Device for sampling one or more analytes

Abstract

<DP=1>²The application relates to a device (100) for non-invasively sampling ²interstitial fluid comprising one or more analytes ²from dermis (101 a) to skin surface (101 b) by using the magneto-hydrodynamic ²effect. The device comprises a first electrode (102a) and ²a second electrode (102b) adapted to be positioned adjacent to the skin ²surface, the first electrode separated from the second electrode ²by a distance (103), a power source (104) adapted to induce an electric ²current through the first electrode, the interstitial fluid and the ²second electrode, and also a magnet (105) adapted to produce a magnetic field ²to the interstitial fluid. Direction of the magnetic field ²and direction of the electric current produced by the magnet and the power ²source, respectively, is such that Lorenz force drives the ²fluid from the dermis towards the skin surface.²<DP=2>²²

Description

<DP=1>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²1²DEVICE FOR SAMPLING ONE OR MORE ANALYTES²FIELD²This invention relates to devices based on magneto-hydrodynamics (MHD) to ²extract fluid²comprising one or more analytes from a target, in particular, interstitial ²fluid from skin.² BACKGROUND²Interstitial fluid (IF) is an aqueous solution that serves as a transport ²medium for e.g. glucose ²and electrolytes between the cells and the circulatory system. Therefore, the ²concentration ²of different solutes, such as glucose and lactic acid, in IF and in blood ²exhibits a substantial ²correlation. This makes the analysis of IF relevant to many developing fields, ²including,²io medical diagnosis, early disease detection, pharmacokinetics, and smart ²wearable²technologies. Furthermore, a strong commercial and scientific interest ²promotes research ²on painless and non-invasive IF sampling methods.²U52002 / 0002328A1 discloses a noninvasive IF device and method for sampling ²substances ²such as glucose through skin by reverse iontophoresis. The device is designed ²to monitor²blood glucose levels in people with diabetes. The device is not considered a ²replacement,²but an addition to conventional invasive blood glucose monitoring.²W02010001122A2 discloses a patch for sampling one or more analytes through the ²skin of ²a patient. The patch comprises an electrode layer that is positioned adjacent ²to the skin of ²a patient, and means for actuating an electrode layer to induce the withdrawal ²of analyte²through the skin by reverse iontophoresis. The patch comprises reservoir ²chambers ²containing an electrically conducting medium to induce the process of ²iontophoresis. ²According to the document, the presence of an electrolyte in liquid form ²ensures good ²conductivity between the electrodes and the skin, which enhances the ²effectiveness of the ²reverse iontophoresis process.²The state-of-the-art devices discussed above for noninvasive glucose ²monitoring are based²on the harnessing of osmotic flow or electrophoresis. In these devices, the ²extraction occurs ²locally at the electrode-skin interface. Accordingly, a limited volume of ²fluid can be extracted ²and analyzed, which in turn requires sensitive detection and analysis ²techniques.²Thus, there is still need for further devices for sampling analytes through ²skin with improved²efficacy and extraction rate.²<DP=2>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²2²SUMMARY²The present invention is based on the observation that at least some of the ²state-of-the-art ²problems related to sampling of one or more analytes from skin can be solved ²or at least ²alleviated by exploiting the magneto-hydrodynamic (MHD) phenomenon.²Accordingly, it is an object of the present invention to provide a device for ²sampling interstitial²fluid comprising one or more analytes from dermis to skin surface in a non-²invasive manner, ²the device comprising²- a first electrode and a second electrode adapted to be positioned ²adjacent to the skin ²surface, the first electrode separated from the second electrode by a ²distance,²lo - a power source adapted to induce electric current through the first ²electrode, the interstitial²fluid and the second electrode, and²- one or more magnets adapted to induce magnetic field to the interstitial ²fluid.²According to the device of the present invention direction of the magnetic ²field produced by ²the one or more magnets, and direction of the electric current produced by the ²power source²is adapted to be such that Lorentz force produced by the magnetic field and ²the electric²current is adapted to drive the interstitial fluid from the dermis ²substantially towards the skin ²surface.²According to the device of the present invention, the IF can be sampled from ²the skin not ²only locally at the electrode-skin interface as in the state of the art, but ²also between the²electrodes, where a further volume of IF is available. Furthermore, MHD adds a ²force²component that increases the extraction rate under a negative electrode.