Device, System, and Method for Continuous Real-Time Blood Culture Measurement

Abstract

Provided herein are devices, systems, and methods for determining the presence of an analyte of interest in a sample. Certain embodiments of the present disclosure relate to an incubation measurement system that includes an incubation vial and a sensor, where the sensor is a pH sensor, reactive label, or indicator compound, such that the sensor is incorporated into the incubation vial for measuring the pH of the sample.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 795,911, filed on January 23, 2019, which is hereby incorporated by reference in its entirety.

[0002] The disclosure of the present invention relates to culture measurement devices, systems, and methods, such as, but not limited to, blood culture measurement systems for determining the pH of a blood culture sample.

Background Art

[0003] In many fields (e.g., medical, pharmaceutical, food industry), a rapid and accurate determination of microbial contamination within a particular system (e.g., a patient's blood, a batch of drug product, a food supply) is desirable. To indirectly detect microorganisms within a sample through their biological activity, methods have been developed that use sensors containing fluorescent materials in combination with an indicator material. For example, when microorganisms are present within a culture vial, these microorganisms metabolize nutrients in the culture medium and release carbon dioxide into the sample. The carbon dioxide reacts with a dye and modulates the amount of light absorbed by a sensor within the vial. A photodetector measures an absorption level (such as in fluorescence measurement) corresponding to the amount of carbon dioxide released by the microorganisms. Measurement systems employing these methods incorporate a fluorescence sensor or a fluorescence detector for detecting the fluorescence signal emitted from a container or vial containing the sample and the sensor. Then, a software and / or hardware system is utilized to process the data collected by the detector.

[0004] Currently available culture measurement systems have several limitations, including, for example, sensitivity to measurement variations, vial introduction delay (DVE) time, lack of consistency due to temperature variations, complexity of multi-component sensors, and lack of real-time feedback regarding measurement system signal quality. Further, these systems may include components that are difficult to obtain and difficult to incorporate into the measurement vial. Further, these limitations result in sensors that produce inconsistent results from vial to vial. Embodiments of the disclosed technology of the present invention address or mitigate at least some of these and / or other drawbacks in blood culture measurement systems.

Summary of the Invention

Problems to be Solved by the Invention

[0005] This specification describes devices, systems, and methods for measuring characteristics or properties within a sample that are subject to change over time, for example, for measuring pH changes within a sample.

Means for Solving the Problems

[0006] Some embodiments provided herein relate to a device for measuring blood culture pH. In some embodiments, the device is a culture vial such as a blood culture vial. In some embodiments, the vial includes a pH sensor positioned on its inner surface and configured to transmit a signal of a pH measurement value. In some embodiments, the pH sensor is an ion-sensitive field effect transistor (ISFET) or an ion-selective electrode. In some embodiments, the culture vial further includes a permeable membrane layer that separates the pH sensor from the blood culture vial. In some embodiments, the permeable membrane includes a polymeric material. In some embodiments, the permeable membrane includes Nafion, polyurethane, or a cellulose-based material. In some embodiments, the culture vial is plastic or glass.

[0007] Some embodiments provided herein relate to a system including a culture vial and a reader configured to obtain signals from a pH sensor. In some embodiments, the system further includes a power source. In some embodiments, the device is a culture vial such as a blood culture vial. In some embodiments, the vial includes a pH sensor positioned on its inner surface and configured to transmit a signal of a pH measurement value. In some embodiments, the pH sensor is an ion-specific field effect transistor (ISFET) or an ion-selective electrode. In some embodiments, the culture vial further includes a permeable membrane layer that separates the pH sensor from the blood culture vial. In some embodiments, the permeable membrane includes a polymeric material. In some embodiments, the permeable membrane includes Nafion, polyurethane, or a cellulose-based material. In some embodiments, the culture vial is plastic or glass. In some embodiments, the pH sensor includes an electrical lead that connects to the reader through the blood culture vial. In some embodiments, the electrical lead passes through the bottom portion of the blood culture vial or the septum of the blood culture vial. In some embodiments, the pH sensor is configured to communicate wirelessly with the reader. In some embodiments, the reader is configured to wirelessly transmit the analysis data to an information management system or a cloud data storage location. In some embodiments, the reader is configured to transmit the data to a hospital information management system, a research facility, or a clinical laboratory. In some embodiments, the pH sensor is configured to be wirelessly powered.

