Devices and methods for measuring a concentration of a target analyte in a biological fluid in vivo
Devices and methods for measuring a concentration of a target analyte in a biological fluid in vivo are provided herein. In some examples, a device includes an indwelling sensor and sensor electronics. The sensor may include a substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate to selectively transport the target ion to or within the first electrode; and a second electrode disposed on the substrate. The sensor electronics is configured to generate a signal corresponding to an electromotive force which is at least partially based on a potential difference that is generated between the first electrode and the second electrode responsive to the ionophore transporting the target ion to the first electrode.
1 . A device for continuously measuring a concentration of at least one target analyte in a biological fluid in vivo, the device comprising:
a transcutaneous analyte sensor configured to be inserted into interstitial fluid, the transcutaneous analyte sensor comprising:
a substrate;
a working electrode disposed directly on the substrate;
a solid contact layer disposed on the working electrode, the solid contact layer comprising a conductive polymer;
an ion-selective membrane comprising an ionophore, the ion-selective membrane disposed directly on the solid contact layer opposite the working electrode and configured to selectively transport the at least one target analyte to or within the working electrode;
a first membrane disposed directly on the ion-selective membrane, the first membrane configured to limit leaching from at least the ion-selective membrane;
a reference electrode disposed directly on the substrate; and
a second membrane disposed directly on the reference electrode, the second membrane configured to limit leaching from at least the reference electrode; and
sensor electronics coupled to the transcutaneous analyte sensor, the sensor electronics-comprising at least one processor and memory, wherein the at least one processor executes operations comprising:
determining an electromotive force at least partially based on a potential difference that is generated between the working electrode and the reference electrode responsive to the ionophore transporting the at least one target analyte to the working electrode and responsive to the biological fluid conducting an electrophysiological signal to the working electrode, wherein a first contribution to the electromotive force from the electrophysiological signal varies rapidly relative to a second contribution to the electromotive force from the concentration of the at least one target analyte in the biological fluid, and wherein determining the electromotive force further comprises identifying the first contribution and the second contribution;
generating a signal corresponding to the electromotive force; and
determining the concentration of the at least one target analyte based at least on the signal.
2 . The device of claim 1 , wherein the ion-selective membrane is a fluorosilicone rubber, a polydimethylsiloxane polymer, a silicone rubber, a polyurethane with a polysiloxane soft segment, a polyurethane with a hard and soft segment, a water-based polyurethane, polyvinyl butyral, polymethylmethacrylate, polyvinyl acrylate, or blends or graft polymers thereof.
3 . The device of claim 1 , wherein the working electrode or the reference electrode, independently, is a metal, metal alloy, or conductive polymer selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), and poly(3-octylthiophene) (POT).
4 . The device of claim 1 , wherein the ionophore is selected from the group consisting of: 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X); calix[4]arene-25,26,27,28-tetrol (calix[4]arene); potassium ionophore I (valinomycin); potassium ionophore II: bis[(benzo-15-crown-5)-4′-ylmethyl] pimelate (BB15C5); potassium ionophore III: 2-dodecyl-2-methyl-1,3-propanediyl bis[N-[5′-nitro (benzo-15-crown-5)-4′-yl]carbamate] (BME44); 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit); 1,3,5-Tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI); calcium ionophore I (ETH 1001); calcium ionophore II (ETH129); tridodecylmethylammonium chloride (TDMAC); and nonactin.
5 . The device of claim 1 , the ion-selective membrane further comprising a lipophilic salt selected from the group consisting of sodium tetrakis [3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis [3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl) borate (KTCIPB).
6 . The device of claim 1 , wherein the at least one target analyte is selected from the group consisting of sodium ion, potassium ion, hydrogen ion, lithium ion, magnesium ion, calcium ion, chloride ion, sulfite ion, sulfate ion, phosphate ion, ammonium ion, uric acid, urea, ketone, and glucose.
7 . The device of claim 1 , further comprising a biointerface membrane disposed on the ionophore and the working electrode, wherein the biointerface membrane comprises a polymer selected from the group consisting of polyvinyl butyral (PVB), polyurethane, and silicone.
8 . The device of claim 1 , further configured to release a therapeutic compound into the biological fluid.
9 . The device of claim 1 , wherein the sensor electronics comprises a galvanostat.
10 . The device of claim 1 , wherein the sensor electronics is configured to: (a) measure the electromotive force with a dynamically configurable frequency; (b) maintain the reference electrode at a substantially constant potential; or (c) combinations thereof.
11 . The device of claim 1 , wherein the electrophysiological signal comprises a cardiac electrical signal.
12 . The device of claim 1 , further comprising an enzyme configured to generate a target ion responsive to acting upon the at least one target analyte, wherein the enzyme is selected from an oxidase.
13 . The device of claim 1 , wherein the sensor electronics further comprises an amplifier.
14 . A method for continuously measuring a concentration of a target analyte in a biological fluid in vivo, the method comprising:
generating, via a transcutaneous analyte sensor configured to be inserted into interstitial fluid, a signal corresponding to an electromotive force, wherein the transcutaneous analyte sensor comprises:
a substrate;
a working electrode disposed on the substrate;
a solid contact layer disposed on the working electrode, the solid contact layer comprising a conductive polymer;
an ionophore disposed on the solid contact layer opposite the working electrode and configured to selectively transport a target ion to or within the working electrode;
a first membrane disposed over the ionophore opposite the solid contact layer, the first membrane configured to limit leaching from the working electrode;
a reference electrode disposed on the substrate; and
a second membrane disposed on the reference electrode, the second membrane configured to limit leaching from at least the reference electrode,
wherein the electromotive force is at least partially based on a potential difference that is generated between the working electrode and the reference electrode responsive to the ionophore transporting the target ion to the working electrode and responsive to the biological fluid conducting an electrophysiological signal to the working electrode, wherein a first contribution to the electromotive force from the electrophysiological signal varies rapidly relative to a second contribution to the electromotive force from the concentration of the target analyte in the biological fluid, and wherein generating the signal corresponding to the electromotive force further comprises identifying the first contribution and the second contribution; and
determining the concentration of the target analyte in the biological fluid in vivo based at least on the signal.
15 . The method of claim 14 , further comprising an enzyme configured to generate the target ion.