²Further objects of the present invention are described in the accompanying ²dependent ²claims.²Exemplifying and non-limiting embodiments of the invention, both as to ²constructions and to²methods of operation, together with additional objects and advantages thereof, ²are best²understood from the following description of specific exemplifying embodiments ²when read ²in connection with the accompanying drawings.²The verbs "to comprise" and "to include" are used in this document as open ²limitations that ²neither exclude nor require the existence of un-recited features. The features ²recited in the²accompanied depending claims are mutually freely combinable unless otherwise ²explicitly²<DP=3>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²3²stated. Furthermore, it is to be understood that the use of "a" or "an", i.e. ²a singular form, ²throughout this document does not exclude a plurality.²BRIEF DESRCIPTION OF THE DRAWINGS²Figure 1 illustrates the principle of the device according to the present ²invention for sampling².. e.g. extracting an analyte such as glucose (black dots) from skin; (+): the ²first electrode; (-):²the second electrode; dotted arrow: direction of electric current; (B): ²magnetic field; upper ²layer: the epidermis; middle layer: dermis; lower layer: hypodermis; white ²arrows: fluid ²displacement in the direction of the Lorentz force; black arrows: direction of ²electrophoresis,²figure 2 illustrates an exemplary non-limiting device according to the present ²invention,² io figure 3 illustrates exemplary non-limiting electrode shapes,²figure 4 illustrates an exemplary magnet array suitable for use in the device ²according to the ²present invention,²figure 5 illustrates a schematic view of a non-limiting exemplary device in ²form of a wristband ²according the present invention, and².. figure 6 illustrates result of treatment of a skin sample using an ²exemplary device of the²present invention (MHD to the left) and by using a device according to state ²of the art ²(electrophoresis to the right).²DESCRIPTION²According to one embodiment, the present invention concerns a device for ²sampling IF in a²non-invasive manner. The IF comprises one or more analytes to be analyzed. ²According to²the invention, the IF is extracted from the skin by exploiting the MHD ²phenomenon.²Figure 1 shows the working principle of the present invention. In the figure, ²the device serves ²to extract IF from skin. Accordingly, an electric current produced by a power ²source is ²established through a pair of electrodes (marked with + and -) and the skin. ²The magnetic²field (B) is produced by a magnet. The current density in the middle skin ²layer (dermis) is²substantially higher than in the inner (hypodermis) or outer (epidermis) skin ²layers because ²the higher content of IF in the dermis offers a lower impedance electric path. ²When the ²device is in operation, the direction of the magnetic field is substantially ²perpendicular to the ²skin surface, particularly within the distance and at the location of the ²electrodes, and²substantially perpendicular to desired direction of fluid displacement from ²the dermis to the²<DP=4>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²4²skin surface. Therefore, the current-carrying fluid in the magnetic field ²experiences a Lorentz ²force towards the skin surface. This force serves to drive IF out of the skin. ²The driving force ²exerted in the fluid is described by the equation F = J x B; where F, J, and B ²are the force, ²current density, and magnetic field vectors respectively, and x indicates a ²cross product.²Based on this equation, the vectors of Lorentz force, electric current, and ²magnetic field are²all perpendicular to each other. Also, the force distribution is defined by ²the distribution of ²the electric current and the magnetic field. The distribution of Lorentz force ²in the current ²carrying fluid permits directional driving of the IF out of the skin along the ²whole / entire current ²path i.e. along the distance between the electrodes. The fluid displacement in ²the direction²lo of the Lorentz force is indicated with white big arrows. The IF ²containing relevant analytes,²such as glucose, shown as black dots in the figure, is extracted also along ²the distance ²between the electrodes and not only under the negative electrode wherein also ²electrophoresis (black small arrows) promotes movement of fluid towards the ²electrode-skin ²interface.