WO2025137690A1 - In-vivo electrochemical affinity biosensing with artifact attenuation - Google Patents

Abstract

A device for measuring an analyte comprises a sensor including an electrode with an aptamer and an attached redox couple. The sensor is adapted to electrochemically measure a change in concentration of the analyte. The device further comprises a detection circuit configured to select a sampling frequency at which a measurement is taken. The detection circuit is further configured to periodically apply an input voltage to an electrode to obtain a measured response of the electrode. The measured response includes a target signal of the aptamer and an artifact. The detection circuit is further configured to detect the artifact using a transformative tool. The detection circuit is further configured to apply a filter to the measured response of the electrode to attenuate or remove the artifact. The detection circuit is further configured to measure the analyte using the target signal and not the artifact.

Description

IN-VIVO ELECTROCHEMICAL AFFINITY BIOSENSING WITH ARTIFACT ATTENUATION

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under R21EB033874 awarded by National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0002] This section is intended to introduce the reader to various aspects of the art that may be related to various aspects of the present invention, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0003] Aptamers are molecules that bind to a specific target molecule. Electrochemical aptamer sensors are a class of affinity biosensors that include an aptamer sequence that specifically binds to an analyte of interest, and that is attached to an electrode. The aptamer has an attached redox active molecule (redox couple) which can transfer electrical charge to or from the electrode. When an analyte binds to the aptamer, the aptamer changes shape, changing the availability of the redox couple to transfer charge to and from the electrode. This results in a measurable change in electrical current that can be translated into a measure of concentration of the analyte.

[0004] A major unresolved challenge in the development of aptamer-based electrochemical sensors is adapting these sensors to the in-vivo testing environment. In real world biological systems, the sensor is exposed to a wide variety of “artifacts” that can significantly reduce the precision and accuracy of the sensor’s measurements. Artifacts may include mechanical artifacts, physiological artifacts, and electrical artifacts. Mechanical artifacts may include motion changes, pressure changes, and/or the like. For example, a mechanical force can temporarily press the aptamer closer to the electrode surface, artificially increasing the electron transfer rate and measured current. This causes a false spike in the signal that is unrelated to analyte concentration. [0005] Physiological artifacts (e.g., heartbeat, breathing, etc.) generate periodic pressure changes and tissue motion that can affect sensor readings. These low-frequency physiological signals appear as periodic noise superimposed on the true redox current. These artifacts may distort the redox peak height, leading to inaccurate concentration measurements. Electrical artifacts (e.g., line noise, etc.) may cause exposure to ambient electrical signals that interfere with the sensor’s measurements. Electrical artifacts introduce high-frequency oscillations that reduce the accuracy of the measured signal. The true redox signal, which may be a low- frequency event (e.g., 0.5 Hertz (Hz)), may be overshadowed by stronger electrical noise, reducing the signal-to-noise ratio (SNR). This makes it difficult to detect subtle changes in analyte concentration.

[0006] Thus, a need exists for an improved device design and method that detects and filters out artifacts that would otherwise reduce the accuracy or precision of the aptamer sensor.

SUMMARY OF THE INVENTION

[0007] Certain exemplary aspects of the invention are set forth below. It should be understood that these aspects are presented merely to provide the reader with a brief summary of certain forms the invention might take and that these aspects are not intended to limit the scope of the invention.

[0008] In an embodiment of the invention, a device for measuring an analyte is provided. The device includes a sensor including an electrode with an aptamer and an attached redox couple. The sensor is adapted to electrochemically measure a concentration or change in concentration of the analyte. The device further includes a detection circuit operatively coupled to the sensor. The detection circuit is configured to select a sampling frequency at which a measurement is taken. Using the sampling frequency, the detection circuit is further configured to periodically apply an input voltage to an electrode to obtain a measured response of the electrode. The measured response includes a target signal of the aptamer appearing at a first frequency and one or more artifacts appearing at one or more other frequencies. The detection circuit is further configured to detect, using a transformative tool, the one or more artifacts that otherwise reduce accuracy or precision of the measurement being taken. The detection circuit is further configured to apply a filter to the measured response of the electrode to attenuate the one or more other frequencies of the one or more artifacts. The detection circuit is further configured to measure the analyte using the target signal and not the one or more artifacts. [0009] In an aspect of the invention, the sampling frequency is at least >1 Hertz (Hz) and at least less than 10 kHz.

[0010] In another aspect of the invention, the sampling frequency is higher than a largest known artifact frequency by a threshold amount. For example, if the threshold amount is set to 50 Hz, and the largest known artifact frequency is 60 Hz, the sampling frequency may be set to 110 Hz.

[0011] In another aspect of the invention, the transformative tool is a Fourier Transform (FT). In this aspect, the detection circuit, when detecting the one or more artifacts, is configured to use the FT to convert the measured response from a time domain signal to a frequency domain signal. The measured response, once converted, permits the one or more frequencies of the one or more artifacts to be specifically identified for attenuation.

[0012] In another aspect of the invention, the detection circuit, when applying the filter, is configured to apply a high pass filter to attenuate a signal component of an artifact of the one or more artifacts. The high pass filter allows frequencies above a cutoff frequency and attenuates frequencies below the cutoff frequency.

|0013 | In another aspect of the invention, the detection circuit, when applying the filter, is configured to apply a low pass filter to attenuate a signal component of an artifact of the one or more artifacts. The low pass filter to allow frequencies below a cutoff frequency and to attenuate frequencies above the cutoff frequency.

[0014] In another aspect of the invention, the detection circuit, when applying the filter, is configured to: apply a high pass filter to attenuate a signal component of a first artifact, and to apply a low pass filter to attenuate a signal component of a second artifact.

[0015] In another aspect of the invention, the measurement is taken using square wave voltammetry (SWV). In this aspect, the detection circuit, when measuring the analyte, is configured to determine a current differential measurement based on a forward current measurement and a reverse current measurement. In this case, a redox current of a redox tag is measured based in part on the current differential measurement.

[0016] In another aspect of the invention, the measurement is taken using continuous square wave voltammetry (cSWV). In this aspect, the detection circuit, when measuring the analyte, is configured to determine a current differential measurement based on a plurality of forward current measurements and a plurality of reverse current measurements. In this case, a redox current of a redox tag is measured based in part on the current differential measurement. [0017] In another aspect of the invention, one or more artifacts include at least one of an artifact indicative of a physiological disturbance, an artifact indicative of an electrical disturbance, or an artifact indicative of a mechanical disturbance.

[0018] In another aspect of the invention, the measurement is one of a periodic voltammetry measurement, a periodic amperometry measurement, or a periodic impedance measurement.