[0008] Some embodiments provided herein relate to a device for measuring the pH of a blood culture. In some embodiments, the device is a culture vial such as a blood culture vial. In some embodiments, the culture vial includes a reactive label positioned on its inner surface. In some embodiments, the reactive label is configured to emit an absorption intensity signal corresponding to the pH measurement value. In some embodiments, the reactive label includes a pH-reactive agent. In some embodiments, the pH-reactive agent is fluorescent, phosphorescent, or colorimetric. In some embodiments, the reactive label includes a permeable membrane that separates itself from the contents of the blood culture vial. In some embodiments, the permeable membrane includes a polymeric material. In some embodiments, the permeable membrane includes Nafion, polyurethane, or a cellulose-based material.

[0009] Some embodiments provided herein relate to a device for measuring the pH of a blood culture. In some embodiments, the device is a culture vial such as a blood culture vial. In some embodiments, the culture vial includes an indicator compound directly incorporated therein. In some embodiments, the indicator compound is a pH-reactive agent configured to be reactive to fluorescence excitation, phosphorescence excitation, or colorimetric excitation. In some embodiments, the indicator compound is a pigment, dye, organic compound, or inorganic compound. In some embodiments, the culture vial includes an impermeable membrane that covers a portion of itself. In some embodiments, the blood culture vial is plastic or glass.

[0010] Some embodiments provided herein relate to a system that includes a culture vial and one or more detectors configured to measure the intensity of one or more signals released from a pH-responsive agent after exposure to an interrogating energy source. In some embodiments, the device is a culture vial, such as a blood culture vial. In some embodiments, the culture vial includes a reactive label positioned on its inner surface. In some embodiments, the reactive label is configured to emit an absorption intensity signal corresponding to a pH measurement. In some embodiments, the reactive label includes a pH-responsive agent. In some embodiments, the pH-responsive agent is fluorescent, phosphorescent, or colorimetric. In some embodiments, the reactive label includes a permeable membrane that separates itself from the contents of the blood culture vial. In some embodiments, the permeable membrane includes a polymeric material. In some embodiments, the permeable membrane includes Nafion, polyurethane, or a cellulose-based material. In some embodiments, the culture vial includes an indicator compound directly incorporated therein. In some embodiments, the indicator compound is a pH-responsive agent configured to be reactive to fluorescence excitation, phosphorescence excitation, or colorimetric excitation. In some embodiments, the indicator compound is a pigment, dye, organic compound, or inorganic compound. In some embodiments, the culture vial includes an impermeable membrane that covers a portion of itself. In some embodiments, the blood culture vial is plastic or glass. In some embodiments, the system further includes a wireless transmitter configured to wirelessly transmit the analysis data to an information management system, a cloud data storage location, or an electronic storage medium (e.g., a hard drive).

[0011] Some embodiments provided herein relate to a method for measuring the pH in a blood culture sample. In some embodiments, the method includes inoculating a blood culture sample into a culture vial as described herein and measuring the pH of the blood culture sample by detecting a signal of a pH measurement value using a system as described herein. In some embodiments, the pH measurement value signal is obtained by measuring a fluorescence signal, a phosphorescence signal, or a colorimetric signal emitted from a sensor within the blood culture vial. In some embodiments, the method further includes measuring the pH of the blood culture sample at a second or subsequent time point. In some embodiments, the measured pH of the blood culture sample correlates with the degree of the amount of pathogens in the blood culture sample. In some embodiments, the pathogen is a bacterium or a fungus. In some embodiments, the system includes a processor configured to ignore measurements that are higher or lower than a sensitivity range. In some embodiments, the method further includes wirelessly transmitting the analysis data to an information management system, a cloud data storage location, or an electronic storage medium (e.g., a hard drive).

Brief Description of the Drawings

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Modes for Carrying Out the Invention

[0013] As will be apparent from the circumstances, from this description, and from the knowledge of those skilled in the art, any feature or combination thereof described herein is included within the disclosure of the invention so long as the features included in any such combination do not conflict with each other. Further, any feature or combination thereof can be specifically excluded from any embodiment of the disclosure of the invention. To summarize the disclosure of the invention, certain aspects, advantages, and novel features of the disclosure of the invention are described herein. Of course, it is to be understood that not all such aspects, advantages, or features need be present in any particular embodiment of the disclosure of the invention.

