CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a U.S. National Stage of International Application No. PCT/EP2018/083864, filed Dec. 6, 2018, which claims the benefit of Great Britain Patent Application No. 1720353.0 filed on Dec. 6, 2017; the entire disclosures of all are hereby incorporated by reference in their entireties into the present disclosure for all purposes.

BACKGROUND

Embodiments of the present application provide sensors, in particular smart medical and/or pharmaceutical sensors, with a stable reference and/or reference correction. More particularly, but not by way of limitation, the present application describes sensor systems comprising a monitoring electrode that is configured to monitor sensor operation to provide for accurate/precise sensor measurements.

In chemistry, pH is a numeric scale used to specify the acidity or basicity (alkalinity) of an aqueous solution. It is approximately the negative of the logarithm to base10of the molar concentration, measured in units of moles per liter of hydrogen ions. More precisely, it is the negative of the logarithm to base10of the activity of the hydrogen ion. Solutions with a pH less than 7 are acidic and solutions with a pH greater than 7 are basic. Pure water is neutral, being neither an acid nor a base.

pH measurements are important in a variety of fields such as healthcare, medical, pharmaceutical, environmental, industrial, and many more. In addition to pH, other important measurements often need to be taken in these fields. For instance in medical/pharmaceutical applications it is often necessary to also measure oxygen-reduction potential, glucose concentration and/or the like. There are several problems in making sensor measurements, including monitoring/controlling sensor operation in-situ. Moreover, in-situ monitoring and controlling sensor operation without manual intervention is often a requirement in these fields. In-situ, monitoring and control is important, because in any of the above fields, it may not be possible/practicable to remove a sensor to monitor and control its operation, or it may simply be advantageous for the sensor to be able to remain in a single location for long periods of time. For example, in the pharmaceutical field, testing may be performed on cells, cell cultures and/or the like in a controlled environment, which environment may not be kept integral by the removal/adjustment of sensors. Similarly, in the medical field, for example for point-of-care applications, for monitoring applications and/or the like, it may not be possible to remove sensors for operation purposes after sensing procedures, point-of-care or monitoring procedures have commenced.

The issue of monitoring/control of sensors is enhanced in all the aforementioned fields, by the need for accurate, precise measurements that may be required to be made over a period-of-time, whilst the sensor is deployed, for example for a medical/pharmaceutical procedure. Furthermore, an understanding of how the sensor is operating in real-time is required to provide that tests do not have to be repeated, which is costly, and/or may not even be possible. Real-time updates also prevent the need for repeated access to the sensors which may be time consuming and costly when located remotely, or even a cause for discomfort when the sensors are used in medical applications.

Furthermore, with respect to pH measurements, there are a number of issues that make measuring pH using existing sensors problematic in the aforementioned fields. These problems include, fragility and reference drift of glass electrode pH sensors and instability of the reference used for voltammetric pH measurement. For both the glass electrode and the voltammetric based pH sensors, use in low buffering capacity solutions, such as many saline solutions used in the healthcare, medical and/or pharmaceutical fields, or water/seawater often found in environmental studies, may adversely affect pH measurement. Moreover, the reference drift found in glass electrodes is also problematic for other sensors used in the aforementioned fields. For example, a number of sensors such as glucose sensors, reduction-oxidation potential sensors and/or the like use a reference electrode, often a silver-silver chloride reference electrode, that is prone to drift. This drift is well-known and is caused, at least in part, by an exchange of liquids into and out of the reference chamber.

For nearly a century, pH has most commonly been measured using a glass electrode. The glass electrode is a combination electrode that combines both a glass and a reference electrode into one body. The combination electrode consists of the following parts: a sensing part of the electrode, a bulb made from a specific glass; an internal electrode, usually silver chloride electrode or calomel electrode; an internal solution, usually a 3M and/or saturate KCl gel and/or aqueous solution; a reference electrode, usually the same type with a reference internal solution, usually 3M and/or saturate KCl gel and/or aqueous solution; a junction with studied solution, usually made from ceramics or capillary with quartz fiber; and the body of the electrode, made from non-conductive glass or plastics.