[0019] In another embodiment of the invention, a method is provided for measuring an analyte with a device comprising a sensor and a detection circuit. The method includes selecting, by the detection circuit, a sampling frequency at which a measurement is taken. The method further includes using, by the detection circuit, the sampling frequency to periodically apply an input voltage to an electrode to obtain a measured response of the electrode. The measured response includes a target signal of the aptamer appearing at a first frequency and one or more artifacts appearing at one or more other frequencies. The method further includes detecting, by the detection circuit and by using a transformative tool, the one or more artifacts that otherwise reduce accuracy or precision of the measurement being taken. The method further includes applying, by the detection circuit, a filter to the measured response of the electrode to attenuate the one or more other frequencies of the one or more artifacts. The method further includes measuring, by the detection circuit, the analyte using the target signal and not the one or more artifacts.

[0020] In an aspect of the invention, the transformative tool is a Fourier Transform (FT) tool. In this aspect, when detecting the one or more artifacts, the method includes using the FFT tool to convert the measured response from a time domain signal to a frequency domain signal. The measured response, once converted, permits the one or more frequencies of the one or more artifacts to be specifically identified for attenuation.

[0021] In another aspect of the invention, when applying the filter, the method includes applying a high pass filter to attenuate a signal component of an artifact of the one or more artifacts. The high pass filter allows frequencies above a cutoff frequency and attenuates frequencies below the cutoff frequency.

[0022] In another aspect of the invention, when applying the filter, the method includes applying a low pass frequency filter to attenuate a signal component of an artifact of the one or more artifacts. The low pass filter allows frequencies below a cutoff frequency and attenuates frequencies above the cutoff frequency.

[0023] In another aspect of the invention, the measurement is taken using square wave voltammetry (SWV). In this aspect, when measuring the analyte, the method includes determining a current differential measurement based on a forward current measurement and a reverse current measurement. In this aspect, a redox current of a redox tag is measured based in part on the current differential measurement.

[0024] In another aspect of the invention, the measurement is taken using continuous square wave voltammetry (cSWV). In this aspect, when measuring the analyte, the method includes determining a current differential measurement based on a plurality of forward current measurements and a plurality of reverse current measurements. In this case, a redox current of a redox tag is measured based in part on the current differential measurement.

[0025] In another aspect of the invention, the one or more artifacts include at least one of an artifact indicative of a physiological disturbance, an artifact indicative of an electrical disturbance, or an artifact indicative of a mechanical disturbance.

[0026] Many of the drawbacks and limitations stated above can be resolved by creating novel and advanced interplays of chemicals, materials, sensors, electronics, microfluidics, algorithms, computing, software, systems, and other features or designs, in a manner that affordably, effectively, conveniently, intelligently, or reliably brings sensing technology into proximity with sample fluids containing at least one analyte of interest to be measured.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The objects and advantages of the present invention will be further appreciated in light of the following detailed descriptions and drawings in which:

[0028] FIG. 1 is a schematic view of a sensing device in accordance with an embodiment of the invention.

[0029] FIG. 2 is a cross-sectional view the sensing device in accordance with another embodiment of the invention.

[0030] FIG. 3 is a cross-sectional view of the sensing device in accordance with yet another embodiment of the invention.

[0031] FIG. 4 is a cross-sectional view of the sensing device in accordance with yet another embodiment of the invention.

100321 FIG. 5 is a cross-sectional view of the sensing device in accordance with yet another embodiment of the invention.

[0033] FIG. 6A shows a series of graphs illustrating signals that are part of a Square Wave Voltammetry (SWV) sampling method.

[0034] FIG. 6B shows traditional square-wave voltammetry (SVW) and continuous SWV (cSWV). [0035] FIG. 7 is a cross-sectional view of the sensing device in accordance with yet another embodiment of the invention.

[0036] FIG. 8 A is a graphical view of a voltammogram that illustrates raw SWV data that is affected by the presence of one or more artifacts.

[0037] FIG. 8B is a graphical view illustrating the Fast Fourier Transform (FFT) of the voltammogram shown in FIG. 8A.

[0038] FIG. 8C is a graphical view illustrating frequencies of several example artifacts such as heart rate and breathing rate.

[0039] Fig. 8D is a graphical view illustrating a cleaned frequency spectrum after artifact attenuation via filtering.

[0040] Fig. 8E is a graphical view illustrating a cleaned voltammogram using a second order low pass filter.

DEFINITIONS

[0041 ] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, pH, size, concentration, or percentage, is meant to encompass variations of, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods and operate the disclosed devices.

[0042] As used herein, the term “aptamer” refers to a molecule that undergoes a conformation change as an analyte binds to the molecule and which satisfies the general operating principles of the sensing methods and devices as described herein. Such molecules include, e.g., a natural or modified DNA, RNA, or XNA oligonucleotide sequence, a spiegelmer, a peptide aptamer, an affimer, and/or the like. A modification may include substituting one or more unnatural nucleic acid bases for one or more natural bases within an aptamer sequence, replacing one or more natural sequences with one or more unnatural sequences, and/or any other suitable modification that improves sensor function. In a preferred embodiment, aptamers used in electrochemical sensors are tagged with a redox molecule such as methylene blue. In other embodiments, another type of redox molecule may be utilized.

[0043] The devices and methods described herein encompass the use of sensors. A sensor, as used herein, is a device that is capable of measuring the concentration of a target analyte in a solution. As used herein, an “analyte” may be any an inorganic or organic molecule, such as a small molecule drug, a metabolite, a hormone, a peptide, a protein, a carbohydrate, a nucleic acid, or any other composition of matter. In some embodiments, the target analyte may comprise one or more drugs. For example, the drug may be a drug for the treatment of the cardiac system, a drug for the treatment of the central nervous system, a drug that modulates the immune system, a drug that modulates the endocrine system, an antibiotic agent, a chemotherapeutic drug, an illicit drug, and/or another type of drug known in the art. The target analyte may comprise a naturally occurring factor, for example a hormone, a metabolite, a growth factor, a neurotransmitter, and/or the like. The target analyte may comprise any other species of interest, for example, species such as pathogens (including pathogen induced or derived factors), nutrients, and pollutants, and/or the like.

[0044] As used herein, the term “continuous sensing” refers to a device recording a plurality of readings over a period of time during which the sensing occurs. Thus, even a point- of-care testing device which provides a single data point can be considered a continuous sensing device if, for example, the test has a 15 minute duration, and the testing device operates by taking multiple data points over 15 minutes and averaging them to provide a single data measure.

|0045 | As used herein, the term “electrode” refers to any material that is electrically conductive such as gold, platinum, nickel, silicon, conductive liquid infused material such as an ionic liquid, a PEDOT:PSS, conductive oxide, carbon, a boron-doped diamond, a nanotube or a nanowire mesh, or another suitable electrically conducting material.

