WO2024064700A1

WO2024064700A1 - Photometric detection of analytes

Info

Publication number: WO2024064700A1
Application number: PCT/US2023/074612
Authority: WO
Inventors: Thomas Richard Veltman
Original assignee: Aza Technology, Inc.
Priority date: 2022-09-19
Filing date: 2023-09-19
Publication date: 2024-03-28

Abstract

Disclosed herein are one or more systems, devices, and/or methods for generating and/or measuring a photometric signal based on an amperometric sensor response. In some embodiments, in contrast to directly measuring a current produced by an amperometric sensor (140), the one or more systems, devices, and/or methods provided herein can generate a light signal from the current flowing through the amperometric sensor (140) for remote measurement and/or detection of the generated light signal. In some examples, generating a light signal based on the current output from the amperometric sensor (140) can provide one or more advantages of photometric detection, e.g., such as allowing for and/or facilitating remote monitoring and/or signal multiplexing using multiple wavelengths. In some examples, remote monitoring and/or signal multiplexing can include detection of one or more analytes in a biological sample, e.g., remote monitoring and/or signal detection of gases such as gaseous ammonia, carbon monoxide, hydrogen sulfide, or others.

Description

PHOTOMETRIC DETECTION OF ANALYTES

CROSS-REFERENCE

[001] This Application claims priority to U.S. Provisional patent application serial No. 63/376,254, filed September 19, 2022, the entire disclosure of which is hereby incorporated by reference.

FIELD

[002] The present disclosure relates in general to systems, devices and methods for measuring an amount of an analyte in a substance, and in particular, using a photometric detection system to measure a gaseous response being liberated from a biological sample.

BACKGROUND

[003] Amperometric sensors produce a current proportional to the concentration of a desired analyte. Conventionally, this current can be measured and the concentration of the analyte can be estimated from this measurement. However, accurate quantification requires standardization of each sensor to compensate for manufacturing variations. Since each sensor can have its own characteristic sensitivity, there can be no absolute intrinsic value to the measured current: each sensor will have a different measured current when exposed to the same concentration of analyte.

[004] The foregoing discussion, including the description of motivations for some embodiments of the invention, is intended to assist the reader in understanding the present disclosure, is not admitted to be prior art, and does not in any way limit the scope of any of the claims

SUMMARY

[005] A method and device for measuring an amount of an analyte in a substance is presented, according to some embodiments.

[006] A method for measuring an amount of an analyte in a substance is presented, according to some embodiments. In some embodiments, the method can include positioning the substance in proximity with an amperometric sensor. The method can include mixing the substance with a chemical reagent. In some embodiments, the method includes generating a photometric signal via the amperometric sensor in response to the amount of the analyte in the substance. In some embodiments, the method can include detecting the photometric signal using a detection photodetector, such that the detected photometric signal correlates with the amount of the analyte in the substance.

[007] Various embodiments of the method can include one or more of the following features. In some embodiments, generating the photometric signal includes converting a sensor signal from the amperometric sensor to a photon stream. In some embodiments, the photometric signal can be correlated with the amount of the analyte based on an intensity of the photon stream, as measured by the detection photodetector. In some embodiments, the method can include amplifying the sensor signal from the amperometric sensor. In some embodiments, the method can include amplifying the sensor using one or more Darlington transistor pairs. In some embodiments, the method can include linearizing the photometric signal with a current generated by the amperometric sensor by adjusting an output voltage of a control circuit amplifier in electrical communication with the amperometric sensor. In some embodiments, linearizing the photometric signal can include detecting the photometric signal using a monitor photodiode, such that the monitor photodiode generates a photocurrent for input to the control circuit amplifier. In some embodiments, the photodetector can include at least one of bipolar detector, a photodiode, among other components. In some embodiments, the analyte can include ammonia. In some embodiments, the reagent can include an alkaline reagent. In some embodiments, the substance can include a liquid sample. In some embodiments, the substance can include a biological substance, a chemical substance, and/or both. In some embodiments, the substance can include a biological sample. In some embodiments, the biological sample can include a liquid sample. In some embodiments, the biological sample can include blood, plasma, interstitial fluid, or any combination thereof. In some embodiments, mixing the biological sample with an alkaline reagent can result in a shift in equilibrium of the ammonia in the biological sample to ammonia gas, wherein the amperometric sensor comprises a gas sensor, such that a sensor signal is generated via the interaction between the ammonia gas and the amperometric sensor. In some embodiments, the substance can include a chemical substance. In some embodiments, the chemical substance can include wastewater, industrial waste, drinking water, sewage, hazardous waste, or any combination thereof. In some embodiments, the photodetector can be spaced apart from the amperometric sensor. [008] A device for measuring an amount of an analyte in a substance is presented, according to some embodiments. In some embodiments, the device can include a sensor for detecting the analyte in the substance, the sensor configured to generate a sensor signal based on the detected analyte. In some embodiments, the device can include an electrical circuit configured to convert the sensor signal into a photometric signal.

