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WO2025213214A1 - Distribution d'énergie améliorée pour un capteur électrochimique - Google Patents

Distribution d'énergie améliorée pour un capteur électrochimique

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Publication number
WO2025213214A1
WO2025213214A1 PCT/AU2025/050316 AU2025050316W WO2025213214A1 WO 2025213214 A1 WO2025213214 A1 WO 2025213214A1 AU 2025050316 W AU2025050316 W AU 2025050316W WO 2025213214 A1 WO2025213214 A1 WO 2025213214A1
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WO
WIPO (PCT)
Prior art keywords
potential
electrode
connecting arrangement
arrangement
source
Prior art date
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Pending
Application number
PCT/AU2025/050316
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English (en)
Inventor
Jeremy VAN EPS
Garry Chambers
Sahil KHANNA
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Nutromics Technology Pty Ltd
Original Assignee
Nutromics Technology Pty Ltd
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Publication of WO2025213214A1 publication Critical patent/WO2025213214A1/fr
Pending legal-status Critical Current
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/002—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the work function voltage
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3276—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a hybridisation with immobilised receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/22—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements

Definitions

  • the present disclosure relates generally to electrochemical sensors, and particularly electrochemical aptamer-based sensors.
  • the disclosure provides an improvement in the delivery of electrical power to electrochemical sensors allowing for more accurate determination of target analyte concentration.
  • Electrochemical sensors have been proven to be useful in the real-time detection of target analytes in diverse media including air, water, process intermediates, and biological fluids.
  • a biological or a chemical analyte recognition element is applied to an electrically conductive element to form a working electrode.
  • a current is produced.
  • a feature of the current may be used determine the amount of analyte in the test fluid.
  • Electrochemical aptamer-based (EAB) sensors are showing increasing promise in industry and medicine.
  • the working electrode is coated with a plurality of aptamers that specifically recognise a target analyte.
  • a redox reporter (such as methylene blue) is typically covalently linked to the aptamer at its free end.
  • the recognition manifests as a conformational change in the aptamer upon analyte binding.
  • the conformational change in turn alters the accessibility of the redox reporter to the working electrode surface, thereby producing an analyte-induced change in the level of electron transport between the redox reporter and the electrode.
  • the change in speed of electron transport contributes to a change in Faradaic current that is detected by a potentiostat.
  • Chronoamperometry is a technique often used in the operation of electrochemical sensors.
  • the potential of the working electrode is stepped and the resultant current arising from Faradaic processes at the electrode is measured as a function of time.
  • the Faradaic current is due to electron transfer between the electrode surface and the redox reporter, and is therefore the current component of interest. Since the Faradaic current decays over a relatively long time period, chronoamperometry provides a superior signal- to-noise ratio in comparison to other amperometric techniques.
  • chronoamperometry is undoubtedly a useful technique when applied to electrochemical sensors, the accuracy of the target analyte concentration determined for a test fluid may depart from the actual concentration. Such departures are seen particularly for EAB sensors.
  • the present disclosure provides an electrochemical sensor apparatus comprising: an electrode arrangement comprising a working electrode, a counter electrode, and optionally a reference electrode; and a connecting arrangement comprising first and second electrical inputs and an electrical output, the electrical output being connected directly or indirectly to the electrode arrangement; wherein the first and second electrical inputs are biased at respective first and second potentials, the first potential being unequal to the second potential, and the connecting arrangement is configured so as to apply the first potential or the second potential to the electrode arrangement.
  • the connecting arrangement is configured so as to substantially instantaneously transition from applying the first potential to applying the second potential to the electrode arrangement.
  • the connecting arrangement is configured so as to transition from applying the first potential to applying the second potential to the electrode arrangement within 50 ns, 40 ns, 30 ns, 20 ns, 10 ns, 9 ns, 8 ns, 7 ns, 6 ns, 5 ns, 4 ns, 3 ns, 2 ns, or 1 ns.
  • the connecting arrangement is configured to limit a time period for which a potential that is intermediate between the first potential and the second potential is applied to the electrode arrangement.
  • the connecting arrangement is configured such that the potential at the output transitions from the first potential to a second potential in a step-wise manner.
  • the connecting arrangement is a multiplexor or a set of discrete switches functioning in a coordinated manner.
  • the connecting arrangement is a solid state device.