[0014] It is to be understood that the embodiments provided herein are provided by way of example and not by way of limitation. While exemplary embodiments are discussed, the intent of the following detailed description is not to be construed as encompassing all modifications, alternatives, and equivalents of these embodiments that may fall within the spirit and scope of the disclosure of the invention. In this specification, embodiments of the technology of the disclosure of the invention will be described with respect to a blood culture measurement device system such as, but not limited to, the BD BACTEC® blood culture device system by Becton, Dickinson and Company. However, it will be understood that the embodiments of the technology of the disclosure of the invention are not limited to blood culture measurement devices and systems and can be applied to other types of detection devices and systems.

[0015] The detection of blood-borne pathogens is an important function of microbiology laboratories. Blood culture media are essential for identifying the pathogens responsible for bacteremia and sepsis. Currently, several automated blood culture systems are available. Some systems use fluorescence technology to detect the growth of organisms within the blood culture vial. FIG. 1 shows a schematic diagram of a currently available measurement system 100. As shown in FIG. 1, when microorganisms are present within the culture vial 102, these microorganisms metabolize nutrients in the sample 104 and release carbon dioxide into the sample. A dye sensor 106 within the culture vial 102 reacts with the carbon dioxide and modulates the amount of light absorbed by a fluorescent material within the sensor 106. A light source 108 that emits light for exciting the fluorescent material of the sensor 106 can be incorporated. A detector 110, such as a photodetector, measures the fluorescence level corresponding to the amount of carbon dioxide released by the microorganisms. The system 100 can include an excitation filter 114 or an emission filter 116 that filters a wavelength or wavelength range. The system 100 can include a processor 112 that processes the fluorescence level to determine the amount or quantity of growth of the microorganisms within the sample. Such systems present several limitations as described herein.

[0016] Embodiments of the devices, systems, and methods described herein address at least some of the limitations and disadvantages of currently available culture measurement systems. In particular, embodiments of the devices, systems, and methods relate to a culture measurement system having a sensor positioned on the inner surface of a culture vial that directly measures the pH of a sample disposed within the culture vial. The sensor can be a pH sensor positioned within the vial, incorporated within a reactive label positioned within the vial, or incorporated within the measurement vial material itself. Also provided herein are methods of using a culture measurement system, for example, for pH determination, determination of the presence, variation, or quantity of a pathogen, or analysis of an analyte within a sample. Further provided is a method of manufacturing a culture measurement device and system.

[0017] Some of the embodiments of the devices, systems, and methods described herein include, for example, eliminating sensitivity to measurement variations, shortening vial introduction delay (DVE) times, reducing sensitivity due to temperature variations, shortening delay times to detection, eliminating multi-component aspects of current technology, thereby reducing manufacturing complexity and reducing supply interruptions, and enabling real-time feedback regarding the signal quality of the measurement system, including one or more advantages over currently available culture measurement systems.

[0018] In conventional culture measurement systems, the output of the measurement system at any given time is generated based on the ratio of the current detector reading to the initial detector reading obtained at the time the vial was first placed in the system ("time zero"). In these systems, the current detector reading is normalized by dividing subsequent detector readings by the initial detector reading at time zero. Defining the detector reading at any time as i reading and the initial detector reading as i reading #1 and further defining the time at which the initial detector reading was obtained as t reading #1 the variation in the measurement system reported reading shown to the end user can be expressed by the following equation. Variation in measurement system reported reading = Δ(i reading / i reading #1 ) + Δt reading #1 As shown in this equation, the variation in the measurement system reported reading is "i reading #1It is a variation of any of the initial system reading values represented by 「」. This variation may reduce the sensitivity of the measurement system. For example, to distinguish that the variation in the output signal reading value from the test sample is not the result of detector variation but the result of the presence of microorganisms, a greater variation in the output measurement value may be required. In other words, detector variation may affect the measurement threshold required to determine the presence of an analyte in a sample. In some embodiments, the devices, systems, and methods described herein provide absolute measurement values of a sample, such as the absolute pH measurement value. The absolute measurement value is obtained because the sensor incorporated in the culture vial does not require calibration. In some embodiments, the sensor is calibrated before being placed in the culture vial. In some embodiments, an indicator compound is optionally mixed at a specified concentration in the materials used to manufacture the culture vial. In some embodiments, the sensor or indicator compound is responsive to the excitation or interrogation of fluorescence or phosphorescence by the energy source of the colorimetric system. In some embodiments, the sensor or indicator compound is excited and the excitation signal corresponds to a characteristic or property of the sample, such as the pH level of the sample. In any of these embodiments, the incorporation of the sensor or indicator compound eliminates the need to take readings relative to another reference point, such as a time-based reference reading or a standard analytical reference.