[0046] As used herein, the term “redox tag” or “redox molecule” or “redox mediator” refers to any species such as a small or large molecule with a redox active portion that, when brought adjacent to an electrode, can reversibly transfer at least one electron with the electrode. Redox tag or molecule examples include, but are not limited to, methylene blue, ferrocene, quinones, or any other suitable species that satisfies the definition of a redox tag or redox molecule. Redox tags or molecules may also exchange electrons with other redox tags or molecules.

[0047] As used herein, the term “analyte” means any solute in a solution or fluid which can be measured using a sensor. An analyte can be a small molecule, a protein, a peptide, an electrolyte, an acid, a base, an antibody, a molecule with one or more other small molecules bound to said molecule, DNA, RNA, a drug, a chemical, a pollutant, or another solute in a solution or a fluid.

[0048] As used herein, the term “sample fluid” refers any solution or fluid that may contain at least one analyte to be measured.

[0049] As used herein, the midpoint voltage of a scan range refers to an average of the minimum voltage and the maximum voltage of the scan range. [0050] As used herein, the term “attenuate” refers to modifying characteristics of an artifact that has been detected. For example, a device or detection circuit may attenuate an artifact (e.g., a noise signal) by modifying an amplitude or frequency of the artifact such that artifact is not present when a final measurement is taken. The degree of attenuation may vary depending on the devices and methods being implemented. In some situations, the attenuation could be at least -40 dB, -60 dB, or -80 dB for “complete” attenuation or signal removal.

DETAILED DESCRIPTION OF THE INVENTION

[0051] One or more specific embodiments of the present invention are described below. In an effort to provide a concise description of these embodiments, all features of an actual implementation may not necessarily be described in the specification. It should be appreciated that in the development of any such actual implementation, as in any engineering or design project, numerous implementation- specific decisions must be made to achieve the developers’ specific goals, such as compliance with system-related and business-related constraints, which may vary from one implementation to another. Moreover, it should be appreciated that such a development effort might be complex and time consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill having the benefit of this disclosure.

[0052] Certain embodiments of the present invention show sensors as simple individual elements. It is understood that many sensors require two or more electrodes, reference electrodes, or additional supporting technology or features that, for purposes of clarity, are not necessarily described herein. Sensors may measure one or more characteristics of an analyte. Sensors are typically electrical in nature, but may also include optical, chemical, mechanical, or other known sensing mechanisms. Multiple Sensors can be implemented to provide improved data and readings. Sensors may provide continuous or discrete data and/or readings. Certain embodiments of the present invention may show certain sub-components of sensing devices, but may omit additional sub-components inherent in the device in various applications that are known, e.g., a battery, an antenna, or adhesive. These omissions may be for purposes of brevity, and to focus on certain inventive aspects of the disclosed embodiments of the present invention.

[0053] FIG. 1 depicts a sensing device 10 in accordance with an embodiment of the present invention that includes a sensor 12 and a detection circuit 14. The sensor 12 may include one or more electrodes, e.g., a working electrode 16, a reference electrode 18, and a counter electrode 20. Alternately, the working electrode 16 may include a sensing portion and a conductive portion. The sensing portion may be affinity-based, and may include, for example, one or more redox-tagged aptamers. The aptamers may be selective in reversible binding to an analyte, thiol bonded to the conductive portion, and used to sense an analyte by means of electrochemical detection. The conductive portion of working electrode 16 may include a suitable conductive material, such as gold, carbon, or other suitable electrically conducting material. The aptamers of the sensing portion of working electrode 16 that are not bound to their target molecule may position their redox tags at an unbound distance from the conductive portion of the working electrode 16. In response to binding with a target molecule, each aptamer may change shape, thereby moving its redox tag closer to (or further away from) the conductive portion of working electrode 16. This change in distance may produce a corresponding change in the ability of the redox tag to transfer electrical charge between the working electrode 16 and a sample fluid. Thus, the sensing device 10 may be electrical in nature, and may utilize an attached redox couple to transduce an electrochemical signal, e.g., by increasing or decreasing the resistance of the sensor 12 to faradaic currents in response to changes in the concentration of target molecules in the sample fluid.

[0054| The detection circuit 14 may include a voltage sensor 22, a current sensor 24, a voltage source 26, and a controller 28. The voltage sensor 22 may be operatively coupled to the working and reference electrodes 16, 18 to measure a voltage therebetween. The current sensor 24 may be operatively coupled to the working and counter electrodes 16, 20 to measure a current flowing therebetween. The voltage source 26 may be operatively coupled to the working and counter electrodes 16, 20 and may be controlled by the controller 28 to selectively apply voltages between the working and counter electrodes 16, 20. In an alternative embodiment of the invention, the reference electrode 18 may be omitted, in which case the voltage sensor 22 may be configured to measure the voltage between the working and counter electrodes 16, 20.

[0055] The controller 28 may comprise a computing device that includes a processor 30, a memory 32, an input/output (I/O) interface 34, and a Human Machine Interface (HMI) 36. The processor 30 may include one or more devices selected from microprocessors, microcontrollers, digital signal processors, microcomputers, central processing units, field programmable gate arrays, programmable logic devices, state machines, logic circuits, analog circuits, digital circuits, or any other devices that manipulate signals (analog or digital) based on operational instructions stored in memory 32. Memory 32 may include a single memory device or a plurality of memory devices including, but not limited to, read-only memory (ROM), random access memory (RAM), volatile memory, non-volatile memory, static random access memory (SRAM), dynamic random access memory (DRAM), flash memory, cache memory, or data storage devices such as a hard drive, optical drive, tape drive, volatile or nonvolatile solid state device, or any other device capable of storing data.

[0056] The processor 30 may operate under the control of an operating system 38 that resides in memory 32. The operating system 38 may manage computer resources so that computer program code embodied as one or more computer software applications 40 residing in memory 32 can have instructions executed by the processor 30. One or more data structures 42 may also reside in memory 32, and may be used by the processor 30, operating system 38, or application 40 to store or manipulate data.

[0057] The I/O interface 34 may provide a machine interface that operatively couples the processor 30 to other devices and systems, such as the voltage sensor 22, current sensor 24, and voltage source 26. The application 40 may thereby work cooperatively with the other devices and systems by communicating via the I/O interface 34 to provide the various features, functions, applications, processes, or modules comprising embodiments of the invention.

[0058] The HMI 36 may be operatively coupled to the processor 30 of controller 28 to allow a user to interact directly with the sensing device 156. The HMI 36 may include video or alphanumeric displays, a touch screen, a speaker, and any other suitable audio and visual indicators capable of providing data to the user. The HMI 36 may also include input devices and controls such as an alphanumeric keyboard, a pointing device, keypads, pushbuttons, control knobs, microphones, etc., capable of accepting commands or input from the user and transmitting the entered input to the processor 30.