²An exemplary device according to the present invention is shown in figure 2. ²Accordingly, a²device 100 for sampling IF comprising one or more analytes from dermis 101a to ²skin ²surface 101b comprises²- a first electrode 102a and a second electrode 102b adapted to be ²positioned adjacent to ²the skin surface, the first electrode separated from the second electrode by a ²distance 103,²- a power source 104 adapted to induce an electric current through the first ²electrode, the²interstitial fluid and the second electrode, and²- a magnet 105 adapted to induce a magnetic field to the interstitial ²fluid, wherein direction ²of the magnetic field produced by the magnet and direction of the electric ²current produced ²by the power source is such that that Lorentz force is adapted to drive the ²interstitial fluid²from the dermis substantially towards the skin surface along the entire ²current path, in²particular within the distance and the (-)-electrode.²When the device is in operation, the electric current flows substantially in ²three different ²directions as described by the dotted arrow in figure 2: initially from the ²first electrode ²towards the skin, in particular towards the dermis comprising the IF, then ²within the distance²between the electrodes, substantially parallel to the skin surface, and ²finally from the dermis²towards the second electrode (i.e. the (-)-electrode), i.e. in ¨y-, x- and y-²directions,²<DP=5>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²respectively of the coordinate system 199 of figure 2. Accordingly, the ²electric current ²contributes to driving a certain volume of IF towards the second electrode.²In order to produce a Lorentz force in the current-carrying IF in the skin ²towards the skin ²surface, the magnet should produce a magnetic field that is substantially in z-²direction of the²5 coordinate system 199. Accordingly, the MHD effect produced by the ²magnetic field and the²electric current drives the IF comprising the one or more analytes from the ²dermis ²substantially towards the skin surface within the distance and below the (-)-²electrode 102b. ²Accordingly, the direction of the flow of the IF is substantially in y-²direction of the coordinate ²system 199.²io According to an exemplary embodiment the first electrode, and the second ²electrode is a ²silver-silver chloride (Ag-AgCI) electrode to avoid electrolysis of water and ²pH drifts. ²However, other inert and non-ferromagnetic materials are also suitable. ²Exemplary further ²materials are carbon, gold, and platinum.²The electrodes can be coated with different materials, for instance, enzymes ²and catalysts²such as glucose oxidase, dehydrogenase and Prussian blue. Furthermore, ²different²materials or combination of materials can be used as an interface between the ²electrodes ²and the skin for instance to reduce the electric impedance, to protect the ²electrode coating ²and to facilitate the analysis of the extracted IF samples. Suitable materials ²for this purpose ²include biocompatible membranes (i.e. permeable or semipermeable) made of ²regenerated² cellulose, silicone and monofilament fabric of polyamide.²The interface serves to maintain a low electric impedance between the ²electrodes and the ²skin, to facilitate the transport of analytes towards the device, to preserve ²electrochemical ²conditions (e.g. pH) and activity of the enzyme. In one embodiment, the ²electrode skin ²interface is preferable a gel or hydrogel. In another preferred embodiment, ²the electrode².. skin interface is a membrane which is permeable or semipermeable, ²electrically conductive,²and hypoallergenic. Exemplary materials suitable for this purpose include ²biocompatible ²membranes (i.e. permeable or semipermeable) made of regenerated cellulose, ²silicone and ²monofilament fabric of polyamide. These membranes can be treated with agents ²that work ²as humectants (i.e. glycerol, agarose gel and phosphate buffered saline) to ²help maintain²the desired pose structure and to increase its electric conductivity. The ²membranes can also²be loaded with agents, such as corticosteroids and other drugs, to prevent or ²reduce ²potential skin reactions induced by the extraction procedure.²<DP=6>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²6²According to the exemplary embodiment shown in figure 2, the first electrode ²102a is acting ²as a positive electrode and the second electrode 102b is acting as a negative ²electrode. It ²is to be understood that the polarity of the electrodes can be flipped and ²that other ²configurations are possible. The first electrode and the second electrode are ²preferably²substantially parallel to each other. The device may include plurality of ²first electrodes and²plurality of second electrodes. The electrodes can be same of different.