[009] Various embodiments of the device can include one or more of the following features. In some embodiments, the device can include a light source in operative communication with the electrical circuit, the light source configured to generate the photometric signal. In some embodiments, the light source can include a light emitting diode (LED). In some embodiments, the photometric signal can include a photon stream. In some embodiments, the device can include one or more Darlington transistor pairs for amplifying the sensor signal. In some embodiments, the device can include a control circuit amplifier for amplifying the sensor signal. In some embodiments, the device can be configured to linearize the photometric signal with the sensor signal by adjusting an output voltage of the control circuit amplifier. In some embodiments, the device can include a monitor photodiode configured to generate a photocurrent for input to the control circuit amplifier based on the photometric signal. In some embodiments, the analyte can include ammonia. In some embodiments, the substance can include a liquid sample. In some embodiments, the substance can include a biological sample. In some embodiments, the biological sample can include blood, plasma, interstitial fluid, or any combination thereof.

[0010] A system for measuring an amount of an analyte in a substance is presented, according to some embodiments. In some embodiments, the system comprises any device embodiment described herein. In some embodiments, the system includes a detector spaced apart from the sensor and the electrical circuit, the detector configured to detect and measure an intensity of the photometric signal, the intensity of the photometric signal correlating with the amount of the analyte in the substance. In some embodiments, the system includes a photodetector. In some embodiments, the photodetector includes at least one of bipolar detector, a photodiode, among other components. In some embodiments, the system includes a detector circuit and a detector amplifier, in operative communication with the photodetector. In some embodiments, at least a portion of the sensor, the electrical circuit, and/or the detector are disposed on a circuit board. In some embodiments, the system includes a housing within which at least a portion of the sensor, the electrical circuit, and/or the detector are encapsulated. In some embodiments, the housing includes a sample port to receive the substance. In some embodiments, the housing includes a display in communication with the detector, such that the display is configured to depict the detected amount of the substance.

[0011] The foregoing Summary, including the description of some embodiments, motivations therefor, and/or advantages thereof, is intended to assist the reader in understanding the present disclosure, and does not in any way limit the scope of any of the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0013] FIG. 1 shows a circuit depiction of an exemplary photometric detection system, according to an embodiment described herein;

[0014] FIG. 2 shows a circuit depiction of another exemplary photometric detection system, according to an embodiment described herein;

[0015] FIG. 3 show results from an example comparing amount of ammonia detected using an amperometric system described herein and expected spiked ammonia concentration, according to an example described herein;

[0016] FIG. 4 shows a circuit depiction of another exemplary photometric detection system, according to an embodiment described herein ;

[0017] FIG. 5 shows a graph showing an exemplary measurement of gaseous ammonia being liberated from the sample, according to an example described herein;

[0018] FIG. 6 a graph showing photon intensity in response to an alkalized blood sample, according to an example described herein;

[0019] FIGS. 7A, 7B show an exemplary printed circuit board (PCB) of photometric detection system implemented based on any combination of the systems of FIG. 1, 2 and 4, according to an embodiment described herein;

[0020] FIG. 8 shows an assembled photometric detection system based on any combination of the systems of FIG. 1, 2 and 4, according to an embodiment described herein; DETAILED DESCRIPTION

[0021] Disclosed herein are one or more systems, devices, and/or methods for generating and/or measuring a photometric signal based on an amperometric sensor response. In some embodiments, in contrast to directly measuring a current produced by an amperometric sensor, the one or more systems, devices, and/or methods provided herein can generate a light signal based on the current flowing through the amperometric sensor for remote measurement and/or detection of the generated light signal. In some examples, generating a light signal based on the current output from the amperometric sensor can provide one or more advantages of photometric detection, e.g., such as allowing for and/or facilitating remote monitoring and/or signal multiplexing using multiple wavelengths. In some examples, remote monitoring and/or signal multiplexing can include detection of one or more analytes, e.g., remote monitoring and/or signal detection of gases such as gaseous ammonia, carbon monoxide, hydrogen sulfide, among other gases.

[0022] In some instances, generating a light signal based on the current from the amperometric sensor may provide the advantage of utilizing less sensor calibration in contrast to directly measuring the current from the amperometric sensor. In some embodiments, the one or more systems, devices, and/or methods presented herein can be implemented in numerous applications where direct current measurement can be sub-optimal and/or undesirable. In some examples, an exemplary instance where direct current measurement can be sub-optimal can include where a distance, gap, and/or physical separation can exist between the measurement apparatus and the amperometric sensor. In some examples, the elimination of wiring can be beneficial, and/or in situations where it may not be possible for direct current measurement of the current output from the amperometric sensor itself.

[0023] In some embodiments, although one or more systems, devices, and/or methods herein can be directed toward ammonia detection in blood samples, other applications of the one or more systems, devices, and/or methods described herein can be contemplated and/or used. In some examples, the one or more systems, devices, and/or methods can be configured to measure, detect and/or determine a degree of smoking cessation, dementia, Alzheimer's disease, COPD, asthma, among other medical conditions. In some examples, the one or more systems, devices, and/or methods described herein can use the detection of carbon monoxide in a substance (e.g., blood sample, chemical substance) to analyze and/or determine a degree of smoking. In some examples, the one or more systems, devices, and/or methods described herein can use the detection of hydrogen sulfide as a biomarker for dementia, COPD, asthma, among other medical conditions.