[0059] With reference to FIG. 2, in an embodiment of the present invention, an exemplary sensing device 100 is depicted as being placed partially in-vivo into a subject’s skin 102, which includes an epidermis 102a, dermis 102b, and subcutaneous or hypodermis 102c. The sensing device 100 includes a non-conductive substrate 110 (e.g., a polymer), a microneedle assembly 112, and one or more electrodes 120-122 operatively coupled to the substrate 110. A portion of the sensing device 100 receives a fluid, e.g., an invasive biofluid such as interstitial fluid from the dermis 102b and/or blood from a capillary 102d. Access to the fluid may be provided, for example, by the microneedle assembly 112. The microneedle assembly 112 may be formed of metal, polymer, semiconductor, glass, or other suitable material, and include a plurality of microneedles 114. Each microneedle may include a lumen 132 having an inlet 134 that provides access to the fluid.

[0060] The sensing device 100 may further include a sample volume 128 comprising a space 130 defined between the microneedle assembly 112 and the substrate 110 and the lumens 132. The sample volume 128 may be filled with a microfluidic component such as capillary channels, a hydrogel, or other suitable material that operatively couples the fluid to the electrodes 120-122. Thus, a diffusion and/or advective flow pathway may be provided between the fluid and the electrodes 120-122. This pathway may begin at the inlets 134 to the microneedles 114 and reach the electrodes 120-122. Alternative arrangements and materials may also be possible, such as using a single needle, hydrogel polymer microneedles, or other suitable means to couple the fluid to the one or more electrodes 120-122. Thus, embodiments of the present invention are not limited to the depicted sensing device 100. In addition, a portion of sensing device 100, or even the entire sensing device 100, could be implanted into the body and perform similarly as described herein. For example, the electrodes 120-122 may be implanted inside the body on the end of an indwelling needle like those used in continuous glucose monitors.

[0061] The electrodes 120-122 may comprise or be part of a sensor, such as an affinitybased electrochemical aptamer sensor that has a redox tag. In some embodiments, one of the electrodes (e.g., electrode 121) may be a working electrode functionalized with an aptamer and the other electrodes (e.g., electrodes 120, 122) may be a counter electrode and/or a reference electrode. The aptamer may be selective in reversible binding to an analyte, thiol bonded to the conductive portion of the working electrode, and used to sense an analyte by means of electrochemical detection.

[0062] In some embodiments, multiple electrodes of electrodes 120-122 may be the same type of electrode. For example, multiple electrodes 120-122 may be a working electrode functionalized with an aptamer, a reference electrode, and/or a counter electrode. In some embodiments, two working electrodes may be configured to detect the same analyte but may be used to detect the analyte at different time periods or time intervals. In some embodiments, two working electrodes may be configured to detect different analytes. For example, one working electrode may be configured to detect a drug such as cocaine, and another may be configured to detect a metabolite such as phenylalanine.

[0063] In some embodiments, there may be only two electrodes 120, 121, such as a working electrode and a counter electrode. As can be appreciated by one of ordinary skill in the art, other electrode configurations may be implemented.

[0064] The sensing device 100 of FIG. 2 is exemplary only for microneedle access of interstitial fluid, and it should be understood that the principles of the present invention may apply to any application of an aptamer sensor such as monitoring for environmental pollutants, for food processing safety, for implanted sensors, or for other applications and devices. [0065] With reference to FIGS. 3-5, where like numerals refer to like features of the previous figures, FIG. 3 depicts an exemplary sensing device 200 in accordance with an alternative embodiment of the present invention that includes a substrate 210 and one or more electrodes 220-222. The electrodes 220-222 may be coupled to the substate 210 and located in the dermis 102b such that the electrodes 220-222 are in contact with a sample fluid. FIGS. 4 and 5 depict additional exemplary sensing devices 300, 400 in accordance with alternative embodiments of the present invention. Sensing device 300 includes a substrate 310 and a needle 370 having a plurality of electrodes 320-322. In use, the needle 370 may be inserted through the epidermis 102a so that a distal end of the needle 370 extends into the dermis 102b. The electrodes 320-322 may be located at the distal end of the needle 370 so that the electrodes 320-322 are exposed to fluids in the dermis 102b. In FIG. 5, the sensing device 400 may be implanted in the skin 102 or some other location in the body. The sensing device 400 includes one or more electrodes 420-422 that may be in contact with fluids so as to detect the presence of one or more analytes at the implantation site.

[0066] In operation, an input signal may be applied to one or more of the electrodes (e.g., a voltage may be applied across the working electrode and the counting electrode), and one or more electrical signals measured (e.g., a voltage between the working and reference electrodes, and a current flowing between the working and counter electrodes) while the input signal is applied. The response of the sensor to the input signal may then be determined. For example, a sensor response may be generated by plotting the current flowing between the working and counter electrodes as a function of the voltage measured across the working and reference electrodes. How efficiently the redox tag transfers electrical charge between the working electrode and sample fluid may depend in part on the characteristics of the input signal. Peak charge transfer efficiency may occur, for example, at one or more of a particular input voltage, current, frequency, or scan rate. As a result, the sensor response (e.g., a plot of current verses voltage) may include a redox peak corresponding to the input signal at which this peak charge transfer efficiency occurs. This redox peak may coincide with a peak electron transfer rate krr of the working electrode and may be analyzed to determine an amount of the total current that is due to the redox tags transferring charge between the working electrode and fluid sample. Thus, one or more characteristics of the redox peak (e.g., height, width, area, etc.) may provide an indication of the amount of the target molecule in the sample fluid.

[0067] With reference to FIGS. 6A and 6B, embodiments of the present invention may use any periodic sampling method for measuring the concentration or change in concentration of at least one analyte. In FIG. 6A, graph 500 shows a square wave voltage signal and a current response. In SWV, current is measured at two points within each square wave cycle: at the end of the forward pulse (positive step), and at the end of the backward pulse (negative step). By sampling current at these precise moments, the sensor maximizes the redox signal and minimizes background noise (like capacitive charging current). These current samples are later compared to calculate the net current (forward - reverse). The top half of graph 500 shows a square wave voltage signal with alternating forward and backward pulses. The variable t_p represents a pulse duration for one half cycle of the square wave (upward or downward pulse). The formula f = — 2tp can be used to determine the frequency of the square wave signal.

[0068] The bottom half of graph 500 represents a current response measured at the working electrode 16. The current response may be sampled at two points: a forward sample average (if) which is measured at the end of the forward voltage pulse and a reverse sample average (i_r) which is measured at the end of the reverse voltage pulse. This differential current is plotted against the applied voltage to produce the characteristic SWV graph, where redox peaks indicate analyte presence and concentration. Continuous square wave voltammetry may also be used, where if and i_r may be sampled at multiple time points during each forward and reverse voltage pulses (as will be discussed in greater detail for FIG. 6B).