  • the connecting arrangement is implemented as an integrated circuit.
  • the apparatus comprises a first potential source and a second potential source, wherein the first potential source is connected to the first electrical input of the connecting arrangement, and the second potential source is connected to the second electrical input of the connecting arrangement.
  • the first potential source and the second potential source are each a discrete power source.
  • the first potential source and the second potential source are provided by a single power source in operable connection with a voltage divider or functional equivalent thereof.
  • the electrical output of the connecting arrangement and a ground are connected across the working electrode and the counter electrode so as to apply the potential of the electrical output to the working electrode.
  • the electrical output of the connecting arrangement is connected to an input of a potentiostat that is in operable connection with the electrode arrangement.
  • the apparatus comprises a processor, and the connecting arrangement is controllable by the processor.
  • the processor has access to processorexecutable instructions to apply a potential step useful in a chronoamperometry technique.
  • the processor-executable instructions direct transition of the electrical output of the connecting arrangement from the first potential to the second potential.
  • the working electrode and/or counter electrode and/or reference electrode are configured to penetrate the skin of a mammal so as to be contactable to the interstitial fluid, or another bodily fluid thereof.
  • the working electrode and/or counter electrode and/or reference electrode is/are selected from a needle, a microneedle and a wire.
  • the apparatus is configured to be wearable on a surface of a mammal.
  • the apparatus comprises an adhesive surface configured to retain the sensor on the skin of a mammal.
  • the present disclosure provides an electrochemical sensor comprising the apparatus of any embodiment of the first aspect.
  • the working electrode is coated in a redox- modified aptamer species capable of selective interaction with a target analyte.
  • the present disclosure provides a method for determining the concentration of a target analyte in a test fluid, the method comprising use of a connecting arrangement to make an electrical connection alternately between (i) a first potential source and an input of a sensor, and (i) a second potential source and the input of a sensor, the first potential source providing a first potential that is unequal to a potential provided by the second potential source.
  • the senor comprises an electrode arrangement comprising a working electrode, a counter electrode and optionally a reference electrode; and the connecting arrangement comprises first and second electrical inputs and an electrical output, the electrical output being connected directly or indirectly to the electrode arrangement; wherein the first and second electrical inputs are connected respectively to the first potential source and the second potential source, biased at respective first and second potentials, the first potential being unequal to the second potential, and the connecting arrangement is configured so as to apply the first potential or the second potential to the electrode arrangement.
  • the connecting arrangement substantially instantaneously transitions from applying the first potential to applying the second potential to the electrode arrangement.
  • the connecting arrangement transitions from applying the first potential to applying the second potential to the electrode arrangement within 50 ns, 40 ns, 30 ns, 20 ns, 10 ns, 9 ns, 8 ns, 7 ns, 6 ns, 5 ns, 4 ns, 3 ns, 2 ns, or 1 ns.
  • the connecting arrangement substantially prevents applying a potential that is intermediate between the first potential and the second potential to the electrode arrangement.
  • the potential at the electrical output of the connecting arrangement transitions from the first potential to a second potential in a step- wise manner.
  • the connecting arrangement is a multiplexor or a set of discrete switches functioning in a coordinated manner.
  • the connecting arrangement is a solid state device.
  • the connecting arrangement is implemented as an integrated circuit.
  • a first potential source is connected to a first electrical input of the connecting arrangement, and a second potential source is connected to a second electrical input of the connecting arrangement.
  • the first potential source and the second potential source are each a discrete power source.
  • the first potential source and the second potential source are provided by a single power source in operable connection with a voltage divider or functional equivalent thereof.
  • an electrical output of the connecting arrangement and a ground are connected across a working electrode and a counter electrode of the sensor so as to apply the potential of the electrical output to the working electrode.
  • an electrical output of the connecting arrangement is connected to an input of a potentiostat that is in operable connection with the electrode arrangement.
  • the connecting agent is controlled by a processor.
  • the processor has access to processorexecutable instructions to apply a potential step useful in a chronoamperometry technique.
  • the processor-executable instructions direct transition of the electrical output of the connecting arrangement from the first potential to the second potential.
  • the working electrode and/or counter electrode and/or reference electrode penetrate the skin of a mammal so as be contactable to the interstitial fluid, or another bodily fluid thereof.