²The first electrode and the second electrode comprise a contact surface. The ²contact ²surfaces are shown in figure 2 with reference numbers 106a and 106b for the ²first electrode ²and the second electrode, respectively. According to one exemplary embodiment, ²the²io contact surface of the electrodes is flat and either circular e.g. disk-²shaped, rectangular,²elliptical or pyramidal. According to another embodiment the contact surface ²is adapted to ²the shape of the skin surface. For example, if the skin is in a finger or in ²the wrist, the contact ²surface may be substantially curved to allow maximal mechanical and electric ²contact with ²the skin. The contact surface may comprise extrusions and / or protrusions to ²facilitate² maximal adherence to the skin surface.²The area of the contact surface of each electrode is preferably between 0.01 ²cm2 and 9 cm2, ²and most preferably between 0.15 cm2 and 1 cm2. The distance between the first ²electrode ²and the second electrode is preferably between 1 mm and 5 cm, and most ²preferably ²between 5 mm and 3 cm. According to an exemplary embodiment the distance is 1 ²cm.²According to one embodiment, the shape of the contact surface of the ²electrodes is elliptical,²and the major axis of the ellipsis is substantially larger than the minor ²axis. This allows to ²set a larger current density through the dermis without increasing the current ²density at the ²electrode-skin interface. Exemplary electrode shapes are shown in figure 3. ²This figure ²depicts five cases illustrating different electrode configurations (first ²electrode to the left, and²second electrode to the right). The current density through the target such as ²skin can be²different in all cases even if the contact area of the electrodes is the same. ²The electrode ²shape can alter the distribution of electric current in the skin, and ²therefore, the local current ²density to increase the Lorentz force and the extraction rate of IF. For this ²reason, the ²elliptical electrode shapes illustrated in case 3 are preferable.²The power source 104 can be a direct current (DC) power source and / or an ²alternating ²current (AC) power source that limits and regulates the energy i.e. the ²intensity of the electric ²current and / or voltage delivered through the electrodes. According to an ²exemplary²<DP=7>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²7²embodiment, the power source is a floating current source that provides means ²to establish ²a direct electric current preferably in the range of 10 pA to 10 mA, and more ²preferably in ²the range 0.1 mA to 1 mA. The current density at the electrode-target, such as ²skin interface ²is preferably between 1 pA / cm2 and 10 mA / cm2, and most preferably between 0.1 ²mA / cm2²and 1 mA / cm2. The voltage provided by the current source is preferable ²between 1 and 100²V.²In a particular embodiment, the electric current established by the floating ²current source ²exhibits a unipolar (unidirectional) or bipolar (e.g. bidirectional or ²alternating) waveform. The ²frequency of the electric signal is preferably between 0.1 Hz and 100 kHz, and ²more²io preferably between 10 Hz and 10 kHz. The electric signal can be ²modulated in amplitude²and / or frequency, and can have different waveforms, for instance, sine, ²square, pulsed (e.g. ²rectangular), triangle, and saw tooth. Also, the signal can be burst- and / or ²duty-cycle-²modulated.²The magnet 105 can be a permanent magnet or an electromagnet. The intensity of ²the²magnetic field at the surface of the magnet is preferably between 0.01 mT and ²2 T, and most²preferably between 0.1 mT and 500 mT. The distance between the magnet and the ²electrodes is preferably less than 5 cm, more preferably less than 3 cm, and ²most preferably ²less than 1 cm. According to an exemplary embodiment, the magnetic field is ²provided by a ²neodymium magnet located 0.5 cm apart from the skin surface when the device is ²at its²operational position. Also, when the device is at its operational position, ²the direction of the²magnetic field is substantially perpendicular to the skin surface within the ²distance and ²substantially perpendicular to desired direction of fluid displacement from ²the dermis to the ²skin surface. Consequently, the dermal IF is driven towards the surface of the ²skin.²According to another embodiment the device comprises plurality of magnets. ²According to²an exemplary embodiment, the magnetic field is provided by an array of magnets ²or ²electromagnets. An exemplary array is a Halbach array 211 shown in Figure 4. ²Two of the ²magnets are shown with the reference numbers 205a and 205b. The overlapping ²magnetic ²fields of the magnets in the array combine to produce a resultant magnetic ²field acting in ²one direction marked with the letter B. The electrodes (not shown) are ²positioned inside the²array so that the electric field E is as shown in the coordinate system 299. ²Accordingly, the²direction of IF extraction can be adapted to be towards the skin surface.