (WE I - squares) with glucose oxidase.
  • WE2 triangles
  • WE3 circles
  • the processing performed by the processor 20 will depend on the manner in which the electrodes have been functionalized. In this embodiment there are three working electrodes, which have been functionalized in the same way, and one reference electrode .
  • the processor is arranged to record sample values of each of the electrode signals taken at a regular sample frequency.
  • the processor 20 is then arranged for each sample time to determine for each of the working electrodes a normalised signal value by determining the difference between the working electrode and the reference electrode.
  • the processor is then arranged to compare the three normalised values and determine an average value for all three and record that as an average signal for that sample time.
  • the processor prior to calculating the average, can be arranged to determine a measure of dissimilarity of each of the signals of the three working electrodes from the other two, and if the degree of dissimilarity for one of the signals exceeds a predetermined level, to discard that signal in calculating the average output value .
  • the processor is arranged to output the average value at the output 24 as a real time output. However it is also arranged to analyse them to determine whether the variation on the average signal over time meets any of a number of predetermined conditions. These may include, exceeding a predetermined rate of change with respect to time, exceeding a predetermined threshold, or falling below a predetermined threshold. If one of these conditions is met, then the processor is arranged to transmit a warning signal via the Bluetooth transmitter 26. It will be appreciated that the analysis of the electrode signals can be carried out in a variety of ways depending on the type of test that is being done . The averages can be calculated in different ways or over different time periods, either the real time signal output, or the analysis of stored sample values can be omitted.
  • one of the three sensing electrodes functionalized in a different way from the other two so as to act as a compensation electrode.
  • the two sensing electrodes can be functionalized to respond to glucose, but will typically also respond to other analytes or 'interfering species' . Therefore the compensation electrode functionalized so as to respond to the interfering species, but not to glucose.
  • the controller is arranged to compare the signals from the compensation electrode with those from the sensing electrodes to generate two compensated sensing signals, which are then averaged to generate an output .
  • the signal from the reference electrode is used to normalize the signals from each of the three other electrodes prior to the comparison.
  • the output value is then generated at the output 24 of the device .
  • a stimulation electrode device comprises the electrode array structure of Figures 1 and 2, but without functionalization of the electrodes 16.
  • the processor 20 is connected to a power source and arranged to generate a stimulating signal from the power source and to apply the stimulating signal to the electrodes 16 so as to provide stimulating signals at the electrodes.
  • the provision of separate electrodes on the same device allows different signals to be applied to each of the electrodes and therefore to different areas of the skin.
  • the processor is not present on the device, and the electrodes are connected to a remote power supply and controller, which applies the stimulating signals to the electrodes.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Medical Informatics (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Emergency Medicine (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un réseau d'électrodes microstructuré qui comprend une base (12) sur laquelle sont formés plusieurs groupes de sondes (14), une couche conductrice étant formé sur chaque groupe (13) de sondes de façon que le groupe (13) forme une électrode unique, les électrodes étant électriquement isolées les unes des autres.
PCT/GB2015/052090 2014-07-17 2015-07-17 Réseaux microstructurés à sondes multiples WO2016009228A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP15741293.3A EP3169234A1 (fr) 2014-07-17 2015-07-17 Réseaux microstructurés à sondes multiples

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1412696.5A GB201412696D0 (en) 2014-07-17 2014-07-17 Multi-probe microstructed arrays
GB1412696.5 2014-07-17

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WO2016009228A1 true WO2016009228A1 (fr) 2016-01-21

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EP (1) EP3169234A1 (fr)
GB (1) GB201412696D0 (fr)
WO (1) WO2016009228A1 (fr)

Cited By (7)