  • the working electrode and/or counter electrode and/or reference electrode is/are selected from a needle, a microneedle and a wire.
  • the method comprises wearing the sensor on the surface of a mammal.
  • the method comprises use of an adhesive surface configured to retain the sensor on the skin of a mammal.
  • the present disclosure provides a chronoamperometry method for use with an electrochemical sensor apparatus, comprising the method defined by any embodiment of the third aspect.
  • the electrochemical sensor apparatus is according to any embodiment of the first aspect.
  • the present disclosure provides computer readable medium having stored thereon software instructions to perform the method of any embodiment of the third or fourth aspect.
  • the medium is non-transitory.
  • FIG. 1A is a graph showing an ideal step waveform used in the application of potential across a working electrode and a counter electrode of an EAB sensor subject to a chronoamperometry technique, for the determination of target analyte concentration in a test fluid.
  • FIG. IB is a graph showing a real step waveform used in the application of potential across a working electrode and a counter electrode of an EAB sensor subject to a chronoamperometry technique, for the determination of target analyte concentration in a test fluid. It will be noted that the real step waveform departs from the ideal step waveform of FIG. 1A
  • FIG. 2 is a prior art circuit diagram of an EAB sensor in operable communication with a potentiostat for use in a chronoamperometry technique for the determination of target analyte concentration in a test fluid.
  • Input potential for the potentiostat op-amp is generated by a digital to analogue converter (DAC).
  • DAC digital to analogue converter
  • the DAC output is a stepped potential that is non-ideal, and in general accordance with the curve shown in FIG. IB.
  • FIG. 3A is a circuit diagram of an EAB sensor in operable connection with a potentiostat for use in a chronoamperometry technique for the determination of target analyte concentration in a test fluid.
  • Input potential for the potentiostat op-amp is generated by first and second discrete power sources (Vi and V2), with a multiplexor being actuatable to alternately connect Vi and V2 to the potentiostat.
  • the multiplexor is set to direct potential from Vi to the potentiostat for the period of time shown in the graph of FIG. 3B.
  • FIG. 4A is the same circuit as shown in FIG. 3 A, although with the multiplexor set to direct potential from V2 to the potentiostat for the period of time shown in the graph of FIG. 4B. It will be noted that the transition from Vi to V2 is substantially instantaneous to form a step waveform that is substantially the same as the ideal waveform shown in FIG. 1A.
  • FIG. 5 is a circuit diagram of another prior art EAB sensor in operable connection with a potentiostat for use in a chronoamperometry technique for the determination of target analyte concentration in a test fluid.
  • Input potential for the potentiostat op-amp is generated by a DAC.
  • the DAC output is a stepped potential that is non-ideal, and in general accordance with the curve shown in FIG. IB.
  • FIG. 6 is a circuit diagram the same as for FIG. 5, although utilising two potential sources Vi and V2 which can be alternately applied to the potentiostat op-amp by way of a multiplexor (100), as for the circuits of FIG. 3 A and FIG. 4A.
  • the nonideal step waveform is a source of error in analyte concentration determined chronoamperometrically by EAB sensors.
  • FIG. 1A showing an ideal step waveform for the application of potential applied to the working electrode in a chronoamperometry technique. Potential transitions sharply from a first voltage (Vi), to a second voltage (V2).
  • the waveform is often generated by a power source providing output that is compromised in some way.
  • a digital to analogue converter may be used as power source, with a typical output waveform being shown in FIG. IB.
  • the waveform is clearly less than ideal, with the shoulder formation being the result of a slow settling time of the DAC.
  • Settling time is the elapsed time from input code application until the output arrives at and remains within a specified error band about the final value. It is proposed that the shoulder in the step waveform leads to a current decay curve that is not reflective of the concentration of target analyte about the working electrode of the electrochemical sensor.
  • the DAC is replaced with a two-input single-output multiplexor.
  • the first of the two inputs of the multiplexor is set at potential Vi and the second is set at potential V2 with the output connected to an input of the electrochemical sensor (such as the potentiostat).
  • FIG. 2 showing a circuit diagram of prior art electrochemical sensor having an electrode arrangement (10) comprising a working electrode (15), a counter electrode (20) and a reference electrode (25) connected to a potentiostat having an input (Vi) being set at a potential by the output of DAC (30).