[0024] In some embodiments, the one or more systems, devices, and/or methods can be configured to measure and/or detect the presence and/or amount of an analyte in a substance. In some embodiments, the substance comprises a biological sample (e.g., blood). As used herein, a biological sample is used as an example for the substance. In some embodiments, it is understood that although a biological sample is described, descriptions used herein can equally apply to one or more substances, e.g., no particularly limited to the biological sample. In some embodiments, the substance comprises a chemical substance. In some embodiments, the substance comprises wastewater, industrial waste, drinking water, sewage discharge, hazardous waste, or any combination thereof.

[0025] In some embodiments, the analyte includes ammonia. In some examples, the presence and/or amount of ammonia is measured and/or detected. In some embodiments, as described herein, ammonia in the blood is detected, and/or the amount of ammonia in the blood is measured, based on gaseous ammonia released from the alkalized biological sample. The one or more systems, devices, and/or methods can, in some examples, detect ammonia in a range of approximately 0 to 5000 micromolar. In some embodiments, the amount of ammonia can be determined based on a determined molarity, and/or other concentration units as known in the art. In some embodiments, although the systems, devices, and/or methods are described herein with respect to ammonia detection in blood samples, other applications of the one or more systems, devices, and/or methods can be contemplated and/or used. In some examples, the one or more systems, devices, and/or methods can be configured such that a light intensity measured can be calibrated to correspond to a concentration of ammonia in a sample.

[0026] In some embodiments, the one or more system, device, and/or method can include one or more three-electrode amperometric sensors. In some embodiments, the system, device, and/or method can include two-electrode sensors. In some embodiments, the system, device, and/or method include at least two-electrode sensors. In some embodiments, the system, device, and/or method can include up to 5, up to 10, or up to 15, or more amperometric sensors. Accordingly, in some embodiments, any system, device, and/or method described herein, using a plurality of amperometric sensors, is configured to process a plurality of samples simultaneously and/or in parallel. For example, a system comprising a plurality of sensors may be configured for different analytes and measure them simultaneously on different color channels. In some embodiments, a system described herein includes multiple ammonia sensors to read multiple samples at once with the same machine. In some embodiments, the system, device, and/or method includes an amperometric system (e.g., comprising, at least in part, an amperometric sensor and measurement circuit), a photometric signal generator circuit, and/or a photometric detector circuit. In some embodiments, the photometric detector circuit can be separated from the amperometric system and/or the photometric signal generator circuit. In one example, the photometric detector circuit can be electrically separated from the amperometric system and/or the photometric signal generator circuit. In some examples, the photometric detector circuit is spaced apart from the amperometric system and/or the photometric signal generator circuit. For example, one or more photodetectors (e.g., photodiodes) as part of the photometric detector circuit are spaced apart from one or more light sources (e.g., light emitting diodes (LEDs)) as part of the photometric signal generator circuit. In some embodiments, the amperometric system, the photometric signal generator circuit, and/or a photometric detector circuit are mounted on and/or located on a substrate, such as a printed circuit board (PCB). In some embodiments, the photometric detector circuit, though located on the same PCB as the amperometric system and/or the photometric signal generator circuit, is positioned so as to be spaced apart therefrom, such that there is no direct physical and/or electrical contact therebetween.

[0027] In some embodiments, the detection of an analyte (e.g., ammonia) and/or the amount of the analyte in the biological sample does not require current measurement, such that current generated via an interaction between the analyte and the amperometric sensor enables for a signal to be generated, which itself generates a photometric signal via the photometric signal generator circuit. In some embodiments, as described herein, the analyte is detected and/or measured via the photometric detector circuit based on light intensity, and not current measurement. In some embodiments, the amperometric sensor can be physically and/or electrically separated from a detector circuit. In some examples, the amperometric sensor need not be electrically coupled to a circuit nor measure a current to detect an analyte’s presence and/or amount in a biological sample.

[0028] In some embodiments, the system, device, and/or a method described herein can include a receiving device for receiving a biological sample (e.g., blood). In some embodiments, the amperometric system is in operative communication with the receiving device. In some embodiments, the receiving device comprises further comprises an amperometric sensor, such as a gas sensor, (e.g., an ammonia gas sensor). For example, in some embodiments, the receiving device comprises a blood sample containment member and an ammonia gas sensor coupled with the blood sample containment member, as described in PCT publication WO2015/123346, and/or as described in Point-of-Care Analysis of Blood Ammonia with a Gas-Phase Sensor (DOI: 10.1021/acssensors.0c00480), the entirety of which is incorporated herein by reference. In some examples, the system, device, and/or a method described herein is configured to receive the biological sample (e.g., a substance such as a blood sample) and mix with an alkaline reagent (e.g., potassium carbonate), so as to alkalize the biological sample. In some embodiments, the alkalized biological sample enables gaseous ammonia (within the biological sample) to be released in proximity of the gas sensor. In some embodiments, the system, device, and/or a method described herein includes a single-use consumable cartridge which can be inserted into the said system and/or device, including a solid support onto which potassium carbonate can be deposited. In some examples, once a detected blood sample reaches the solid support, the detected blood sample be alkalized, and thus, liberates its ammonia to the gas sensor, which can be positioned above the paper in the fully inserted position.