[0019] In conventional culture measurement systems, there are often delays between the time a sample is taken and injected into a test vial and the time the vial is placed in the measurement system. In some cases, the inoculated vial is placed in the measurement system hours or even days later, for example, after a weekend. That is, the initial detector readings may not be obtained for 24 to 72 hours after inoculating the vial with the sample. The period between when the sample is placed in the vial and when the vial is placed in the measuring device is generally referred to as the delay in vial introduction (DVE). The DVE period may allow the growth of bacteria or other microorganisms before the vial is placed in the measurement system. The growth of bacteria or other microorganisms before placement in the measurement system can affect the initial detector reading reference signal and, as a result, the test data normalized using the initial detector reading reference signal. DVE is shown graphically in FIG. 5. As shown in FIG. 5, the sample is taken at an initial time point and then analyzed at a later time point (e.g., analyzed at time 0, referred to as "bottle introduction" which means placed in the reader). Following bottle introduction, growth detection is performed. When there is no delay between sampling and bottle introduction, growth detection can be reliably analyzed. In contrast, delaying bottle introduction from the sampling time results in difficult and uncertain growth detection. During the time from sampling to bottle introduction, the pathogens in the sample undergo undetected pathogen growth. For example, in a system that requires relative fluorescence measurements to detect bacterial growth, this undetected growth may be due to the absence of detectable fluctuations (e.g., 24-hour delay incubation at 35°C in FIG. 5). In some embodiments, the devices, systems, and methods described herein are not intended to stop, delay, or slow the growth of pathogens that may be present in the test sample. Obtaining absolute measurements provides the function of setting the output signal threshold level from the sensor or indicator compound. In some embodiments, a signal higher than the output signal threshold level provides the clinician with an immediate feedback that an excessive amount of pathogen growth has occurred in the test sample and a corrective action of obtaining another test sample is required.This immediate feedback saves time for detecting vial introduction delays.

[0020] In conventional culture measurement systems, the initial detector reading reference signal may be affected by temperature variations of the sensor. Variations in the ambient temperature around the sensor can be caused by external factors such as inadequate control of the ambient environment of the sensor and / or sensor equipment by the end user, variations in vial temperature after introduction into the system, and movement of air through the measurement system. These temperature variations affect the partial pressure of the gas in the vial, the diffusion rate of the gas at the sensor, the absorption of the pH indicator, and the emission of signals (such as fluorescence emission, phosphorescence emission, or colorimetric light emission). Temperature variations of the sensor may require compensation to provide accurate readings. In some embodiments, the devices, systems, and methods described herein reduce or eliminate variations in measurement values due to temperature variations by using a pH sensor that is not sensitive to temperature over the temperature range to which the culture sample is exposed. For example, in some embodiments, the sensitivity of the pH sensor is ±0.5 pH or less at temperatures between 10°C and 50°C. For example, the sensitivity of the pH sensor varies by only 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5 pH amount, or by a pH change amount within a range defined by any two of these values, at a temperature of 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or within a temperature range defined by any two of these values. In some embodiments, the incorporation of the sensor into the culture vial uses an improved pH sensor that has only low temperature sensitivity rather than conventional complex polymer-based sensors and pH sensors containing pH indicators and fluorescent compounds, thereby reducing temperature-dependent variables and improving the accuracy of the measurement values obtained during temperature variations.