  • This prior art sensor outputs a non-ideal stepped waveform (as shown in FIG. IB) as a result of the settling time of the DAC (30).
  • Vi is an applied potential (the potentiostatic set point) that is referenced to ground. It will be noted in this generic discussion of potentiostat operation the ground may be real or virtual. Vi applies the inverting negative input on the op-amp.
  • the output Vo connects to the counter electrode (20) lead.
  • the reference electrode (25) lead and the working sense lead (15, WEsense) connect to an electrometer (functioning as a true difference amplifier).
  • the output voltage V feedback from the electrometer feeds into a voltmeter V and into the positive non-inverting input of the op-amp.
  • the working electrode (15) drive lead WEr/rzve connects to a resistor R that connects to ground (real or virtual).
  • the voltmeter (E/I) measures the potential across R, and converts it to a current. WE.s s and WEdrive are shorted together and connect to the working electrode (15).
  • the user applies voltage Vi to the electrochemical cell.
  • An output voltage (Vo) is output from the op-amp into the electrochemical cell through the counter electrode (20).
  • the counter electrode (20) passes current (ictr) through the test fluid to the reference electrode (25), WEsense, and WEdrive. Inputs to an op-amp have a high impedance, hence no current passes. Since the reference electrode (25) and WE.s s are connected to a high impedance operational amplifier, the only viable path for current flow is through WEdrive.
  • the electrometer output voltage is the voltage difference between the reference electrode (25) and WEsense. As the current travels between the counter electrode (20) and WEdrive, the voltage drops across a gradient that is proportional to the bulk solution resistance. This process affects the potential of reference electrode (25) and WEsense. However, the reference electrode is configured to maintain a stable potential, and the potential at reference electrode (25) therefore remains constant. Accordingly any measured changes in the potential originate from WEsense.
  • the voltage difference between reference electrode (25) and WEsense is the output voltage of the electrometer, V feedback. Nfeedback feeds into a voltmeter (V) to measure the difference between the reference electrode (25) and WEsense. It also feeds into the positive non-inverting input of the opamp. Given that the op-amp amplifies the difference between the positive and negative inputs, if N feedbacks not equal to Vi, the op-amp will either increase or decrease V o until they equalise.
  • the working electrode current is not directly measured. Rather the voltage is measured across R, which is a known resistor, and based on the voltage measured across it current can be measured by application of Ohm’s Law. [076], To summarise, the current at the working electrode is measured by voltmeter (E/I) across R, the potential at the working electrode is measured by the electrometer (V), and the applied potential is determined by the potentiostatic set point. By utilising the op-amp’s feedback mechanism, the potential of the working electrode with respect to the reference electrode can be adjusted. Simultaneously adjusting potential while measuring the current at the working electrode is a feature of techniques used in the interrogation of electrochemical sensors.
  • FIG. 3 A and FIG. 4A An embodiment of the present disclosure is shown at FIG. 3 A and FIG. 4A, comprising a multiplexor (100).
  • the multiplexor (100) On the input side, the multiplexor (100) is connected to two sources of potential, each source providing a different potential: Vi or V2.
  • a source of potential may be a DAC, a standard power supply or any other source deemed suitable by the skilled person.
  • the multiplexor (100) is initially set such that the first (105) multiplexor input is connected to the multiplexor output (120), so as to provide Vi potential to the sensor input (Vi). Vi is a relatively large negative potential in this embodiment, and is held for a period of time, as shown in the graph of potential versus time of FIG. 3B.
  • the multiplexor (100) is actuated to connect the second multiplexor input (110) to the multiplexor output (120), so as to provide V2 potential to the sensor input (Vi).
  • Vi V2 potential
  • FIG. 4A Actuation of the multiplexor (100) is rapid, resulting in the virtually instantaneous transition to the V2 potential, as shown in the graph of potential versus time of FIG. 4B.
  • the rapid switching from Vi to V2 provides a step waveform closer to ideal, compared with the waveform provided by a single DAC as shown in FIG. IB. Accordingly, the Faradaic current elicited by the embodiment of FIG. 3 A and FIG. 4A will decay in a manner closer to that assumed in a calculation used to determine analyte concentration.
  • the disclosure may be implemented by first and second discrete on/off switches, the first configured to alternately connect and disconnect a Vi potential to the sensor input Vi, and the second configured to alternately connect and disconnect a V2 potential to the sensor input Vi.