[0069] Graph 502 illustrates the voltage waveform applied to the working electrode 16 during SWV. In particular, graph 502 includes a plot of applied voltage (E) on the vertical axis against time on the horizontal axis. Graph 502 shows the square wave pulses and an underlying baseline voltage changing over time. A starting voltage E_in may be applied at time t - 0. The variable E_sw represents the amplitude of the square wave pulse applied on top of the baseline voltage. Each cycle includes an upward pulse (+E_SW) and a downward pulse (—E_sw). The variable E_step represents the incremental voltage step applied after each full square wave cycle. The baseline voltage decreases gradually over time due to these incremental steps, which contrasts with the upward square wave pulses. The variable f~ represents the period of one full square wave cycle. Overall, the waveform shown in graph 502 is a combination of the staircase voltage baseline (shown as the dashed line E) that decreases stepwise over time by E_step and a square wave pulse (up and down) applied on top of each baseline step. The baseline voltage does not remain constant but decreases incrementally with each step (E_step). This is important because the SWV is to scan across a range of voltages and the downward-sloping baseline allows the applied voltage to progress (e.g., from 0 V toward a negative or positive potential) so that the redox behavior of the analyte can be captured. [0070] Graph 504 shows the results of a SWV by plotting current (jiA) against potential (V). Graph 504 highlights how forward current, reverse current, and their net difference (net sample current) relate to the applied voltage. It also shows the role of capacitive current. The x axis represents the voltage applied to the working electrode 16 relative to a reference electrode. The applied potential is from 0 V to more negative values (e.g., -0.50V) to drive redox reactions. The Y axis represents the current response measured at the working electrode 16. Positive values indicate current flow in one direction (oxidation) while negative values represent flow in the opposite direction (reduction).

[0071] Graph 504 distinguishes between three currents measured during SWV : the forward sample current, the reverse sample current, and the net sample current. The forward sample current is current measured at the end of the forward pulse of the square wave. Forward current reflects oxidation of the redox-active species when the potential is positive enough to drive the redox reaction. The reverse sample current is current measured at the end of the backward pulse of the square wave. It reflects the reduction of the same redox active species as the voltage drops back down. The net sample current is calculated as the difference between the forward and reverse current values. This differential current eliminates much of the capacitive current because capacitive current contributes almost equally to both the forward and reverse measurements. Furthermore, capacitive current arises from the charging/discharging of the double layer capacitance at the electrode interface. Capacitive current is shown as small oscillations superimposed on the forward and reverse sample currents. Capacitive current does not contribute to the redox signal and is considered background noise. The net sample current curve (solid line in the center) shows a distinct redox peak at a specific potential. This peak corresponds to the voltage at which the redox reaction of the analyte occurs. The peak is sharp because SWV enhances the faradaic current while suppressing the capacitive current. The height of the redox peak is directly proportional to the concentration of the analyte in the sample.

[0072] FIG. 6B illustrates graphs 506 including a traditional SWV 508 using a commercial instrument and a continuous SWV (cSWV) 510. In the traditional SWV 508, a square wave voltage signal is applied with alternating forward and back pulses. The duration of a single pulse is shown using t_p, which corresponds to the pulse width. The frequency f of the square wave is computed using f = — 2tp , where 2t„ is a total period of one full square wave cycle. The current response is sampled once during the forward pulse and once during the backward pulse. Each current sample is recorded at the end of the respective pulse to minimize the influence of transient capacitive currents. The forward and reverse currents are averaged over the pulse duration to produce the respective measurements (if and i_r

[0073] Similar to the traditional approach, cSWV involves applying a square wave signal with alternating forward and backward pulses. However, in cSWV, the current is sampled continuously at shorter time intervals (5t). Within each forward and backward pulse, multiple current samples are taken instead of a single averaged sample. For example, forward current samples are taken at multiple points during the upward pulse and reverse current samples are taken at multiple points during the downward pulse. The sampling frequency for cSWV is shown as nf = where 5t is the smaller time interval between samples within each pulse.

cSWV collects more granular data, capturing the dynamic current response more accurately than traditional SWV. This higher sampling rate enhances temporal resolution and improves signal analysis by providing finer details on the redox reaction.

[0074] In some situations, one or more artifacts may disrupt or alter accuracy and/or precision of the signal being measured. An artifact refers to an unwanted signal or disturbance in sensor data that originates from an external or non-target source. Example artifacts include signals originating from physiological sources (e.g., heartbeats, respiration, etc.), signals originating from mechanical sources (e.g., a movement, a change in pressure, a vibration, etc.), signals originating from electrical sources (e.g., line nose from power lines, electronic interference, etc.), signals caused by high frequency or capacitive noise, and/or any other artifact or unwanted signal or disturbance known in the art.

[0075] The ability to detect these artifacts depends on a sampling resolution and/or a sampling frequency. For example, discrete sampling, as shown in FIG. 6A, provides fewer data points which may miss rapid or subtle variations caused by high-frequency artifacts. Continuous sampling, such as that shown in FIG. 6B, provides a higher density of data points, improving the detection of artifacts with rapid fluctuations or complex patterns. As will be shown using the examples below, artifacts occur at specific frequencies (e.g., heartbeat at 1 Hz, breathing at 0.5 Hz, electrical noise at 60 Hz, etc.). The sampling frequency must be sufficiently high to capture these artifact frequencies in the data. Continuous sampling enables detection of both low frequency (e.g., motion) and high frequency (e.g., electrical noise) artifacts more effectively.

[0076] Several example artifacts are described broadly below. To provide a first example, one or more artifacts may be present from the electrical impulse created by heart beats. A normal heart beat QRS complex should be less than 0.12 seconds (120 milliseconds). The heart beats at approximately 1 Hz, therefore heartbeats generally represent artifacts with a frequency of < 10Hz. This means that a sampling frequency for the sensor of at least > 20Hz, >50 Hz, or >100 Hz could be used with a transformative tool and a filter to attenuate or reject frequencies of less than 10 Hz such as those from heartbeats.

[0077] To provide another example, consider ‘line noise’ from 60 Hz alternating current electricity lines. In this example, the sampling frequency for the sensors could be one of at least <50 Hz, <25 Hz, <10 Hz to allow a transformative tool (e.g., a Fourier Transform (FT) tool) to detect the line noise artifacts and to allow a filter (e.g., a low pass filter, a high pass filter, a notch filter, and/or the like) to attenuate or reject the line noise artifacts. Other artifacts may not need be electrical in nature and can be for example mechanically induced. Aptamer sensors can be sensitive to pressure. For example, an aptamer sensor can be sensitive to the pressure of tissue in the body against the sensor, causing the electrical capacitance of the sensor to change. As another example, pressure may physically press the aptamer closer to the electrode surface which increases current temporarily. To provide yet another example, walking can induce a mechanical noise at 2 Hz frequencies, which again, for sensor sampling frequencies higher than 2 Hz could allow one or more filters to be used to detect and filter those artifact frequencies. In general, if most or all of the major artifact inducing factors are known, a sensor sampling frequency can be chosen to allow filtering (attenuation) of most or all of the artifacts.