Glass electrodes cannot be used for many applications in the aforementioned fields because of their fragility, requirement of calibration before use, need for calibration during use, and need to be stored under appropriate conditions, such as the requirements that the sensor be stored wet.

A number of chemical analysis tools for pH monitoring are known from chemical laboratory practice. Such known analysis tools include, for example various types of chromatography, electrochemical and spectral analysis. Of the analysis tools, the potentiometric method has been widely used for the measurements of water composition both in the laboratory and in the field of ground water quality control.

U.S. Pat. No. 5,223,117 (Wrighton) discloses a two-terminal voltammetric micro-sensor having an internal reference using molecular self-assembling to form a system in which the reference electrode and the indicator electrode are both on the sensor electrode. The reference molecule is described as a redox system that is pH-insensitive, while the indicator molecule is pH sensitive and is formed by a hydroquinone based redox system having a potential that shifts with the pH. Both, reference molecule and indicator molecule layers are prepared by self-assembly on gold (Au) microelectrodes. In the known micro-sensor of Wrighton, a pH reading is derived from analysis of peak readings of the voltammograms, i.e., the shift of the peak reading obtained from the pH sensitive indicator molecule (often referred to as the redox active species).

Recently there has been significant work in the development of pH sensors for use in the water industry, where the concentration of dissolved buffer and/or ionic salt is low. Interest in this area stemmed from the work by Compton et al. (see C. Batchelor-McAuley, B. R. Kozub, D. Menshkau, R. G. Compton,Voltammetric Responses of Surface-Boundary and Solution-Phase Anthraquinone Moieties in the Presence of Unbuffered Aqueous Media, J. Phys. Chem. C 115, pp. 714-718 (2011)), who showed the use of classical quinone/hydroquinone voltammetry to monitor pH in these systems failed. Compton established that the proton coupled electrochemical process perturbed the pH of the solution locally to the electrode when little or no buffer and/or ionic salt was in the analyte solution.

To this end, work by Dr. Nathan Lawrence has shown that this issue can be mitigated by the use of a variety of quinone and phenol based systems, which provide a means of internal hydrogen bonding of the proton being transferred in the electrochemical process. In this work, it was shown that dihydroxyanthraquinone and alizarin were suitable for the quinone systems, where the keto moiety closest to the —OH moiety allowed the facilitation of the proton coupled electron transfer and providing a means for the reaction to follow a concerted rather than non-concerted mechanism. Further to these results, it was shown that oxidation of phenol species containing moieties holding keto groups in the 2-position of the benzene ring, e.g., salicyaldehyde, provided an electroactive polymer species that is pH active and able to measure pH in low buffered media/ionic strength, such as water/seawater. A variety of derivatives were tested by Lawrence and described in U.S. Patent Publication No. 2014/0332398, including the aldehyde, ester and nitrogen based compounds. From further work, Lawrence found that phenolic compounds including a sulphurous atom attached either directly or indirectly to the aromatic ring of the phenolic compound and configured to form a hydrogen bond with the hydrogen atom associated with the hydroxyl moiety of the phenolic compound, provided a stable redox active species for voltammetric measurement of pH in solutions with a low buffering capacity, such as saline solutions or the like used in healthcare, medical and/or pharmaceutical applications.

SUMMARY

Embodiments of the present disclosure provide a smart sensor system for use in a variety of different fields, in particular enviromental, industrial healthcare, medical and/or pharmaceutical. The sensor system comprises a monitoring electrode, which may be held within a reference electrode chamber and thus form a smart reference electrode, wherein the monitoring electrode is configured to produce a calibration output that can be used in-situ and in real-time to monitor and address reference electrode drift and to provide information regarding sensor operation. This monitoring electrode/smart reference electrode when used with a solid-state electrochemical sensor, provides a calibration output that may be used as the reference value for the solid-state electrochemical sensor. In embodiments of the present disclosure, the monitoring electrode comprises a redox chemistry that comprises either a redox species that is not sensitive to changes in a solution being tested/monitored and/or a redox active species configured to set a pH of the local environment proximal to the electrode when the electrode is contacted with a test solution.