²<DP=8>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²8²The use of arrays of magnets allows to modulate (i.e. to augment, decrease or ²cancel) the ²magnetic field directionally or locally. For instance, a circular Halbach ²array consisting on a ²cylinder composed of neodymium magnets can be used to produce an intense ²magnetic ²field confined within the cylinder. Moreover, the array of magnets can be ²positioned²wrapping the electrode and the extraction site, for instance in a ring or ²wristband, where the²electrodes are arranged inside the cylinder. This allows having a strong ²magnetic field at ²the extraction site while keeping a week magnetic field elsewhere.²According to one embodiment the device comprises means 107 adapted to store ²(e.g. to ²collect) and / or means 108 adapted to analyze the IF comprising one or more ²analytes²lo extracted from the skin. According to an exemplary embodiment, the storing ²means ²comprises one or more capillaries located within the distance 103. The one or ²more ²capillaries are preferably coaxial with the electrodes, and one end of the ²capillaries is located ²so that the IF extracted from the skin moves into the one or more capillaries. ²According to a ²particular embodiment, the means adapted to store the fluid, such as the one ²or more²capillaries or a reservoir, act also as means adapted to transfer the fluid to ²means 108²adapted to analyze the one or more analytes. Alternatively, the means 108 is ²adapted to ²record one or more signals derived from the one or more analytes and to send ²the one or ²more signals to means adapted to analyze them. According to an exemplary ²embodiment, ²the means 107 and / or 108 comprises medium such as gel or liquid comprising ²glucose²oxidase adapted to form hydrogen peroxide, the concentration of which is ²determined ²electrochemically and / or optically. The means 107 and 108 are preferably ²located within the ²distance and / or under one or more electrodes. According to another embodiment, ²the device ²comprises means for storing and analyzing interstitial fluid. According to ²still another ²embodiment, the analyzing means is separated from the device.²According to an exemplary embodiment, the device comprises a frame 109 adapted ²to ²position the electrodes, the power source, and the magnet, and any further ²means of the ²device such as the energy storing means (such as a battery), the IF storing ²means and the ²IF analyzing means. The contact surface of the first electrode, the contact ²surface of the ²second electrode, and preferably also the means adapted to store and / or ²analyze the one²or more analytes are on the surface of the frame adapted to be in direct or ²indirect contact²with the skin surface.²According to another embodiment the frame of the device is of pocket size.²<DP=9>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²9²According to an exemplary embodiment, the MHD device of the present invention ²is ²combined with other approaches, such as sonoporation, laserporation, ²electroporation and ²hydraulic pressure, to increase the permeability of the skin. The different ²permeability-²enhancing approaches can be used to disrupt the mechanical properties of the ²upper layer²of the skin (e.g. the stratum corneum) temporarily or permanently. This can ²facilitate the IF²extraction. For instance, sonoporation can be applied before or during IF ²extraction with the ²device of the present invention (e.g. constantly or recurrently). Accordingly, ²the device of the ²present invention may comprise one or more means 110 selected from ultrasound ²generating means, laser light generating means, electroporation generating ²means,² .. hydraulic pressure generating means.²Another exemplary non-limiting device 300 according to the present invention ²is shown in ²figure 5. Frame of the device is in form of a wristband 309. The device shown ²therein ²comprises a first electrode 302a and a second electrode 302b adapted to be ²positioned ²adjacent to skin surface. The first electrode and the second electrode are ²separated by a²distance 303. The device comprises also a power source 304 adapted to induce ²an electric²current through the first electrode, interstitial fluid and the second ²electrode when the device ²is at its operational position. The device comprises also a magnet 305 adapted ²to induce a ²magnetic field to the IF. Direction of the magnetic field and direction of the ²electric current is ²such that Lorentz force is adapted to drive the IF from dermis substantially ²towards the skin²surface. The magnetic field can also be produced by a plurality of magnets, ²such as an array²of magnets as shown in figure 4.