[0078] In some embodiments, a device (e.g., the sensing device 10) may carry out an example process for detecting and attenuating one or more artifacts such that the one or more artifacts do not interface with, or reduce the accuracy or precision of, a measurement of an analyte in a biofluid beneath skin of a user. The device includes a sensor (e.g., sensor 12) with an electrode (e.g., working electrode 16) functionalized with an aptamer and an attached redox couple. The sensor is adapted to electrochemically measure a concentration or change in concentration of the analyte. The device further includes a detection circuit (e.g., detection circuit 14) operatively coupled to the sensor 12.

[0079] The example process includes selecting a sampling frequency at which a measurement is taken. For example, the detection circuit 14 may be configured to select the sampling frequency at which the measurement is taken. The sampling frequency will identify how often the detection circuit 14 measures the signal (e.g., current, voltage, etc.) over time. [0080] In some embodiments, the detection circuit 14 may determine the sampling frequency using a sampling theorem. The sampling theorem may, for example, state that a signal must be sampled at a rate that is at least twice the highest frequency component of the signal (e.g., while considering both artifacts and the true signal). In some embodiments, the detection circuit 14 may determine the sampling frequency by identifying a highest frequency component of the signal and selecting a sampling frequency that is a threshold degree higher than the highest frequency component. In some embodiments, another technique may be used to determine the sampling frequency.

[0081] At a rate consistent with the sampling frequency, the process further includes periodically applying an input voltage to an electrode (e.g., working electrode 16), wherein the detection circuit 14 obtains a measured response of the electrode based on respective input voltages that have been applied. For example, the detection circuit 14 may be further configured to periodically apply an input voltage to working electrode 16. The detection circuit 14 obtains a measured response of the electrode based on respective input voltages that have been applied. The measured response for at least one input voltage includes a target signal of the aptamer appearing at a first frequency and one or more artifacts appearing at one or more other frequencies. For example, the measured response may include a target signal appearing at a first frequency of 0.5 Hz, a first artifact frequency of 2 Hz (e.g., for a heartbeat), and a second artifact frequency of 60 Hz (e.g., electrical line noise).

[0082] In some embodiments, the detection circuit 14 may use square wave voltammetry (SWV) to take the measurement of the analyte. For example, the detection circuit 14 may determine a current differential measurement based on a forward current measurement and a reverse current measurement. A redox current of a redox tag is measured based in part on the current differential measurement. In some embodiments, the detection circuit 14 may use continuous SWV (cSWV) to take the measurement of the analyte. In this case, the sampling frequency may be increased relative to the sampling frequency corresponding to the SWV. In this case, the detection circuit 14 may determine a current differential measurement based on a forward current measurement and a reverse current measurement. A redox current of a redox tag is measured based in part on the current differential measurement.

[0083] In some embodiments, the detection circuit 14 may use periodic voltammetry to take the measurement of the analyte. In some embodiments, the detection circuit 14 may use periodic amperometry to take the measurement of the analyte. In some embodiments, the detection circuit 14 may use periodic impedance to take the measurement of the analyte.

[0084] The example process further comprises detecting, using a transformative tool, the one or more artifacts that would otherwise reduce accuracy or precision of the measurement. For example, the detection circuit 14 may be further configured to detect, using the transformative tool, the one or more artifacts that would otherwise reduce accuracy or precision of the measurement being taken. As used herein, the term “transformative tool” is to refer to any tool capable of detecting one or more artifacts from a signal. Example transformative tools are provided below.

[0085] In an exemplary embodiment, the detection circuit 14 may detect one or more artifacts using a transformative tool such as a Fourier Transform (FT) tool or a Fast Fourier Transform (FFT) tool. To provide a specific example, assume several artifacts are present, including a first artifact (a heartbeat) and a second artifact (e.g., a line noise). In this example, the detection circuit 14 may execute an FFT tool to convert a time-domain signal (e.g., a voltammogram) into a frequency domain where noise frequencies become more apparent. This allows the detection circuit 14 to identify specific frequencies corresponding to artifacts, which can then be filtered out using filtering techniques. In the example above, the first artifact may have a frequency of 2 Hz and the second artifact may have a frequency of 60 Hz. These frequencies may be filtered out by applying a digital filter (e.g., a low pass filter, a high pass filter, a notch filter, and/or the like), as will be described further herein.

[0086] In other embodiments, the transformative tool may be another type of tool, such as a wavelet transform (WT) tool, a Short Time Fourier Transform (STFT) tool, a principal component analysis (PCA) tool, an empirical mode decomposition (EMD) tool, a Kalman filtering tool, an independent component analysis (ICA) tool, and/or another type of tool known in the art.

[0087] The example process further includes applying a filter to the measured response of the electrode to attenuate the one or more frequencies of the one or more artifacts. For example, the detection circuit 14 may apply the filter to the measured response of the working electrode 16 to attenuate the one or more frequencies of the one or more artifacts. The filter may be an analog filter or a digital filter. As will be shown in the embodiments that follow, the filter may be a high pass filter, a low pass filter, a notch filter, a band pass filter, another type of filter known in the art, and/or a combination of filters.

[0088] In some embodiments, the detection circuit 14 may apply a high pass filter to attenuate a signal component of an artifact. A high pass filter may be used to attenuate low frequency components from a filter while retaining high frequency components. This is useful for filtering out low frequency artifacts such as breathing noise ( 1 Hz) while preserving the true redox signal associated with the analyte.

[0089] In some embodiments, the detection circuit 14 may apply a low pass filter to attenuate a signal component of an artifact. A low pass filter may be used to attenuate high- frequency components from a signal while retaining the low-frequency components. This is useful for filtering out artifacts such as high-frequency electrical noise while preserving the true redox signal associated with the analyte. To provide an example, a low pass filter may allow frequencies below a cutoff frequency (/cuto y) and may attenuate frequencies above the cutoff frequency

[0090] In some embodiments, the detection circuit 14 may apply a notch filter. A notch filter attenuates a specific band of frequencies. For example, a notch filter could be used to attenuate a 60 Hz line noise. In some embodiments, the detection circuit 14 may apply a band pass filter. A band pass filter preserves a specific range of frequencies (e.g., the redox signal at 0.5 Hz) while filtering out others. In some embodiments, the detection circuit 14 may apply multiple filters. For example, the detection circuit 14 may apply a high pass and a low pass filter or any other combination of filters described herein and/or known in the art.