[0029] In some embodiments, as described herein, the biological sample is mixed with a chemical reagent. For example, in some embodiments, a received blood sample is mixed with an alkaline reagent. Ammonia is an alkaline gas, such that at alkaline pH, it exists in its gaseous form, dissolved in solution. However, as the solution pH moves increasingly lower (e.g., lower than 9.25) (physiological pH is about 7.4, so very significantly more acidic), the predominant form of ammonia becomes an ammonium ion, because blood/plasma/interstitial fluid (for example) donates protons to the ammonia molecules to form ammonium ions. In some cases, ammonium ions are non-volatile, and thus, in order to increase the gas phase concentration to better facilitate gas measurement, the biological sample (e.g., a substance such as blood) is mixed with an alkaline reagent (e.g., potassium carbonate) to increase the pH of the biological sample, thereby pushing the equilibrium away from ammonium ions and towards ammonia gas. In some cases, sufficient alkaline reagent is mixed so as to shift the equilibrium sufficiently far that there is virtually zero ammonium ion present and all ammonia exists in its gaseous form. [0030] Non-limiting example circuit depictions of photometric detection systems are shown in Figs. 1, 2, 4, and 7a-b, according to some embodiments. The photometric detection systems described herein (e.g., shown in in Figs. 1, 2, 4, and 7a-b) can be referred to as photometric detection devices, among other terms, and are used to show exemplary methods for employing amperometric sensors.

[0031] Fig. 1 shows a circuit depiction of an exemplary photometric detection system, according to some embodiments herein. In an example, the photometric detection system 100 can be referred to as a first photometric detection system 100, a first photometric detection device 100, among other terms. As shown in Fig. 1, the photometric detection system 100 can include a signal generator circuit 120 (e.g., photometric signal generator circuit 120a), and a detector circuit 130. In an example, the one or more photometric signal generator circuits 120a (e.g., see Fig. 1), 120b (e.g., see Fig. 2), 120c (e.g., see Fig. 4) described herein, can collectively be referred to as a signal generator circuit 120 and/or photometric signal generator circuit 120. The detector circuit 130 can also be referred to herein as a photodetector circuit 130, and/or a photometric detector circuit 130. The photometric signal generator circuit 120a can include an amperometric sensor 140 and a measurement circuit 110. In some embodiments, the potential of the amperometric sensor 140 can be controlled by a first amplifier 150, where a control voltage 113 can be applied to an amplifier non-inverting input 153 of the first amplifier 150. In some embodiments, an amperometric sensor reference 142 (e.g., alternatively referred to as amperometric sensor reference electrode 142) can be connected to an amplifier inverting input 152, and a sensor auxiliary electrode 141 is connected to an amplifier output 151. Current can be balanced at the amperometric sensor working electrode 143 by sourcing or sinking current directly from a transistor base 121. As shown in Fig. 1, the amperometric sensor 140 provides for a high gain through the use of one or more Darlington pairs (e.g., shown as a first Darlington pair 122, a second Darlington pair 123 and collectively referred to as Darlington pairs), and also provides for a bipolar current output. In some examples, the gain of the Darlington pair 123 can be at least 1000. In some embodiments, one or more transistor stages can be used, or a single unipolar output could be provided, e.g., which can be varied based on one or more target applications. In the exemplary embodiment presented Fig. 1, the amperometric sensor working electrode’s 143 current can be connected, e.g., as a source or a sink, through the base of one or more transistor(s) (e.g., a first transistor 124, a second transistor 126), providing for an amplified current to flow from the emitter to collector (e.g. collectors 125a, 125b, and/or 127c, 127d, and emitters 127a, 127b and/or 125c, 125d), which in turn flows through a light emitting diode (LED) (or other suitable light emitting device such as a lamp and/or laser diode, but referred to hereafter as LEDs or light source), for example, a first LED 128 and/or a second LED 129, resulting in photon emission. Each Darlington pair (122, 123) can be additionally connected to ground 170 through emitter 127b and collectors 127c and 127d. In some embodiments, the amperometric sensor’s 140 current can induce a proportionately larger current to flow through the light source (e.g., first LED 128 and/or second LED 129), in turn generating a proportional light intensity and/or photon emission from the light source. In some examples, the number of stages and/or gain of the one or more transistors used, can be chosen to suit a targeted range of current of the individual amperometric sensor being used. In some examples, the output photon intensity can then be measured by the photodetector circuit 130, exemplified as a bipolar detector in Fig. 1, by a pair of detection photodiodes 131a, 131b connected to a photodiode amplifier 160 which can output a photocurrent signal 180. In some embodiments, through use of various means (e.g., different wavelength LEDs, focusing lenses, collimation, color filters, etc.), the transmitting light sources 128, 129 and receiving detection photodiodes 131a, 131b can be paired (LED 128 with detection photodiode 131a, and/or LED 129 with detection photodiode 131b, for example). In an example, the pairing of the transmitting light sources 128, 129 and receiving detection photodiodes 131a, 131b can be performed without crosstalk, ensuring that each polarity is kept separate, and the detector provides a bipolar voltage output. In some examples, alternatively, two separate amplifiers can be used with each connected to a single photodiode, or if the amperometric sensor has multiple output channels, an array of detectors suitably configured to permit photometric detection of each channel can be used as either bipolar or unipolar output. In some embodiments, the detection circuit can be separate from the sensor electronics, and with appropriate selection of components, a multiplexed transmission can be achieved. In some examples, the photometric signal generator circuit 120a can be physically and/or electrically separate from the photodetector circuit 130. In some examples, the photometric signal generator circuit 120a can be adjacent to the photodetector circuit 130, but still physically and/or electrically separate from one another. In some examples, the photometric signal generator circuit 120a is not adjacent to the photodetector circuit 130. In some embodiments, the multiplexed transmission can include (a) using two light emitting diodes (LEDs) of different colors, (b) filtering the LEDs based on their color and/or wavelength, (c) (optionally) apply the light from both sources onto one detector, (d) or (optionally) apply them to two separate photodetector circuits, e.g., which may or may not include color filtering.