²In order to produce Lorentz force in the current-carrying IF in the skin ²within the distance ²and below the negative electrode towards the skin surface, the magnet 305 ²should produce ²a magnetic field that is substantially in z-direction of the coordinate system ²399. Accordingly,².. the MHD effect generated by the magnetic field produced by the magnet 305 ²or plurality of²magnets and the electric current established by the power source 304 drives ²the IF ²comprising the one or more analytes from dermis substantially towards the skin ²surface. ²Accordingly, the direction of the flow of the IF is substantially in y-²direction of the coordinate ²system 399. The location of the power source and the magnet in figure 5 are ²only illustrative.²The advantages of this embodiment are that the wristband can offer means to ²position the²first electrode and the second electrode in contact with the skin, for ²instance, by using ²adhesive materials, pneumatic force and / or mechanical pressure. According to ²the²<DP=10>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²embodiment shown in the figure, a permanent magnet is arranged in the ²wristband close to ²target site of interstitial fluid extraction, so that the magnetic field is ²substantially ²perpendicular to the skin surface within the distance and substantially ²perpendicular to the ²direction of fluid from the dermis to the skin surface. To accomplish this, ²the wristband may²5 have movable parts such as a retractable magnet holder. Furthermore, the ²wristband can²offer means to collect, transport, store and / or analyze the interstitial fluid ²sample (not shown ²in figure 5). Also, the wristband can be provided with an electronic or ²electro mechanical ²user interface comprising, for instance, a display 310, such as a touch screen ²display, push ²buttons, and mechanical, visual and / or audio indicators (e.g. light emitting ²diodes,²io loudspeaker and vibrating alarms). Furthermore, the wristband may have ²means to store ²data such as an electronic circuit and means to send data, preferably ²wirelessly, to another ²electronic device such as a cellphone, a tablet, a computer or an insulin ²pump. Also, the ²device may have means to connect to Internet. An electronic circuit in the ²wristband can ²also serve to monitor the electric current and / or voltage applied to the skin ²to assess the²electrode-skin electric contact. The energy required for the operation of the ²electronic circuit²can be provided by, for instance, a rechargeable battery adapted in the ²wristband. In one ²particular embodiment of the invention, the wristband encompasses one or more ²capillaries ²made of organic or inorganic materials (e.g. polyfluorocarbon, polyethylene, ²polyvinyl ²chloride, and borosilicate glass) to collect the interstitial fluid sample. ²The tip of the²capillaries is arranged close to, or in contact with, the extraction site. For ²instance, they can²be arranged in the electrode gap and / or integrated in the first electrode ²and / or in the second ²electrode. Other suitable elements to collect the extracted IF samples or ²compounds in the ²IF samples include electrically and / or magnetically charged materials, ²hydrophobic and / or ²hydrophilic materials, and absorbent materials. In another particular ²embodiment of the²invention, the electrodes are coated with a substance or mixture that reacts ²(e.g. chemically²or physically) or that binds to one or more constitutes of the IF sample. ²Exemplary electrode ²coatings include gels, such as hydrogels and polymeric gels, where the gels ²can be further ²loaded with reagents such as enzymes, for instance, glucose oxidase. The ²electrode coating ²can serve to collect the sample of interstitial fluid or particular components ²of the sample²and to allow further sample analysis, for instance, to measure the content of ²glucose, lactic²acid or other compounds in the IF sample by applying current technologies or ²technologies ²developed in the future. Also, in humans, this invention can also be ²implemented in different ²parts of the body, including (but not limiting to) the head, earlobe, eyes, ²neck, nose, mouth, ²chest, abdomen, arms, forearms, legs, fingers (e.g. as in a ring), feet, and ²toes. Furthermore,²<DP=11>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²11²the invention can be used in any living or dead biological organism, including ²but not limiting ²humans and animals (e.g. in the ears, legs, or in the tail of dogs or rats).²The device of the present invention is suitable for sampling one or more ²analytes that can ²be withdrawn from skin by using the MHD phenomenon. Exemplary non-limiting ²analytes²comprise amino acids, sugars, fatty acids, co-enzymes, hormones, ²neurotransmitters, lactic²acid, and drugs. A particular analyte is glucose. Another particular analyte ²is lactic acid.²EXAMPLES²Example 1 ²The efficacy of the device according to the present invention to extract ²dermal IF was²compared to electrophoresis. Postmortem abdominal porcine skin samples (3 cm x ²3 cm) ²dissected from adjacent tissue were treated with 1) the device according to ²the present ²invention and 2) the device according to the present invention but omitting ²the magnetic ²field. Accordingly, in experiment 1) and experiment 2) the sampling was ²performed by MHD ²and electrophoresis, respectively.