[0021] In conventional culture measurement systems, the measurement and data processing techniques may result in a detection delay of the presence of the target specimen. Signal fluctuations from noise sources (such as user interference, temperature variations) may appear as the growth of organisms. The algorithms used to process detector data can compensate for these signal fluctuations using a moving average. Random noise can be reduced by smoothing the signal using a moving average, but it may also delay the detection of signal fluctuations caused by the growth of organisms. Optical blood culture sensor systems should also distinguish impulse noise (such as rough opening and closing of the bottle during movement and withdrawal) from the growth of organisms. Therefore, the algorithms for processing detection signals in these systems employ a certain form of delay, for example, to ensure that the measured signal fluctuations are sustained. Such sustained signal fluctuations are more likely to occur when the signal fluctuations are due to the growth of organisms in the blood culture bottle rather than impulse noise. However, this embedded delay may contribute to a longer waiting time from the time the sample is taken to the time the blood culture test result is generated. Therefore, when analyzed over a period longer than 10 minutes, the signal-to-noise ratio cannot be made high enough to accurately measure the sample. In contrast, in some embodiments of the devices, systems, and methods described herein, the signal-to-noise ratio for measuring a sample is shorter than 5 minutes, for example, shorter than 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 60 seconds, or shorter than 1 minute, 2 minutes, 3 minutes, 4 minutes, or 5 minutes, or within a period defined by any two of these values, and only requires one, two, or three measurements. Therefore, in some embodiments, these systems, methods, and devices reduce the time delay to detection due to the elimination of absolute pH measurement and calibration. Some embodiments of these systems reduce the incidence of false-negative test readings due to the detection of positive cultures that were not previously detected due to the time delay to detection. In particular, when the detection time is delayed, the logarithmic growth portion of the growth curve may already have occurred before the measurement.

[0022] In conventional culture measurement systems, the sensors employed adopt multi-component chemical-based formulations that may contain more than 10 components. Any variation, such as the chemical properties or purity of a single component of the sensor, may adversely affect sensor performance. Further, any delay or interruption in the supply of a single component of the sensor may result in the stoppage of sensor production and thus may cause a delay in the production of culture vials. For example, when a single component is no longer available later, manufacturing may be halted or delayed, thereby adversely affecting the product production volume. In some embodiments, the devices, systems, and methods described herein eliminate the drawbacks of multi-component chemical-based sensors by reducing the complexity of the sensors incorporated within the culture vial. In some embodiments, the sensor comprises only 1, 2, 3, or 4 or fewer components.

[0023] In conventional culture measurement systems, the manufacture of sensors requires the stages of compounding, dispensing, and curing of the sensor formulation. Each sensor manufacturing stage may reduce the manufacturing consistency of the sensors or may reduce the associated performance uniformity. Further, each sensor manufacturing process may result in the production of sensors outside the tolerance range, reducing the production yield and increasing the product cost. These three manufacturing stages are carried out in sequence, and thus any variation at each stage propagates to result in an aggregate variation in the uniformity among the sensors. In some embodiments, the devices, systems, and methods described herein eliminate the drawbacks associated with these sensor manufacturing stages. In particular, in some embodiments, the sensors of the systems and devices described herein do not require the stage of compounding a multi-component chemical system, the stage of dispensing such a material system into the culture vial, or the stage of curing such a material system within the culture vial. Instead, in some embodiments, the systems and devices herein incorporate a sensor such as a pH sensor, a reactive label, or an indicator compound into the culture vial, thereby simplifying the manufacture of the chemical formulation-based sensors.

[0024] In conventional culture measurement systems, current normalization techniques fail to provide real-time feedback regarding the signal quality of measurement system components. This system architecture of the measurement system may result in inaccurate measurements. For example, some light source components for exciting the fluorescent material within the sensor may deteriorate in emission intensity during their useful life. Similarly, the performance of the optical detector may also deteriorate. Any variation in the energy emission from the light source components or the sensitivity of the optical detector may cause the measurement system to report inaccurate test data. In some embodiments, the devices, systems, and methods described herein enable the emission intensity to function as a real-time quality indicator for the assay measurement system. When the emission intensity is too high or too low, the sensor measurement device can be programmed to automatically ignore the measurement assay test vial, or the vial measurement test station can be programmed to display an intensity outside the specified value range. For example, the system can include a processor configured to ignore measurement readings that are higher or lower than a certain range, such as two times, three times, four times, five times, six times, seven times, eight times, nine times, or ten times higher than the normally expected reading, or lower than 0.5 times, 0.1 times, 0.05 times, or 0.01 times the normally expected reading.