[0032] In some embodiments, the photometric detection system 100 can experience nonlinearity with respect to output light intensity as compared to the current received by the light sources (e.g., LEDs 128, 129), e.g. depending on a working range of the sensors (e.g., detection photodiodes 131a, 131b) and properties of the light sources, transistors, and other electronics used. In some embodiments, Fig. 2 depicts a circuit depiction of another exemplary photometric detection system, according to some embodiments, 200 which can be configured to overcome non-linearity that can be experienced by the photometric detection systems described herein, e.g., the photometric detection system 100 depicted in Fig. 1.

[0033] As referred to herein, the photometric detection system 200 can be referred to herein as a second photometric detection system 200, a second photometric detection device 200, among other terms. The photometric detection system 200 can include a photometric signal generator circuit 120b, and a detector circuit 130. In some examples, the photometric signal generator circuit 120b can be physically and/or electrically separate from the detector circuit 130. As shown, the photometric detection system 200 can include a first amplifier 150 (e.g., alternatively referred to herein as a control amplifier) connected to the amperometric sensor 140 such that the amperometric sensor reference electrode 142 can be connected to the inverting input 152, and the auxiliary electrode 141 can be connected to the output 151. In some examples, a non-inverting input 153, shown in Fig. 1 and 2, can be held at ground. In some embodiments, the working electrode 143 can be held at the desired potential by a second amplifier 210. In some examples, the working electrode 143 can be connected to the inverting input 212 of the second amplifier 210, while the non-inverting input 213 can be held at the target potential. In some embodiments, the output of the second amplifier 210 can be connected in between two LEDs 228, 229 (e.g., or other light source, hereafter referred to solely as LEDs) in series to provide a bipolar output signal. In some examples, each LED 228, 229 can illuminate a monitor photodiode 214, 215, respectfully, which can be connected at one terminal to the working electrode 143 and/or the inverting pin (e.g., alternatively called the inverting input 212) of the second amplifier 210.

[0034] In some embodiments, the second amplifier 210 can automatically increase and/or decreases its output voltage such that the light generated by the corresponding polarity LED 228 or 229 also generates a photocurrent to the corresponding photodiode 214 or 215. In some examples, the photocurrent can flow into the working electrode 143, completing the circuit (e.g., alternatively referred to as control circuit 216 herein) through the amperometric sensor 140. In some embodiments, the resulting circuit (e.g., control circuit 216) can therefore create a photon intensity that can be linearly proportional to the current being generated by the amperometric sensor 140.

[0035] For example, in some embodiments, the emission of the LEDs 228, 229 can cause a photocurrent to flow through the monitor photodiode 214, 215, e.g., which sources or sinks from the working electrode and terminates at ground. In some examples, the LEDs 228, 229 can allow current to flow in one direction, where by wiring the LEDs 228, 229 in series with ground in between, the potential of the working electrode 143 can be configured to move in either direction in comparison to ground. In some examples, such a configuration can allow the potential of the working electrode equal to Vin. In some embodiments, the amplifier 210 can be a comparator. In some examples, provided the working voltage can be higher than Vin, the amplifier output can vary towards a negative rail, resulting in an LED 229 emitting a lower intensity light. In some embodiments, the resulting lower intensity light can reduce the photocurrent flowing through LED 215, thereby reducing the positive potential that is dropped across the diode. In some embodiments, the resulting working electrode can be lowered to move towards Vin.

[0036] As shown in Fig. 2, the detector circuit 130 can include detection photodiodes 131a, 131b connected to a photodiode amplifier 160. In some examples, the detection photodiodes 131a, 131b can then be configured such that they are illuminated by a portion the light generated by the LED 228, 229 as a result of the action of the second amplifier 210. In some examples, provided the LED 228, 229 output has been linearized by the action of the control circuit 216, the measured photon intensity at the detection photodiodes 131a, 131b can be linearly proportional to the amperometric sensor signal, where the signal is transmitted via a photon stream, the detector circuit 130 and/or the detection photodiodes 131a, 131b thereof, can be physically and/or electrically separate from the amperometric sensor 140. In some examples, the detection photodiodes 131a, 131b can be set up in a remote location if desired (e.g., spaced apart from the amperometric sensor 140). In some examples, suitable selection of color filters for photodiodes (e.g., detection photodiodes 131a, 131b) and LED wavelengths can yield independent signals for multiplexed detection of multiple sensors and/or polarities. In some embodiments, these examples are meant to be illustrative of potential means of reducing the invention to practice, however, should not be construed to limit the scope of the invention to the aforementioned components. For example, other photodetectors apart from photodiodes can be used by those skilled in the art (e.g., phototransistors) upon reading the disclosure herein to achieve the same outcome, or laser diodes with built-in monitor photodiodes can be used to provide a compact package and reduce component count.