²The two experiments were run simultaneously and applying the same ²parametrization and²electrode configuration. In each case, the first electrode and the second ²electrode were ²made of graphite. The contact surface of all the electrodes was flat and round ²(diameter = 7 ²mm). A single current source was used to establish a 0.4 mA direct electric ²current serially ²in the two treatments. The estimated current density at the electrode-skin ²interface was 1²mA / cm2. The separation between the first electrode and the second electrode in ²both ²experiments was 1 cm. For the device according to the present invention ²exclusively, a ²permanent neodymium magnet with a 0.8 T magnetic field at its surface was ²arranged at ²distance of 1 cm from the extraction site. The magnet was arranged in such a ²way that the ²magnetic field was established in a direction substantially perpendicular to ²the skin surface²within the distance and substantially perpendicular to desired direction of ²fluid displacement²from the dermis to the skin surface. Consequently, a Lorentz force was ²generated towards ²the skin surface in the current-carrying fluid in the skin. An exposure-to-²treatment time of 1 ²hour revealed a clear difference in the volume of dermal IF extracted by the ²two methods. ²As seen in figure 6, the fluid extracted with the device according to the ²present invention²forms a drop (marked with an arrow in figure 6, left) that can be seen by the ²naked eye and²whose volume is substantially larger than the volume of fluid extracted by ²electrophoresis, ²which is not sufficiently large to be distinguished by the naked eye. ²Considering that the²<DP=12>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²12²extracted fluid is subject to evaporation, the accumulation of fluid observed ²in the sample ²treated with the device according to the present invention is a strong ²indicator that this ²method is substantially faster than electrophoresis.²Example 2 ²The concentration of glucose in intestinal fluid and blood was measured by ²using a device²according to the present invention and by using a conventional fingertip ²pricking instrument ²in a group of healthy adult humans (n = 11).²For each measurement, paired samples of interstitial fluid and blood were ²concurrently ²obtained using either the device according to the present invention or ²conventional fingertip²io pricking instrument (CareSensTMN; model GM505PAD, i-SENSm inc, Seoul, ²Korea), ²respectively. The concentration of glucose in the samples of interstitial ²fluid was measured ²using a commercial assay kit (AB65333, Abcam Cambridge, UK). The results ²showed a ²direct relationship between the concentration of glucose in the samples of ²interstitial fluid ²and blood. The results confirm that the concentration of glucose in the ²samples extracted²with a device according to the present invention can be used to estimate blood ²glucose. ²Furthermore, no pain, skin reactions, or evident sample disruption was induced ²by the ²extraction procedure.²The concentration of glucose in interstitial fluid correlates with the ²concentration of glucose ²in blood. In one preferred embodiment, once the concentration of glucose in ²the sample of²interstitial fluid is measured, a mathematical algorithm or mathematical model ²can be used²to estimate the corresponding level of blood glucose. This mathematical ²algorithm can ²consist of arithmetic operations, statistical functions and even artificial ²intelligence ²algorithms.²Further embodiments are disclosed in the following numbered clauses.²1. A method for sampling interstitial fluid comprising one or more analytes ²from dermis to²skin surface, the method comprising steps of:²- positioning a first electrode and a second electrode adjacent to the skin ²surface,²- inducing an electric current through the first electrode, the ²interstitial fluid and the second ²electrode, and²<DP=13>²CA 03019678 2018-10-01²WO 2018 / 091771 ²PCT / F12017 / 050767²13²- inducing a magnetic field to the interstitial fluid comprising the one or ²more analytes, ²wherein direction of the magnetic field and the electric current is such that ²Lorentz force ²drives the interstitial fluid from the dermis substantially towards the skin ²surface.²2. The method according to clause 1 comprising treating the skin surface by ²one or more of:² ultrasound, laser light, hydraulic pressure, electric field.²3. The method according to clause 1 or 2 comprising storing and / or collecting ²the interstitial ²fluid comprising the one or more analytes sampled from skin.²4. The method according to clause 1 or 2 comprising transporting the ²interstitial fluid ²comprising one or more analytes withdrawn from skin to a location where the ²one or more²analytes are analyzed.²5. The method according to any or clauses 1-4, wherein the one or more ²analytes comprises ²amino acids, sugars, fatty acids, co-enzymes, hormones, neurotransmitters, ²lactic acid, ²drugs.²6. The method according to any of clauses 1-5 wherein the analyte is glucose, ²proteins,²and / or lactic acid.²7. The method according to any of clauses 1-6, wherein the method further ²comprises ²analyzing the one or more analytes.²The specific examples provided in the description given above should not be ²construed as ²limiting the scope and / or the applicability of the appended claims.²