[0091] In some embodiments, one or more of the filters described herein may be a digital filter. The digital filter operates on discrete (discretized) signals and is implemented in software or firmware using mathematical algorithms. In other embodiments, one or more of the filters described herein may be an analog filter. The analog filter may be used with a scanning method such as cyclic voltammetry or another applicable type of scanning method known in the art. The analog filter operates on continuous time signals and is implemented using physical components such as a resistor, a capacitor, an inductor, an operational amplifier, and so forth. To provide a specific example, assume a true redox signal has a peak of 0.5 Hz and that high frequency line noise is present is at 50 Hz and 60 Hz. Without filtering, the measured current contains both the true redox signal and the high frequency noise. The noise distorts the voltammogram which makes it more difficult to identify the redox peaks. Now assume a resistor-capacitor (RC) low pass filter is applied, where R = 5.3kQ, C = I pF, and fcutoff =₂ R_c- In Ibis case, f_cutoff is 30 Hz. The raw signal is continuously fed into the filter and frequencies above 30 Hz are attenuated to reduce the contribution of the high frequency noise artifacts.

[0092] The example process further includes measuring the analyte using only the target signal and not the one or more artifacts. For example, the detection circuit 14 measures the analyte using only the target signal and not the one or more artifacts. By attenuating the artifacts, the detection circuit 14 enhances the clarity of the true signal, making it easier to analyze redox peaks or concentration changes. This reduces a signal to noise (SNR) ratio, making it easier to determine the peak height or position of the redox signal. [0093] FIG. 7 depicts an exemplary sensing device 600 that includes a detection circuit 14, a conductive substrate 610 having a projection 612 which extends into the dermis 102b of skin 102, a working electrode 620, and one or more of a reference electrode 622 and a counter electrode. The detection circuit 14 may be operatively coupled to the working electrode 620, and one or both of the reference electrode 622 and counter electrode 624. The working electrode 620 may be located on a distal end of the projection 612 so that the working electrode 620 is in contact with a dermal fluid. The reference electrode 620 and counter electrode 622 may be located externally to (e.g., on the surface of) the skin 102. Although depicted as separate electrodes, it should be understood that in an alternative embodiment, the sensing device 600 may have only one electrode that serves as both the reference and counter electrode. [0094] Depending on the materials chosen for the electrodes 622, 624 (e.g., gel-adhesive, metal, other suitable electrode materials) as well as variabilities in contact/pressure between the electrodes 622, 624 and the skin 102, or other confounding factors, the reference potential may shift dramatically, e.g., by hundreds of mV or more. Therefore, the devices and methods described herein may also be employed to correct for this drift in reference potential. In addition, when using external electrodes, the impedance between the reference electrode and the body should be low enough so that the potential of the region of the body proximate to the working electrode 620 where aptamers and redox tags are measured is reliably dropped. That is, the potential of this region should not vary greatly due to contact and impedance of the external electrodes 622, 624 with skin 102.

[0095] For example, a dry gold electrode having an area of 0.5 cm² exposed to a 1 V peak- to-peak sinusoid (0.5V) may have a real impedance of about 10 kQ, and thus conduct a 0.5 V/10 kQ - 50 A current. In this example, the working electrode 620 could rely on 5 nA of current generation due to electron transfer from the redox tag plus background current. Therefore, the potential at the working electrode 620 would be as good as or better than if a reference electrode 622 or counter electrode 624 were placed in the body. By scaling the electrode area, location, contact material, wet vs. dry electrodes, or other features of the nonworking electrodes to maintain the real impedance below a maximum allowable impedance, the voltage drop at the working electrode 620 may be maintained at >20%, >50%, or >90% of the total applied voltage.

[0096] The reference electrode need not be outside the body or out of direct contact with a biofluid, and yet the potential used at the working electrode 620 may still need to be determined using one or embodiments of the present invention, because the reference potential may not be fully stable. For example, a reference electrode could be a pseudo-reference electrode, such as gold, which is placed along with the working and counter electrodes in interstitial fluid. A pseudo-reference electrode, or other imperfect reference electrodes, can similarly benefit from the present invention regardless of location of those electrodes on or in the body.

[0097] FIGS. 8A-8E demonstrate how artifacts can impact in-vivo sensor data and how these artifacts can be detected using detection tools, such as Fourier analysis, and attenuated using and filters (e.g., low pass, high pass, etc.). In particular, FIGS. 8A-8E provide examples of data with and without artifact attenuation collected from an anesthetized rat with an in-vivo aptamer sensor. By detecting and attenuating artifacts, the sensing device described herein provides improved precision and accuracy for in-vivo measurements.

[0098] FIG. 8A depicts a graph 700 that plots current (p A) versus voltage (V) for a square wave voltammogram measured in-vivo. As can be seen, the graph 700 includes a baseline current 702 along with a set of artifacts that are represented visually as peaks 704 and troughs 706. The gradual rise and fall of the baseline current 702 around the center of the graph 700 represents the true redox signal. This signal corresponds to the faradaic current generated by the aptamer’s interaction with the analyte (e.g., electron transfer due to redox reactions). The artifacts interfere with the signal, reducing the accuracy and precision of measurements taken by the sensing device described herein.

[0099] FIG. 8B shows the Fast Fourier Transform (FFT) of the voltammogram in FIG. 8A, where artifacts are visible across a wide range of frequencies. In particular, Fig. 8B shows a graph 708 that plots the FFT magnitude versus frequency for the data in FIG. 8A. The FFT converts the time-domain signal (voltammogram) into a frequency domain where artifacts become apparent. As shown in FIG. 8B, the plot includes a redox peak region 710 and a series of artifacts 712 (shown as distributed peaks). The artifacts 712 appear across a wide range of frequencies and these artifacts 712 can obscure the true electrochemical signal.

[00100] FIG. 8C shows a graph 714 that identifies several of the artifact origins such as heart rate and breathing rate. For example, the FFT plot identifies specific frequencies corresponding to known physiological noises, such as frequency 716 which corresponds to a respiratory rate (e.g., a low frequency peak, such as -57.2 per minute) and frequency 718 which corresponds to a cardiac cycle (e.g., frequencies at ~261.8/minute and ~384.5/minute, corresponding to the heartbeats). The FFT analysis makes it possible to separate noise components (like breathing and heartbeat) from the true sensor signal.

[00101] FIG. 8D shows a graph 720 that plots a cleaned frequency spectrum after using FFT to identify artifacts and uses a digital filter to subsequently attenuate the artifacts 712 shown in FIGS. 8B and 8C. By applying the FFT tool or a similar technique in conjunction with a digital filter, some (or all) of the artifacts have been rejected, leaving only the relevant signal frequencies. This ensures the final data reflects the true electrochemical signal without interference.

[00102] FIG 8E shows a graph 722 that plots the cleaned square wave voltammogram (current vs voltage) after applying a second order low-pass filter to the raw data in FIG. 8A. The noise spikes and oscillations are smoothed out, revealing the underlying redox peak signal. In particular, FIG. 8E shows a filtered signal 724 which includes a clear, smooth redox peak. The noisy, high-frequency artifacts have been attenuated. By using a low pass filter, the low frequency redox signal remains while rejecting high-frequency noise caused by artifacts.