[0025] In some embodiments, the devices, systems, and methods described herein utilize existing culture vials, readers, and detectors, but incorporate improved sensors that address the drawbacks associated with conventional culture measurement systems.

[0026] Embodiments of a culture measurement device and system The embodiments provided herein relate to culture measurement devices and systems. In some embodiments, the device includes a culture vial that contains a sensor. In some embodiments, the system further includes a reader or a detector. In some embodiments, the sensor measures the pH of a sample disposed within the vial. In some embodiments, the measurement of the pH correlates with the growth of pathogens within the sample.

[0027] Some embodiments provided herein relate to a culture measurement device including a culture vial having a pH sensor positioned on an inner surface of the culture vial. In some embodiments, the pH sensor is configured to measure the pH of a test sample. In some embodiments, the pH sensor is configured to transmit a signal of the measured pH value to a reader. In some embodiments, the reader is configured to acquire a signal of the measured pH value from the pH sensor. The signal of the measured pH value can be transmitted to the reader wirelessly or through an electrical lead. In embodiments where the signal is transmitted wirelessly, the pH sensor can acquire the measured pH value, and a signal indicating the pH level, the presence, absence, or amount variation of a pathogen, or the level of an analyte is transmitted to the reader. In embodiments where the signal is transmitted through an electrical lead, the electrical lead can pass through the bottom portion of the culture vial or through a partition wall of the culture vial to pass through the culture vial. The electrical lead can function as a conduit for transmitting a signal to the reader and can further function as a conduit for supplying power to the pH sensor. In some embodiments, the device and system further include a power source. In some embodiments, the system further includes a potentiostat that supplies power to the electrical lead of the pH sensor and receives a current reading value from the pH sensor. In some embodiments, the pH sensor is configured to be wirelessly powered.

[0028] In some embodiments, a signal indicating the pH level, the presence, absence, or amount variation of a pathogen, or the analyte level is transmitted to the reader through an electrical lead. In any of these embodiments, the reader includes a processor having a function of correlating the pH level with the quantity or quantity variation of the pathogen. In any of these embodiments, the reader includes a display for indicating to the user the measurement result, for example, the pH level, the quality of the sample, or the presence or quantity of the pathogen. In some embodiments, the reader is configured to wirelessly transmit these data to a patient, a clinician, or a researcher by transmitting data including the test result to a data management system or a cloud data storage location including, for example, a hospital information management system, a research facility, or a clinical laboratory.

[0029] In some embodiments, the pH sensor is an ion-specific field effect transistor (ISFET) sensor. In some embodiments, the pH sensor is an ion-selective electrode (ISE).

[0030] In some embodiments, the pH sensor includes a permeable membrane arranged to separate it from a sample placed in a culture vial, with the outer surface of the permeable membrane in liquid contact with the sample and the inner surface in contact with the pH sensor, thereby preventing the sample from being in direct contact with the pH sensor. In some embodiments, for example, the permeable membrane is configured to allow the passage of certain components such as ions while blocking the passage of any other components, so that the pH sensor can have the function of detecting analytes in the sample without directly contacting the sample to avoid pH sensor fouling.

[0031] The permeable membrane can include any material suitable for permitting the permeability of specific ions. In some embodiments, the permeable membrane includes a polymeric material. Materials that can be used for the permeable membrane can include, for example, Nafion, polyurethane, silicone, polytetrafluoroethylene, polyethylene-tetrafluoroethylene copolymer, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymer, copolymer, terpolymer of polyurethane, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), cellulose-based polymer, or polysulfone, or a combination thereof. In some embodiments, the permeable membrane is a bioprotective layer, has selective permeability, allows certain analytes (such as ions) to contact the sensor, while preventing others from contacting the sensor, thereby preventing sensor fouling.

[0032] Some embodiments provided herein relate to culture measurement devices and systems. In some embodiments, the device includes a culture vial and a reactive label positioned on its inner surface. In some embodiments, the system further includes a detector having a function of detecting a signal from the reactive label. In some embodiments, the reactive label is positioned on the inner surface of the culture vial so as to contact the sample when the sample is placed in the culture vial.