Claims

<DP=1>²14²What is claimed is²1. A device (100, 300) for sampling interstitial fluid comprising one or more ²analytes from ²dermis (101a) to skin surface (101b), the device comprising²- a first electrode (102a, 302a) and a second electrode (102a, 302b) ²adapted to be²positioned adjacent to the skin surface, the first electrode separated from ²the second²electrode by a distance (103, 303),²- a power source (104, 304) adapted to induce an electric current through ²the first electrode, ²the interstitial fluid and the second electrode, characterized in that the ²device further ²comprising²- one or more magnets (105, 205a,b, 305) adapted to induce magnetic field to ²the interstitial²fluid, and in that direction of the magnetic field produced by the one or more ²magnets, and ²direction of the electric current produced by the power source are adapted to ²be such that ²Lorentz force produced by the magnetic field and the electric current is ²adapted to drive the ²interstitial fluid from the dermis towards the skin surface.²..

2. The device according to claim 1, wherein the one or more magnets ²comprises a single²magnet.²3. The device according to claim 1, wherein the one or more magnets comprises ²a plurality ²of magnets (205 a,b).²4. The device according to any one of claims 1 to 3, wherein the magnetic ²field is adapted²to be substantially in z-direction, the electric field is adapted to be ²substantially in x-direction,²and the skin surface is adapted to be perpendicular to y-direction of ²coordinate system (199, ²399), within the distance, the first electrode and the second electrode, when ²the device is at ²its operational position.²5. The device according to any one of claims 1 to 4 comprising a frame (109, ²309) adapted²to position the first electrode, the second electrode, the power source and ²the one or more²magnets.²6. The device according to any one of claims 1 to 5, wherein the first ²electrode and the ²second electrode are adapted to be perpendicular to the skin surface when the ²device is at ²its operational position.²..

7. The device according to any one of claims 1 to 6, wherein the distance ²is 1 mm - 5 cm.²Date Recue / Date Received 2023-09-13²<DP=2>²15²8. The device according to claim 7, wherein the distance is 5 mm - 3 cm.²9. The device according to any one of claims 1 to 8, wherein the device ²comprises means ²(107) adapted to collect and / or store the one or more analytes sampled from ²the dermis.²10. The device according to any one of claims 1 to 9 wherein the device ²comprises means² .. (108) adapted to analyze the one or more analytes.²11. The device according to any one of claims 1 to 10 wherein contact surface ²(106a) of the ²first electrode and / or contact surface (106b) of the second electrode is ²elliptical.²12. The device according to any one of claims 1 to 11, wherein contact surface ²(106a) of ²the first electrode and / or contact surface (106b) of the second electrode ²comprises².. extrusions and / or protrusions.²13. The device according to claim 5, wherein the frame is in form of ²wristband, ring.²14. The device according to claim 13, wherein the frame is in from of ²wristband, and the ²wristband comprises one or more of: user interface, means adapted to store ²data, means ²adapted to send and receive data, means adapted to provide energy to the power ²source.²15. The device according to any one of claims 1 to 14, comprising means (110) ²selected²from one or more of: ultrasound generating means, laser light generating ²means, ²electroporation generating means, and hydraulic pressure generating means.²16. The device according to any one of claim 5, 13 or 14,wherein the frame ²comprises ²adhesive material adapted to be positioned in contact with the skin.²17. The device according to any one of claims 1 to 16, wherein the first ²electrode and / or²the second electrode is / are coated with one or more enzymes and / or one or more ²²catalysts.²18. The device according to any one of claims 1 to 17, wherein the device ²comprises a ²membrane and / or electrically conducting material adapted to be positioned ²between the²first electrode and the skin, and between the second electrode and the skin.²Date Recue / Date Received 2023-09-13²