  • actuation of the first and second switches is coordinated such that initially the first switch is “on”, and the second switch is “off’, thereby supplying Vi potential to the sensor.
  • first switch is “off’, and the second switch is “on”, thereby supplying V2 potential to the sensor.
  • Actuation of the first and second switches should be coordinated such that at the instant the first switch is moved to “off’, the second switch is moved to “on” such that at substantially no time is sensor input Vi exposed to both Vi and V2 potential, and at substantially no time is sensor input exposed to neither Vi nor V2 potential.
  • FIG. 5 showing an EAB sensor circuit. Vi and V2 potentials are provided to the potentiostat in a step waveform for chronoamperometry by DAC (30). The step waveform will be a departure from ideal, such as shown in FIG. IB.
  • FIG. 6 is a variation of the circuit of FIG. 5, having two potential sources to apply Vi and V2 potentials alternately to the potentiostat by way of multiplexor (100).
  • the multiplexor is set such that V2 potential is supplied to the potentiostat.
  • any connecting arrangement used in the present disclosure to transition from Vi to V2 is preferably sufficiently rapidly responsive so as to provide, as far as is practical, the idealised step waveform shown in FIG. 1 A or a waveform that is at least similar.
  • the transition from Vi potential to V2 potential should occur over a very short time period, preferably measured in nanoseconds, more preferably less than about 10 ns.
  • Actuation of the multiplexor, discrete switches or another connecting arrangement will typically be effected by a microprocessor unit (MCU) in accordance with software instructions directed to execute all or part of a chronoamperometry technique.
  • MCU microprocessor unit
  • the time for which Vi is held (ii) the time at which Vi transitions to V2, (iii) and (iii) the time for which V2 is held should be accurately controllable in the context of a chronoamperometry technique.
  • the multiplexor or switches or other type of connecting arrangement may be provided in the form of an integrated circuit.
  • the integrated circuit may be responsive to the output of a microcontroller under software instructions.
  • the multiplexor may have a logic input feature allowing for logic output (“0” or “1”) from a microcontroller to control the switch state of the multiplexor so as to alternate the power source to the sensor between Vi and V2.
  • the potential sources providing Vi and V2 may be selected by the skilled person for suitability to a particular application.
  • a DAC may be used for each potential source, with potential being set at a required voltage by use of a voltage divider.
  • the multiplexor may be selected from any one of a large number of potentially suitable products.
  • a potentially useful multiplexor is a CMOS-type switch such as the P15A3157CEX (Pericom Semiconductor Corporation).
  • the PI5A3157 is a high- bandwidth, fast single-pole double-throw switch, operable as an analog switch or as a low- delay bus switch. Operable over a wide operating power supply voltage range, 1.65V to 5.5V, the PI5A3157 has a maximum ON resistance of 12-ohms at 1.65V, 9-ohms at 2.3V and 6-ohms at 4.5 V.
  • MCU CC2652R7 (Texas Instruments), being a SimpleLinkTM ArmTM CortexTM-M4F multiprotocol 2.4-GHz wireless MCU with 704-kB Flash.
  • electrochemical sensor may be an EAB sensor having a working electrode coated in a redox-modified aptamer that is specific for glucose.
  • the electrodes of the sensor are each a microneedle capable of penetrating the skin of a subject (such as a human) and contacting the underlying interstitial fluid (ISF). Upon interrogation the working electrode of the sensor detects the concentration of glucose in the ISF.
  • ISF interstitial fluid
  • Such a sensor may be used in the management of diabetes, and the accuracy of a glucose reading should be high given that an inaccurate value could cause the subject to become dangerously hyperglycaemic or hypoglycaemic.
  • the disclosure may be useful in other applications such as in sensors for the determination of clinically relevant analytes in a pathology laboratory.
  • An electrochemical sensor may be interrogating using a DAC, leading to analyte values of suboptimal accuracy being reported.
  • Replacement of the DAC with a connecting arrangement capable of alternately directing Vi and V2 potential to the sensor potentiostat as described herein may improve the accuracy of analyte values output by a pathology laboratory.
  • the disclosure may have applicability also in non-clinical applications such as the monitoring of target analyte concentrations in environmental settings (such as waste water), and industrial settings (such as process intermediates).