In addition to the monitoring electrode, the smart sensor system comprises at least one sensor, for example an electrochemical sensor for detecting and monitoring pH of liquids; a glass electrode, an oxidation-reduction potential sensor; a glucose sensor and/or other ion selective electrode sensor.

In some embodiments, a voltammetric signal is applied to the monitoring electrode to generate a response signal from the monitoring electrode. Because the monitoring electrode is either insensitive to changes in the test solution or configured to set the pH proximal to the electrode, the response signal comprises a voltammetric response with a constant peak voltage, as well as other constant features in the voltammetric response. In embodiments of the present application, a difference between the constant peak voltage and a reference voltage of a reference system associated with the at least one of the sensors of the sensor system, may be determined and then used to correct any drift of the reference system. For example, the difference between the constant peak voltage and the reference voltage may be measured when the sensor using the reference system is calibrated, may be determined by batch testing, may be calculated based upon the characteristics of the reference system and/or the like.

In some embodiments, the voltammetric signal may be applied between the monitored reference electrode and one or more electrodes of at least one of the electrochemical sensors. The voltammetric response produced in response to a voltammetric signal applied between the monitored reference electrode and the electrode of one of the sensors of the sensor system may be processed to provide real-time, in-situ data regarding operation of the one of the sensors.

In some embodiments, such as where the sensor in the sensor system comprises an electrochemical sensor, the monitoring electrode may comprise the reference electrode for the sensor, where the constant peak voltage is used as a reference voltage for the sensor.

In some embodiments, where the sensor system comprises an electrochemical sensor the electrochemical sensor may comprise a plurality of working electrodes, a working electrode comprise a plurality of areas on the working electrode comprising a redox active species and/or a working electrode comprising an array of microelectrodes. In some embodiments of the present disclosure, the sensor system may control the electrochemical sensor to switch between working electrodes, areas on the working electrode comprising a redox active species and/or electrodes in the microelectrode array when a signal produced by the working electrode is too small and/or too noisy to process.

In some embodiments, where the sensor system comprises a glass electrode, a voltammetric signal may be applied between the monitoring electrode and the reference electrode and/or between the monitoring electrode and the working electrode of the glass electrode. The voltammetric response produced by applying a voltammetric signal between the monitoring electrode and the reference electrode may determine any drift in the reference electrode, may identify breakdown of the reference electrode and/or the reference solution, may identify entry of contamination into the reference solution, may identify dilution of the reference solution and/or the like. The voltammetric response produced by applying a voltammetric signal between the monitoring electrode and the working electrode may provide information regarding the glass electrode membrane and other operational characteristics of the glass electrode.

In some embodiments, when used in the pharmaceutical field, an immobilized redox species is held either within or upon a sensing electrode to determine the cellular condition of cells, such as liver cells, when exposed to various drugs/pharmaceuticals. In such embodiments, sensors may measure the properties of a solution containing the cells and/or the cells themselves. For purposes of this application both the solution containing the cells and the solution contained within the cells may be referred to as a test solution. In some embodiments, sensors may be used to measure key markers of cell condition, such as pH, oxygen/reduction potential, glucose concentration and/or the like. A knowledge of these three parameters provides an insight into the behavior and healthiness of the cells.

In some embodiments, a plurality of electrochemical based sensors may be tied to a single smart reference electrode. The smart reference electrode is designed to overcome issues of electrode drift, by providing in-situ calibration. In some embodiments, algorithms are used to provide a sensor made smart where measurement parameters can be altered in line with any measured changes in reference electrode potential.