Examples

[0037] Example 1 : An exemplary embodiment of a system was implemented using a commercially available three-electrode amperometric sensor selective for ammonia gas controlled by the systems, devices, and/or methods shown in Fig. 2 and described with reference thereto. In some examples, this system was calibrated by using aqueous standards with known concentrations of ammonium chloride by exposing the standards to an alkaline reagent in close proximity to the amperometric sensor 140. Once calibrated, individual samples of whole capillary blood were spiked with ammonium chloride to generate final concentrations approximately over the relevant clinical range of blood ammonia measurements. The samples were then placed in proximity of the amperometric sensor 140, thereby enabling photon emission via LED (e.g., 228 and/or 229) due to the presence of ammonia. Each data point of the four data points shown represents a different alkalized blood sample used (see Fig. 3). The photon intensity detected by the detection photodiodes (e.g., 131a and/or 131b) was recorded when the blood was alkalized in proximity to the sensor and the results 300 plotted in Fig. 3.

[0038] Fig. 3 indicates that measured values 300 (micromolar concentration 302 calculated from Photon Intensity 304 in arbitrary (arb) Units on the y-axis) can all correspond with the expected spiked concentrations (micromolar concentration of ammonia on the x-axis) within 20% with a R^A2 variance of 0.9984, e.g., as shown at 306. Given the unknown starting concentration of ammonia in these capillary samples, the deviations from linearity are can be likely due to physiological differences between samples.

[0039] Example 2: Fig. 4 shows a circuit depiction of another exemplary photometric detection system, according to some embodiments. In an example, the photometric detection system 400 includes a photometric signal generator circuit 120c, and a detector circuit 130. In some examples, the photometric signal generator circuit 120c can be physically and/or electrically separate from the detector circuit 130. The photometric signal generator circuit 120c includes an exemplary amperometric sensor (e.g., 140). As shown, an amperometric ammonia sensor 140 is connected to a circuit as provided and described with respect to Fig.

2. The amperometric ammonia sensor 140 is further configured to detect the presence and/or amount of ammonia in a biological sample (e.g., a substance such as blood). The specific sensor chemistry depicted in Fig. 4. generates 10 electrons for every 12 molecules of ammonia that reach the working electrode (e.g., 143) of the amperometric sensor 140. The working electrode 143 is connected to the photometric measurement portion of the circuit such that when ammonia is present, electrons flow out of the working electrode 143. In order to maintain the set potential Vin vs ground (GND), the second amplifier 210 must lower its voltage output, which causes a first LED (e.g., 228) to emit light until the appropriate current flows through a corresponding monitor photodiode (e.g., 214). In this manner, the light output of the first LED 228 is kept linear as a function of the current demand produced by the amperometric sensor 140. To balance the charge at the amperometric sensor 140, the first amplifier 150 adjusts its output 151 to provide an equal cell current to keep the reference potential at ground. Therefore, although current is flowing through the cell, no measurement of that current happens. The photon stream can be split between the first monitor photodiode 214 and a first detection photodiode (e.g., 131a) by any ratio desired if amplification of the photon flux is desired. For example, a 2: 1 beam splitter 220 could be inserted between the first LED 228 and the first monitor photodiode 214 and the first detection photodiode 131a such that two photons 217 reach the first detection photodiode 13 la for every one photon 217 that reaches the first monitor photodiode 214. In the system presented in Fig. 4, the control circuit continues to provide the appropriate cell current through the action of the first monitor photodiode 214, but more light reaches the first detection photodiode 131a, which can be useful for offsetting natural variations in photodiode sensitivity or accommodating larger transmission lengths to overcome atmospheric attenuation. The photons 217 that reach the first detection photodiode 131a generate a photocurrent that is linearly proportional to the photocurrent generated in the first monitor photodiode 214, and photodiode amplifier 160 converts and optionally amplifies this signal into a voltage output.

[0040] Referring to Fig. 5, a graph showing an exemplary measurement over time 502 of photometric intensity 504 of gaseous ammonia being liberated from the sample using a photometric detection system is shown, according to some embodiments. The measurement was taken upon gaseous ammonia being liberated from the sample . From Fig. 5, a measurement prior to exposure is shown at 510, and a rapid rise at 512 of the photometric intensity is observed upon exposure to gaseous ammonia liberated from the sample. At 514, stabilization of the measurement is shown.