  • the present disclosure may be embodied in the form of a fully functional EAB sensor, having a working electrode coated with analyte-specific DNA, RNA or XNA. Gold is often used as the probe surface for the working electrode.
  • the aptamer has an associated redox-active species which acts as a reporter.
  • the redox reporter is often methylene blue.
  • target e.g., drug
  • the aptamer undergoes a conformational change, bringing the redox reporter more proximal to the working electrode surface. This increase in proximity increases electron transfer from the redox reporter to the electrode.
  • the increase in speed of electron transfer contributes to a change in Faradaic current that is detected by a potentiostat.
  • Aptamers are small (usually from 20 to 60 nucleotides) single-stranded RNA, DNA or XNA oligonucleotides able to bind a target drug with high affinity and specificity. Aptamers may be considered as nucleotide analogues of antibodies, but aptamer production is an in vitro cell-free process that is significantly easier and cheaper than the production of antibodies by cell culture or in vivo methods.
  • RNA aptamers are usually selected from combinatorial library having a vast number (up to 10 15 ) of different oligonucleotides. While RNA aptamers provide a significantly greater structural diversity compared to DNA aptamers, their application is complicated by stability issues in the presence of RNases, high temperature, and unfavourable pH.
  • Selection of an aptamer that is selective for a given drug may be facilitated by a process known as SELEX (systematic evolution of ligands by exponential enrichment).
  • the process may be considered as two alternating stages.
  • the library oligonucleotides are amplified by a polymerase chain reaction (PCR) to the desired concentration.
  • PCR polymerase chain reaction
  • the single-chained oligoribonucleotides are generated by in vitro transcription of double-stranded DNA with T7 RNA-polymerase.
  • DNA aptamers a pool of single-stranded oligodeoxyribonucleotides is generated by strand separation of double-stranded PCR products.
  • the products of amplification are incubated with target drug and oligonucleotides which bind the drug are used in the next SELEX round.
  • Separation of oligonucleotides with higher affinity for target drug and removal of unbound oligonucleotides are achieved through intense competition for binding sites. The selection pressure rises with every SELEX round. Maximum enrichment of the oligonucleotide pool with aptamers with the strongest affinity for the target molecule is usually achieved after 5 to 15 rounds.
  • EAB sensors are typically incorporated into a circuit having a reference electrode.
  • the reference electrode is the site of a known chemical reaction that has a known redox potential.
  • AgCl) redox pair has a fixed and known potential forming the point against which the redox potential of the working electrode is measured.
  • a counter electrode typically included in the circuit is a counter electrode which functions as a cathode or an anode to the working electrode. Because the applied voltage bias does not pass through the reference electrode (due to an impedance of the potentiostat), any potential generated is attributed to the working electrode. Current is measured as potential of the interrogating electrode versus the stable potential of the reference electrode. The difference in potential produces the current in the circuit thereby generating an output signal.
  • the signal quantifies target binding depending on electron transfer that is ideally stoichiometrically proportional to target binding.
  • EAB sensors are particularly suitable for use as a wearable apparatus, allowing measurements to be performed whilst the subject is undergoing normal activities and/or over a prolonged period of time.
  • the wearable apparatus may be a collar, a bracelet or other suitable jewellery piece, a watch, a garment, a strap, an adhesive, or a patch.
  • means may be provided to assist adhering and/or securing the wearable apparatus, when in use, to a subject, e.g., micro-anchors, or the like.
  • the wearable apparatus may comprise a housing structure comprising one or more other components, such as electronics processing unit.
  • the electronics processing unit is configured to be in direct or indirect electrical communication with at least one electrode, and generally will include any one or more of a power source, a data processing unit, an analogue front-end, and a wireless transmitter.
  • the housing structure may be configured to encase, at least partially, the apparatus, where the electrodes (such as microneedles) are exposed from a plane of the housing structure.
  • the electrodes may be protected by a protective cover, which may be removed to expose the protruding electrodes before use.
  • the apparatus may further comprise means for monitoring temperature or pH of the biological fluid where validity of an output is dependent thereon, or where adjustment to operation or output is possible.
  • the housing structure may be configured to encase and be coupled to the apparatus by any appropriate mechanism.
  • electromagnetic coupling for example, electromagnetic coupling, mechanical coupling, adhesive coupling, magnetic coupling, or the like.
