Aptamer sensors with continuous solute passivation

Abstract

A continuous sensing device for measuring at least one analyte included in a sample fluid is provided. The device 1000 a includes a plurality of aptamers located in a sensor fluid 18 , at least one electrode 1050 , and at least one element configured to passivate the at least one electrode by continuous solute passivation. The device may further include at least one cleaning element 1092 to clean the at least one electrode.

What is claimed is: 
     
         1 . A device for detecting the presence of, or measuring the concentration of, at least one analyte in a sample fluid, the device comprising:
 at least one electrode;   a sensor fluid in communication with the at least one electrode, the sensor fluid including a plurality of aptamers freely diffusing in the sensor fluid; and   at least one element configured to passivate the at least one electrode by continuous solute passivation.   
     
     
         2 . The device of  claim 1 , wherein the element includes a membrane that is impermeable to at least one passivating solute adjacent to the at least one electrode. 
     
     
         3 . The device of  claim 1 , wherein the element includes a membrane that is permeable to at least one passivating solute adjacent to the at least one electrode. 
     
     
         4 . The device of  claim 1 , wherein the element includes one or more solutes of a plurality of solutes endogenous to a sample fluid. 
     
     
         5 . The device of  claim 4 , wherein the sample fluid is one of blood or interstitial fluid. 
     
     
         6 . The device of  claim 2 , wherein the membrane has a molecular weight cutoff that is less than the at least one element. 
     
     
         7 . The device of  claim 3 , wherein the membrane has a molecular weight cutoff that is greater than the at least one element. 
     
     
         8 . The device of  claim 1 , further comprising at least one reservoir fluid. 
     
     
         9 . The device of  claim 8 , wherein the reservoir fluid contains the at least one element. 
     
     
         10 . The device of  claim 1 , wherein one or more aptamers of the plurality of aptamers each include a redox tag; and wherein the device further includes at least one membrane in communication with the sensor fluid and adapted to be in communication with a sample fluid, wherein the membrane is permeable to analyte in a sample fluid, and is impermeable to each aptamer of the plurality of aptamers. 
     
     
         11 . The device of  claim 1 , wherein the plurality of aptamers comprise a plurality of signaling aptamers and a plurality of anchor aptamers. 
     
     
         12 . The device of  claim 11 , further comprising a plurality of redox tags, wherein each redox tag of the plurality of redox tags is bound to a signaling aptamer of the plurality of signaling aptamers. 
     
     
         13 . The device of  claim 10 , wherein the membrane has a molecular weight cutoff of <1000 Da. 
     
     
         14 . The device  claim 1 , further comprising a housing having one or more interior chambers containing the at least one electrode, sensor fluid, and element configured to passivate the at least one electrode; and
 wherein the housing is adapted to be placed outside of the body and the stratum-corneum of the skin of a subject.   
     
     
         15 . The device of  claim 1 , further comprising a housing having one or more interior chambers containing the at least one electrode, sensor fluid, and element configured to passivate the at least one electrode; and
 wherein the housing is at least a portion of an in-dwelling device.   
     
     
         16 . The device of  claim 15 , further comprising one or more microneedles in fluid communication with the one or more interior chambers. 
     
     
         17 . The device of  claim 1  further comprising a housing having one or more interior chambers containing the at least one electrode, sensor fluid, and element configured to passivate the at least one electrode; and
 wherein the housing is adapted to be implanted into a subject. 
 
     
     
         18 . The device of  claim 1 , wherein the at least one element configured to passivate the electrode is located in a passivating layer adjacent to the electrode. 
     
     
         19 . The device of  claim 1 , wherein the at least one element comprises an exogenous molecule. 
     
     
         20 . The device of  claim 1 , wherein the at least one element comprises an endogenous solute from the sample fluid. 
     
     
         21 . The device of  claim 20 , wherein the endogenous solute is configured to leave the electrode and be replaced by another molecule. 
     
     
         22 . The device of  claim 10 , wherein the membrane has a molecular weight cutoff of chosen from at least one of less than 300 Da, less than 1000 Da, less than 3 kDa, less than 10 kDa, less than 30 kDa, less than 100 kDa, and less than 300 kDa. 
     
     
         23 . The device of  claim 10 , wherein the membrane is configured to allow only solutes from the sample fluid to permeate therethrough, and wherein the solutes from the sample fluid include the analyte. 
     
     
         24 . The device of  claim 10 , wherein the membrane is permeable to the analyte and wherein the membrane is positioned to retain the at least one element within at least 500 μm of the electrode. 
     
     
         25 . The device of  claim 1 , further comprising a reservoir fluid in fluid communication with the sensor fluid. 
     
     
         26 . The device of  claim 25 , wherein the reservoir fluid includes albumin, peptides, or non-natural chemical solutes with single or multiple thiol binding sites, and is configured to continuously introduce the albumin, peptides, or non-natural chemical solutes to the electrode. 
     
     
         27 . The device of  claim 26 , wherein the reservoir fluid is configured to supply the at least one element to the sensor fluid, and wherein the membrane has a molecular weight cutoff less than the at least one element. 
     
     
         28 . The device of  claim 26 , wherein the reservoir fluid is configured to accept waste from the sensor fluid. 
     
     
         29 . The device of  claim 1 , wherein the plurality of aptamers further comprising one or more anchor aptamers immobilized via a linkage to a hydrogel. 
     