[0041] Referring to FIG. 6, a graph showing photon intensity in response to alkalized samples is shown, according to some embodiments. Fig. 6 indicates that measured values 600 (micromolar concentration 602 calculated from Photon Intensity 604 in arbitrary (arb) Units on the y-axis) can all correspond with the expected concentrations (micromolar concentration of ammonia on the x-axis) with a R^A2 variance of 0.996, e.g., as shown at 606. Thus, at wide range of ammonia concentrations, Fig. 6 demonstrates linearity of the photometric signal as a function of ammonia concentration, e.g., based on the sample used from Fig. 5.

[0042] Figs. 7A, 7B and 8 show an exemplary photometric detection system, as part of measurement device (e.g., gas analyzer, gas measurement, etc. device), according to some embodiments. The photometric detection system 700 of Figs. 7A, 7B and 8 correspond to an exemplary implementation of the photometric detection systems described herein (e.g., systems 100, 200, 400 of Figs. 1, 2 and 4 respectively) that is part of the device. Fig. 7A shows a back side, and Fig. 7B shows a front side of an exemplary PCB for the photometric detection 700. Fig. 8 shows the photometric detection system 700 fully assembled. The photometric detection system 700 can include a photometric signal generator circuit 120, and a detector circuit 130. In some examples, the LEDs, photodiodes, among other electronic components described herein, can be contained on the same or different IC packages (e.g., see 720 and 722 optoisolators of FIG. 7A). In some cases, the LEDs, photodiodes, among other electronic components described herein, are coupled to the PCB board (e.g., via appropriate pins that are soldered to the PCB board) to provide electrical connections to the respective signal generator circuit 120 and/or the photodetector circuit 130. As shown, the photometric signal generator circuit 120 can include a first optoisolator 720, and a second optoisolator 722. In some examples, the optoisolators 720, 722 can include optoisloators from Vishay semiconductor, e.g., Vishay semiconductor IL300-F-X009T. In some embodiments, the optoisolators 720, 722 can be configured to provide bipolar photometric output, e.g., as shown in Fig 4. In an example, each optoisolator 720, 722 can provide an LED and a pair of photodiodes able to detect the LED output. The first optoisolator 720 can include light emitting diode (LED1) 228, photodiode (PD1) 214 and photodiode (PD3) 131a, and second optoisolator 722 can include light emitting diode (LED2) 229, photodiode (PD2) 215, and photodiode (PD4) 131b of the photometric detection system of Fig. 4. The optoisolator implementation shown in the system 700 can provide an advantage of not requiring a common ground between the photometric signal generator circuit 120 and detector circuit 130. The optoisolator implementation can be configured to minimize electronic component count for photometric detection system 700. As shown, the signal generator circuit 120 can include an amperometric sensor 740, e.g., similar to the sensor 140 of Figs. 1, 2, and 4. For the photometric detection system 700, the amperometric 740 sensor is connected a control circuit (e.g., 216 of Fig. 2) of the signal generator circuit 120, and then exposed to alkalinized samples (e.g., exposed to gas liberated from samples that may be received about the sample receiver 760) containing an amount of ammonium ion. As described in Figs. 1, 2 and 4, the detector circuit 130 can include an amplifier 160, and detection photodiodes 131a, 131b. An integrated circuit package 724 can be used to include the control amplifiers 150, 210 (e.g., from Figs. 1, 2 and 4). In some embodiments, any combination of components of the photometric detection systems described herein can be on either side of the exemplary PCB.

[0043] Fig. 8 shows the fully assembled photometric detection system 700, and a sample consumable 750 for the photometric detection system 700. The photometric detection system 700 can include a screen 762 (e.g., to display measurement results), a keypad 764, among other electronic components.

Terms and Definitions

[0044] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0045] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Any reference to “or” herein is intended to encompass “and/or” unless otherwise stated.

[0046] As used herein, the term “about” in some cases refers to an amount that is approximately the stated amount.

[0047] As used herein, the term “about” refers to an amount that is near the stated amount by 10%, 5%, or 1%, including increments therein.

[0048] As used herein, the term “about” in reference to a percentage refers to an amount that is greater or less the stated percentage by 10%, 5%, or 1%, including increments therein. [0049] As used herein, the phrases “at least one”, “one or more”, and “and/or” are open- ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. The terms “one or more”, “at least one”, “more than one”, and the like are understood to include but not be limited to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,

46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,

71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,

96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,

115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more and any number in between.

[0050] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure.

[0051] Figure Reference Character Key:

First exemplary photometric detection system 100 Measurement circuit 110

Amperometric sensor 140 (which may be an amperometric ammonia sensor) sensor auxiliary electrode 141 sensor reference or sensor reference electrode 142 amperometric sensor working electrode 143 First Amplifier 150 control voltage 113 Amplifier output 151 Amplifier inverting input 152 Amplifier non-inverting input 153

Photometric signal generator circuit 120: 120a, 120b, 120c transistor base 121

First Darlington pair 122

First transistor 124

Collectors 125a, 125b

Emitters 127a, 127b

Second Darlington pair 123

Second transistor 126

Collectors 125c, 125d

Emitters 127c, 127d

Ground 170

First LED 128

Second LED 129

Photometric detector circuit or photodetector circuit 130

Photodiodes 131a, 131b

Photodiode Amplifier 160

Amperometric sensor 140 (which may be an amperometric ammonia sensor)

Second exemplary photometric detection system 200

Second amplifier 210

Second amplifier inverting input 212

Second amplifier non-inverting input 213

First LED 228

Second LED 229

First monitor photodiode 214

Second monitor photodiode 215

Control circuit 216

Photon emitted 217

Claims

What is claimed is:

1. A method for measuring an amount of an analyte in a substance, the method comprising: positioning the substance in proximity with an amperometric sensor; mixing the substance with a reagent; generating a photometric signal via the amperometric sensor in response to the amount of the analyte in the substance; and detecting the photometric signal using a detection photodetector, such that the detected photometric signal correlates with the amount of the analyte in the substance.