  • the coupling mechanism enables the apparatus and the housing structure to be attached and detached, which would enable the housing structure and its other components to be reusable, while the apparatus can be discarded and replaced with another apparatus as necessary.
  • the wearable apparatus may further comprise a computer program product executable as a software application, resident on a mobile communication device in communication with the electronics processing unit, wherein the computer program product is able to control one or more of (i) detection of electrochemical measurements conducted at the electrode-based platform, (ii) data analysis, (iii) data transmission, (iv) apparatus configuration, and (v) apparatus power management.
  • suitable mobile communication devices include, but are not limited to, smartphones, smartwatches, tablets, smartglasses, laptops or other personal computers.
  • the apparatus itself comprises a processor with program instructions configured to drive onboard functions such as voltammetry, and transmitting output to a remote device via a wireless module, such as a BluetoothTM module.
  • a wireless module such as a BluetoothTM module.
  • microprocessors that execute computer software, program codes, and/or instructions on a processor.
  • a microprocessor may be any kind of computational or processing device capable of executing program instructions, codes, binary instructions, and the like.
  • Any microprocessor may access a storage medium (such as electronic memory) through an interface that may store methods, codes, and instructions as described herein and elsewhere.
  • the storage medium associated with the processor for storing methods, programs, codes, program instructions or other type of instructions capable of being executed.
  • the computer software, program codes, and/or instructions may be stored and/or accessed on computer readable media that may include: computer components, devices, and recording media that retain digital data used for computing for some interval of time; semiconductor storage known as random access memory (RAM); mass storage typically for more permanent storage, such as non-volatile memory such as read only memory (ROM).
  • RAM random access memory
  • ROM read only memory
  • the methods described herein may transform physical and/or or intangible items from one state to another.
  • the methods and systems described herein may also transform data representing physical and/or intangible items from one state to another.
  • Software products may be created using a structured programming language such as C, an object oriented programming language such as C++, or any other high-level or low-level programming language (including assembly languages, hardware description languages, and database programming languages and technologies) that may be stored, compiled or interpreted to run on a microprocessor, as well as heterogeneous combinations of processors, processor architectures, or combinations of different hardware and software, or any other machine capable of executing program instructions.
  • a structured programming language such as C
  • an object oriented programming language such as C++
  • any other high-level or low-level programming language including assembly languages, hardware description languages, and database programming languages and technologies
  • any method may be embodied in computer executable code that, when executing on one or more microprocessors, performs the steps thereof.
  • the methods may be embodied in systems that perform the steps thereof, and may be distributed across devices in a number of ways, or all of the functionality may be integrated into a dedicated, standalone device or other hardware.
  • the means for performing the steps associated with the processes described above may include any of the hardware and/or software described above. All such permutations and combinations are intended to fall within the scope of the present disclosure.
  • the disclosure may be embodied in program instruction set executable on one or more microprocessors.
  • Such instructions set may include any one or more of the following instruction types.
  • Data handling and memory operations which may include an instruction to set a register to a fixed constant value, or copy data from a memory location to a register, or vice-versa, to store the contents of a register, result of a computation, or to retrieve stored data to perform a computation on it later, or to read and write data from hardware devices.
  • Arithmetic and logic operations which may include an instruction to add, subtract, multiply, or divide the values of two registers, placing the result in a register, possibly setting one or more condition codes in a status register, to perform bitwise operations, e.g., taking the conjunction and disjunction of corresponding bits in a pair of registers, taking the negation of each bit in a register, or to compare two values in registers (for example, to determine if one is less, or if they are equal).
  • Control flow operations which may include an instruction to branch to another location in the program and execute instructions there, conditionally branch to another location if a certain condition holds, indirectly branch to another location, or call another block of code, while saving the location of the next instruction as a point to return to.
  • Coprocessor instructions which may include an instruction to load/store data to and from a coprocessor, or exchanging with CPU registers, or perform coprocessor operations.
  • a processor of a computer of the present system may include “complex” instructions in their instruction set.
  • a single “complex” instruction does something that may take many instructions on other computers. Such instructions are typified by instructions that take multiple steps, control multiple functional units, or otherwise appear on a larger scale than the bulk of simple instructions implemented by the given processor.