[00103] In general, the routines executed to implement the embodiments of the invention, whether implemented as part of an operating system or a specific application, component, program, object, module or sequence of instructions, or a subset thereof, may be referred to herein as “program code.” Program code typically comprises computer-readable instructions that are resident at various times in various memory and storage devices (e.g., non-transitory storage media) in a computer and that, when read and executed by one or more processors in a computer, cause that computer to perform the operations necessary to execute operations or elements embodying the various aspects of the embodiments of the invention. Computer- readable program instructions for carrying out operations of the embodiments of the invention may be, for example, assembly language, source code, or object code written in any combination of one or more programming languages.

[00104] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the embodiments of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include both the singular and plural forms, and the terms “and” and “or” are each intended to include both alternative and conjunctive combinations, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” or “comprising,” when used in this specification, specify the presence of stated features, integers, actions, steps, operations, elements, or components, but do not preclude the presence or addition of one or more other features, integers, actions, steps, operations, elements, components, or groups thereof. Furthermore, to the extent that the terms “includes”, “having”, “has”, “with”, “comprised of”, or variants thereof are used in either the detailed description or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”.

[00105] While all the invention has been illustrated by a description of various embodiments, and while these embodiments have been described in considerable detail, it is not the intention of the Applicant to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and method, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of the Applicant’s general inventive concept.

Claims

What is claimed is:

1. A device for measuring an analyte, the device comprising: a sensor including an electrode with an aptamer and an attached redox couple, wherein the sensor is adapted to electrochemically measure a concentration or change in concentration of the analyte; and a detection circuit operatively coupled to the sensor and configured to: select a sampling frequency at which a measurement is taken, using the sampling frequency, periodically apply an input voltage to an electrode to obtain a measured response of the electrode, wherein the measured response includes a target signal of the aptamer appearing at a first frequency and one or more artifacts appearing at one or more other frequencies, detect, using a transformative tool, the one or more artifacts that otherwise reduce accuracy or precision of the measurement being taken, apply a filter to the measured response of the electrode to attenuate the one or more other frequencies of the one or more artifacts, and measure the analyte using the target signal and not the one or more artifacts.

2. The device of claim 1, wherein the sampling frequency is at least >1 Hertz (Hz) and at least less than 10 kHz.

3. The device of claim 1, wherein the sampling frequency is higher than a largest known artifact frequency by a threshold amount.

4. The device of claim 1, wherein the transformative tool is a Fourier Transform (FT) tool, wherein the detection circuit, when detecting the one or more artifacts, is configured to: use the FT to convert the measured response from a time domain signal to a frequency domain signal, wherein the measured response, once converted, permits the one or more frequencies of the one or more artifacts to be specifically identified for attenuation.

5. The device of claim 1, wherein the detection circuit, when applying the filter, is configured to: apply a high pass filter to attenuate a signal component of an artifact of the one or more artifacts, the high pass filter to allow frequencies above a cutoff frequency (Jcutoff) and to attenuate frequencies below the cutoff frequency f_cutOff)-

6. The device of claim 1, wherein the detection circuit, when applying the filter, is configured to: apply a low pass filter to attenuate a signal component of an artifact of the one or more artifacts, the low pass filter to allow frequencies below a cutoff frequency (f_cutoff)^ar|d to attenuate frequencies above the cutoff frequency (/_cutOff).

7. The device of claim 1, wherein the detection circuit, when applying the filter, is configured to: apply a high pass filter to attenuate a signal component of a first artifact, and apply a low pass filter to attenuate a signal component of a second artifact.

8. The device of claim 1 wherein the measurement is taken using square wave voltammetry (SWV); and wherein the detection circuit, when measuring the analyte, is configured to: determine a current differential measurement based on a forward current measurement and a reverse current measurement, wherein a redox current of a redox tag is measured based in part on the current differential measurement.

9. The device of claim 1 wherein the measurement is taken using continuous square wave voltammetry (cSWV); wherein the detection circuit, when measuring the analyte, is configured to: determine a current differential measurement based on a plurality of forward current measurements and a plurality of reverse current measurements, wherein a redox current of a redox tag is measured based in part on the current differential measurement.

10. The device of claim 1 wherein one or more artifacts include at least one of: an artifact indicative of a physiological disturbance, an artifact indicative of an electrical disturbance, or an artifact indicative of a mechanical disturbance.

11. The device of claim 1 wherein the measurement is one of a periodic voltammetry measurement, a periodic amperometry measurement, or a periodic impedance measurement.

12. A method for measuring an analyte with a device comprising a sensor and a detection circuit, the method comprising: selecting, by the detection circuit, a sampling frequency at which a measurement is taken; using, by the detection circuit, the sampling frequency, periodically apply an input voltage to an electrode to obtain a measured response of the electrode, wherein the measured response includes a target signal of the aptamer appearing at a first frequency and one or more artifacts appearing at one or more other frequencies; detecting, by the detection circuit and by using a transformative tool, the one or more artifacts that otherwise reduce accuracy or precision of the measurement being taken; applying, by the detection circuit, a filter to the measured response of the electrode to attenuate the one or more other frequencies of the one or more artifacts; and measuring, by the detection circuit, the analyte using the target signal and not the one or more artifacts.

13. The method of claim 12, wherein the transformative tool is a Fourier Transform (FT) tool, wherein detecting the one or more artifacts comprises: using the FT tool to convert the measured response from a time domain signal to a frequency domain signal, wherein the measured response, once converted, permits the one or more frequencies of the one or more artifacts to be specifically identified for attenuation.

14. The method of claim 12, wherein applying the filter comprises: applying a high pass filter to attenuate a signal component of an artifact of the one or more artifacts, the high pass filter to allow frequencies above a cutoff frequency f_cutOff)^and to attenuate frequencies below the cutoff frequency (f_cutoff)-

15. The method of claim 12, wherein applying the filter comprises: applying a low pass frequency filter to attenuate a signal component of an artifact of the one or more artifacts, the low pass filter to allow frequencies below a cutoff frequency ( cutoff)^and to attenuate frequencies above the cutoff frequency (f_cutOff)-

16. The method of claim 12, wherein the measurement is taken using square wave voltammetry (SWV); and wherein measuring the analyte comprises: determining a current differential measurement based on a forward current measurement and a reverse current measurement, wherein a redox current of a redox tag is measured based in part on the current differential measurement.

17. The method of claim 12, wherein the measurement is taken using continuous square wave voltammetry (cSWV); and wherein measuring the analyte comprises: determining a current differential measurement based on a plurality of forward current measurements and a plurality of reverse current measurements, wherein a redox current of a redox tag is measured based in part on the current differential measurement.

18. The method of claim 12, wherein one or more artifacts include at least one of: an artifact indicative of a physiological disturbance, an artifact indicative of an electrical disturbance, or an artifact indicative of a mechanical disturbance.