2. The method of claim 1, wherein generating the photometric signal comprises converting a sensor signal from the amperometric sensor to a photon stream.

3. The method of claim 2, wherein the photometric signal is correlated with the amount of the analyte based on an intensity of the photon stream, as measured by the detection photodetector.

4. The method of claim 2 or 3, further comprising amplifying the sensor signal from the amperometric sensor.

5. The method of claim 4, further comprising amplifying the sensor using one or more Darlington transistor pairs.

6. The method of claim 4, further comprising linearizing the photometric signal with a current generated by the amperometric sensor by adjusting an output voltage of a control circuit amplifier in electrical communication with the amperometric sensor.

7. The method of claim 6, wherein the linearizing the photometric signal further comprises detecting the photometric signal using a monitor photodiode, such that the monitor photodiode generates a photocurrent for input to the control circuit amplifier.

8. The method of any one of claims 1 to 7, wherein the photodetector comprises a bipolar detector.

9. The method of any one of claims 1 to 8, wherein the photodetector comprises a photodiode. The method of any one of claims 1 to 9, wherein the analyte comprises ammonia. The method of any one of claims 1 to 10, wherein the reagent comprises an alkaline reagent. The method of any one of claims 1 to 11, where the substance comprises a liquid sample. The method of any one of claims 1 to 12, wherein the substance comprises a biological substance, a chemical substance, or both. The method of any one of claims 1 to 13, where the substance comprises a biological sample. The method of claim 14, where the biological sample comprises a liquid sample. The method of claim 14 or 15, wherein the biological sample comprises blood, plasma, interstitial fluid, or any combination thereof. The method of any one of claims 14 to 16, where mixing the biological sample with an alkaline reagent results in a shift in equilibrium of the ammonia in the biological sample to ammonia gas, wherein the amperometric sensor comprises a gas sensor, such that a sensor signal is generated via the interaction between the ammonia gas and the amperometric sensor. The method of any one of claims 1 to 17, wherein the substance comprises a chemical substance. The method of claim 18, wherein the chemical substance comprises wastewater, industrial waste, drinking water, sewage, hazardous waste, or any combination thereof. The method of any one of claims 1 to 19, wherein the photodetector is spaced apart from the amperometric sensor. A device for measuring an amount of an analyte in a substance, the device comprising: a. a sensor for detecting the analyte in the substance, the sensor configured to generate a sensor signal based on the detected analyte; and b. an electrical circuit configured to convert the sensor signal into a photometric signal. The device of claim 21, further comprising a light source in operative communication with the electrical circuit, the light source configured to generate the photometric signal. The device of claim 22, wherein the light source comprises a light emitting diode (LED). The device of any one of claims 21 to 23, wherein the photometric signal comprises a photon stream. The device of any one of claims 21 to 24, further comprising one or more Darlington transistor pairs for amplifying the sensor signal. The device of any one of claims 21 to 25, further comprising a control circuit amplifier for amplifying the sensor signal. The device of claim 26, further configured to linearize the photometric signal with the sensor signal by adjusting an output voltage of the control circuit amplifier. The device of claim 27, further comprising a monitor photodiode configured to generate a photocurrent for input to the control circuit amplifier based on the photometric signal. The device of any one of claims 21 to 28, wherein the analyte comprises ammonia. The device of any one of claims 21 to 29, where the substance comprises a liquid sample. The device of any one of claims 21 to 30, where the substance comprises a biological sample. The device of claim 31, wherein the biological sample comprises blood, plasma, interstitial fluid, or any combination thereof. A system for measuring an amount of an analyte in a substance, the system comprising: a. any device of any one of claims 21 to 32; and b. a detector spaced apart from the sensor and the electrical circuit, the detector configured to detect and measure an intensity of the photometric signal, the intensity of the photometric signal correlating with the amount of the analyte in the substance. The system of claim 33, wherein the detector comprises a photodetector. The system of claim 34, wherein the photodetector comprises a bipolar detector. The system of claim 34, wherein the photodetector comprises a photodiode. The system of any one of claims 34 to 36, wherein the detector further comprises a detector circuit and a detector amplifier, in operative communication with the photodetector. The system of any one of claims 33 to 37, wherein at least a portion of the sensor, the electrical circuit, and/or the detector are disposed on a circuit board. The system of any one of claims 33 to 37, further comprising a housing within which at least a portion of the sensor, the electrical circuit, and/or the detector are encapsulated. The system of claim 39, wherein the housing comprises a sample port to receive the substance. The system of claim 40, wherein the housing further comprises a display in communication with the detector, such that the display is configured to depict the detected amount of the substance.