  • Some examples of “complex” instructions include: saving many registers on the stack at once, moving large blocks of memory, complicated integer, and floating-point arithmetic (sine, cosine, square root, etc.), SIMD instructions, a single instruction performing an operation on many values in parallel, performing an atomic test-and-set instruction or other read-modify-write atomic instruction, and instructions that perform ALU operations with an operand from memory rather than a register.
  • An instruction may be defined according to its parts. According to more traditional architectures, an instruction includes an opcode that specifies the operation to perform, such as add contents of memory to register — and zero or more operand specifiers, which may specify registers, memory locations, or literal data. The operand specifiers may have addressing modes determining their meaning or may be in fixed fields. In very long instruction word (VLIW) architectures, which include many microcode architectures, multiple simultaneous opcodes and operands are specified in a single instruction.
  • VLIW very long instruction word
  • TTA Triggered Architectures
  • Forth virtual machine only operand(s).
  • Other unusual “0-operand” instruction sets lack any operand specifier fields, such as some stack machines including NOSC.
  • Conditional instructions often have a predicate field — several bits that encode the specific condition to cause the operation to be performed rather than not performed. For example, a conditional branch instruction is executed, and the branch taken, if the condition is true, so that execution proceeds to a different part of the program, and not executed, and the branch not taken, if the condition is false, so that execution continues sequentially. Some instruction sets also have conditional moves, so that the move is executed, and the data stored in the target location, if the condition is true, and not executed, and the target location not modified, if the condition is false. Similarly, IBM z/Architecture has a conditional store. Some instruction sets include a predicate field in every instruction; this is called branch predication.
  • the instructions constituting a program are rarely specified using their internal, numeric form (machine code); they may be specified using an assembly language or, more typically, may be generated from programming languages by compilers.
  • the disclosure is described mainly by reference to the use of an electrochemical sensor to sense an analyte in the ISF of a mammal.
  • the disclosure may be operable with other test fluids such as blood, saliva, urine, potable water, waste water, industrial process intermediates, industrial products, foods, and many others.

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Abstract

L'invention concerne un appareil de capteur électrochimique ayant un agencement d'électrodes qui comprend une électrode de travail, une contre-électrode et éventuellement une électrode de référence. Un agencement de connexion est fourni, ayant des première et seconde entrées électriques et une sortie électrique, la sortie étant connectée directement ou indirectement à l'agencement d'électrodes. Les première et seconde entrées électriques sont polarisées à des premier et second potentiels respectifs, et l'agencement de connexion est configuré pour appliquer le premier potentiel ou le second potentiel à l'agencement d'électrodes.
PCT/AU2025/050316 2024-04-09 2025-04-03 Distribution d'énergie améliorée pour un capteur électrochimique Pending WO2025213214A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2006109277A2 (fr) * 2005-04-15 2006-10-19 Agamatrix, Inc. Determination de remplissage partiel de bandelettes electrochimiques
US20070170073A1 (en) * 2005-12-30 2007-07-26 Medtronic Minimed, Inc. Method and System for Detecting Age, Hydration, and Functional States of Sensors Using Electrochemical Impedance Spectroscopy
WO2024000017A1 (fr) * 2022-06-27 2024-01-04 Nutromics Technology Pty Ltd Appareil pour commander l'introduction d'une aiguille dans la peau

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Publication number Priority date Publication date Assignee Title
WO2006109277A2 (fr) * 2005-04-15 2006-10-19 Agamatrix, Inc. Determination de remplissage partiel de bandelettes electrochimiques
US20070170073A1 (en) * 2005-12-30 2007-07-26 Medtronic Minimed, Inc. Method and System for Detecting Age, Hydration, and Functional States of Sensors Using Electrochemical Impedance Spectroscopy
WO2024000017A1 (fr) * 2022-06-27 2024-01-04 Nutromics Technology Pty Ltd Appareil pour commander l'introduction d'une aiguille dans la peau

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Title
YIN, HEYU ET AL.: "A compact low- power current-to-digital readout circuit for amperometric electrochemical sensors", IEEE TRANSACTIONS ON INSTRUMENTATION AND MEASUREMENT, vol. 69, no. 5, 10 June 2019 (2019-06-10), pages 1972 - 1980, XP011781942, DOI: 10.1109/TIM.2019.2922053 *

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