     
         30 . The device of  claim 10 , wherein the membrane has a selective permeability based on size, charge, or at least one other property of the at least one element. 
     
     
         31 . A device for detecting the presence of, or measuring the concentration of, at least one analyte in a sample fluid, the device comprising:
 a plurality of aptamers disposed in a sensor fluid;   a plurality of redox tags, wherein each redox tag of the plurality of redox tags is individually coupled to an aptamer of the plurality of aptamers, each redox tag configured to change an electron transfer to between the electrode and the aptamer in response to the analyte coupling to the aptamer;   at least one electrode in communication with the sensor fluid; and   at least one cleaning element configured to clean a surface of the electrode.   
     
     
         32 . The device of  claim 31 , wherein the at least one electrode further comprises a working electrode, a counter electrode, or a reference electrode. 
     
     
         33 . The device of  claim 31 , further comprising a membrane at least partially housing the electrode, the electrode having a surface area 10× smaller than a surface area of the membrane. 
     
     
         34 . The device of  claim 31 , wherein the electrode comprises titanium, nickel, or steel, copper, silicon bronze, or other metal or alloy with <0 V volts vs. saturated calomel, and wherein the electrode is configured to remove an electrode fouling layer from the electrode. 
     
     
         35 . The device of  claim 31 , wherein the electrode is 0.3 to 30 μm thick. 
     
     
         36 . The device of  claim 31 , wherein the cleaning element is configured to clean the electrode at least one of at least once every 24 hours. 
     
     
         37 . The device of  claim 31 , wherein the electrode is configured to have an operational life that is at least 200 minutes, greater than 1 week, or greater than 6 months. 
     
     
         38 . The device of  claim 31 , wherein the cleaning element is a polymer brush configured to mechanically clean the surface of the electrode. 
     
     
         39 . The device of  claim 38 , wherein the polymer brush comprises microbeads or nanobeads configured to mechanically clean the surface of the electrode. 
     
     
         40 . The device of  claim 39 , wherein the microbeads or nanobeads are configured to move in response to a stimulus from a motor, thermally responsive polymer, or external stimuli. 
     
     
         41 . The device of  claim 31 , wherein the cleaning element has a density that is at least greater than 10%, greater than 100%, or greater than 1000% different than the density of water. 
     
     
         42 . The device of  claim 31 , further comprising a stimulating element configured to mechanically vibrate or sonically vibrate the cleaning element. 
     
     
         43 . The device of  claim 31 , wherein the cleaning element is configured to clean the electrode in response to a natural body motion or position change of a user of the device. 
     
     
         44 . The device of  claim 31 , wherein the cleaning element is magnetic or electromagnetic and is configured to be moved in response to a magnetic field from an external electromagnetic transducer. 
     
     
         45 . The device of  claim 31 , wherein the at least one electrode comprises a plurality of electrodes, each electrode of the plurality of electrodes configured to be cleaned at independent times and configured to be used for sensor measurement at independent times. 
     
     
         46 . The device of  claim 45 , wherein at least one of the plurality of electrodes is configured to be used as a sensor after at least 1 hour of physi-absorption of the sensor fluid onto the surface of the electrode following cleaning of the electrode. 
     
     
         47 . The device of  claim 46 , wherein the electrode is configured to be used as a sensing electrode for at least 1 day prior to a subsequent cleaning. 
     
     
         48 . The device of  claim 31 , wherein the device is configured to continuously measure an electrical impedance of the electrode. 
     
     
         49 . The device of  claim 48 , further comprising a second plurality of aptamers, each aptamer of the second plurality of aptamers configured to not respond to changes in analyte concentration in the sample fluid, and each aptamer of the second plurality of aptamers comprising a second redox tag having a redox potential different from the redox tag coupled to the aptamers of the plurality of aptamers, the second plurality of aptamers configured to measure a fouling layer thickness on the surface of the electrode. 
     
     
         50 . The device of  claim 31 , wherein the cleaning element is located in the sensor fluid, in-situ. 
     
     
         51 . The device of  claim 31 , wherein the cleaning element comprises a membrane housing the electrode or is coated onto a membrane housing the electrode. 
     
     
         52 . A method of sensing an analyte in a sample fluid, the method comprising:
 bringing an analyte in the sample fluid into contact with a plurality of aptamers disposed in a sensor fluid, the contact of the plurality of aptamers with any analyte resulting in a change in electron transfer between a redox tag attached to an aptamer bound to analyte and an electrode; and   measuring the change in electron transfer between the redox tag and the electrode;   wherein the electrode is passivated by continuous solute passivation.   
     
     
         53 . The method of  claim 52 , wherein the measuring of the change in electron transfer occurs by voltammetry, scanning wave voltammetry, amperometry, chronoamperometry, coulometry, chronocoulometry, or combinations thereof. 
     
     
         54 . The method of  claim 53 , further comprising cleaning a working electrode, a counter electrode, or a reference electrode in-situ. 
     
     
         55 . The method of  claim 54 , wherein the cleaning is performed electrically or electrochemically in connection to an electronic source. 
     
     
         56 . The method of  claim 54 , wherein the cleaning includes removing 0.3 to 3 nm from the electrode. 
     
     
         57 . The method of  claim 54 , wherein the cleaning includes pulsing a current.