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WO2020069569A1 (fr) * 2018-10-02 2020-04-09 WearOptimo Pty Ltd Système actionneur
WO2020069567A1 (fr) * 2018-10-02 2020-04-09 WearOptimo Pty Ltd Agencement d'électrodes
JP2020514754A (ja) * 2017-03-21 2020-05-21 インターナショナル・ビジネス・マシーンズ・コーポレーションInternational Business Machines Corporation 3次元構造の検知面を有するセンサ、並びに、そのセンサの形成方法および使用方法
CN113040765A (zh) * 2019-12-27 2021-06-29 全康科技股份有限公司 可穿戴感测装置
WO2022090741A1 (fr) * 2020-10-02 2022-05-05 Continuous Diagnostics Ltd Capteur destiné à la surveillance in vivo d'un analyte
EP4033234A4 (fr) * 2019-09-18 2022-11-16 PHC Holdings Corporation Substrat d'électrode, procédé de fabrication associé et biocapteur mettant en oeuvre ledit substrat
US11877846B2 (en) 2021-07-07 2024-01-23 The Regents Of The University Of California Wearable, non-intrusive microneedle sensor

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WO2013055234A1 (fr) * 2011-10-14 2013-04-18 Digital Sensing Limited Matrices et procédés de fabrication
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US20140163346A1 (en) * 2012-12-06 2014-06-12 Medtronic Minimed, Inc. Microarray electrodes useful with analyte sensors and methods for making and using them
WO2014152717A2 (fr) * 2013-03-14 2014-09-25 Sano Intelligence, Inc. Microcapteur porté sur le corps destiné à une biosurveillance

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Publication number Priority date Publication date Assignee Title
WO2012040243A1 (fr) * 2010-09-20 2012-03-29 Emkinetics, Inc. Procédé et appareil permettant une stimulation transdermique des surfaces palmaire et plantaire
WO2013055234A1 (fr) * 2011-10-14 2013-04-18 Digital Sensing Limited Matrices et procédés de fabrication
US20130313130A1 (en) * 2012-05-25 2013-11-28 Medtronic Minimed, Inc. Foldover sensors and methods for making and using them
US20140163346A1 (en) * 2012-12-06 2014-06-12 Medtronic Minimed, Inc. Microarray electrodes useful with analyte sensors and methods for making and using them
WO2014152717A2 (fr) * 2013-03-14 2014-09-25 Sano Intelligence, Inc. Microcapteur porté sur le corps destiné à une biosurveillance

Cited By (14)

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Publication number Priority date Publication date Assignee Title
US11320394B2 (en) 2017-03-21 2022-05-03 International Business Machines Corporation Biosensor electrode having three-dimensional structured sensing surfaces
US11293896B2 (en) 2017-03-21 2022-04-05 International Business Machines Corporation Biosensor electrode having three-dimensional structured sensing surfaces
JP2020514754A (ja) * 2017-03-21 2020-05-21 インターナショナル・ビジネス・マシーンズ・コーポレーションInternational Business Machines Corporation 3次元構造の検知面を有するセンサ、並びに、そのセンサの形成方法および使用方法
JP7024158B2 (ja) 2017-03-21 2022-02-24 インターナショナル・ビジネス・マシーンズ・コーポレーション 3次元構造の検知面を有するセンサ、並びに、そのセンサの形成方法および使用方法
US11092567B2 (en) 2017-03-21 2021-08-17 International Business Machines Corporation Biosensor electrode having three-dimensional structured sensing surfaces
WO2020069567A1 (fr) * 2018-10-02 2020-04-09 WearOptimo Pty Ltd Agencement d'électrodes
WO2020069569A1 (fr) * 2018-10-02 2020-04-09 WearOptimo Pty Ltd Système actionneur
EP4033234A4 (fr) * 2019-09-18 2022-11-16 PHC Holdings Corporation Substrat d'électrode, procédé de fabrication associé et biocapteur mettant en oeuvre ledit substrat
EP3841963A1 (fr) * 2019-12-27 2021-06-30 RichHealth Technology Corporation Dispositif de détection vestimentaire
EP3841975A1 (fr) * 2019-12-27 2021-06-30 RichHealth Technology Corporation Dispositif de détection portable
CN113040765A (zh) * 2019-12-27 2021-06-29 全康科技股份有限公司 可穿戴感测装置
TWI832001B (zh) * 2019-12-27 2024-02-11 全康科技股份有限公司 可穿戴感測裝置
WO2022090741A1 (fr) * 2020-10-02 2022-05-05 Continuous Diagnostics Ltd Capteur destiné à la surveillance in vivo d'un analyte
US11877846B2 (en) 2021-07-07 2024-01-23 The Regents Of The University Of California Wearable, non-intrusive microneedle sensor

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