[0033] In some embodiments, the reactive label includes a permeable membrane disposed to separate it from the sample placed in the culture vial, with the outer surface of the permeable membrane in liquid contact with the sample and the inner surface in contact with the reactive label, thereby preventing the sample from being in direct contact with the reactive label. In some embodiments, the permeable membrane is configured to allow the passage of certain components such as ions while blocking the passage of any other components so that the reactive label can have the function of detecting an analyte in the sample without directly contacting the sample.

[0034] In some embodiments, the reactive label includes a pH-reactive agent. The pH-reactive agent is a chemical that responds to the proton flux in contact with the reactive label and changes the spectral characteristics of the reactive label. For example, the pH-reactive agent can be a compound that emits an absorbance intensity that varies in proportion to the pH of the sample. The absorbance emission can be due to the excitation or interrogation of fluorescence, phosphorescence (luminescence), or colorimetric light by the energy source of a colorimeter system. Suitable pH-reactive agents can include pigments, dyes, fluorescent dyes, phosphorescent dyes, chromophore dyes, organic compounds, or inorganic compounds.

[0035] In some embodiments, the change in absorbance of the reactive label can be measured using an excitation source and a detector. The excitation source can be an excitation source for fluorescence, phosphorescence, or colorimetric light such as a light-emitting diode. The detector can be a detector for fluorescence, phosphorescence, or colorimetric light such as a photomultiplier tube.

[0036] An embodiment of a culture system with a reactive label is shown in FIG. 2. As shown in FIG. 2, the culture measurement system 200 includes a culture vial 202 and a reactive label 206. A sample 204 is placed within the culture vial 202, and a measured value of the specimen (such as pH) is measured at the reactive label 206 through a permeable membrane. An excitation source 208 excites the reactive label 206, exciting the absorption of a pH-reactive agent on the reactive label 206. The pH-reactive agent emits an absorbance intensity signal having an intensity that varies in proportion to the pH of the sample 204, and this signal is detected by a detector 210.

[0037] The culture vial 202 is configured to receive a sample 204 such as a blood culture sample. The measurement system 200 is configured to measure the pH of the sample 204 received within the culture vial 202. The pH of the sample varies or fluctuates based on the presence or absence of a pathogen within the sample, and thus the measured pH value correlates with the presence or absence of the pathogen. The culture vial 202 includes a reactive label 206 that includes a pH-reactive agent. The vial 202 can contain a culture medium that promotes the growth of pathogens therein. The vial 202 can be, for example, a blood culture bottle.

[0038] The excitation source 208 can be activated to emit light of one or more wavelengths or wavelength ranges that excite the pH-reactive agent of the reactive label 206. In certain embodiments, the excitation source 208 can include one or more light-emitting diodes (LEDs).

[0039] Detector 210 can be configured to detect the absorbance intensity signal emitted by the pH-responsive agent of the reactive label 206 following excitation of the reactive label 206. Detector 210 can be a photomultiplier tube, a silicon photodiode, a PIN silicon diode, a GaAsP photodiode, or any other suitable photodetector. In some embodiments, detector 210 can include a photovoltaic device, a photoresistive device, a photoconductive device, or any other device suitable for detecting the absorbance intensity signal emitted from reactive label 206. In certain embodiments, one or more detectors 210 can be employed to measure the absorbance intensity signal emitted by reactive label 206.

[0040] System 200 can include one or more excitation filters 214 configured to filter the light from excitation source 208 to supply only light of a specific wavelength or wavelength range to the fluorescent material. For example, in certain embodiments, one or more excitation filters 214 can filter the light to supply a specific wavelength or wavelength range corresponding to the absorption spectrum of the pH-responsive agent to the pH-responsive agent.

[0041] System 200 can include one or more emission filters configured to filter the light to supply a certain wavelength or wavelength range to the detector. For example, in certain embodiments, one or more emission filters can filter the light to supply a wavelength or wavelength range corresponding to the emission spectrum of the pH-responsive agent to the detector.

[0042] The pH-reactive agent used in system 200 can be selected based on the emission spectrum of the excitation source 208 and / or the specifications of the detector 210. In certain embodiments, the pH-reactive agent can include one or more fluorescent dyes, phosphorescent dyes, or colorimetric dyes, or other agents having the function of giving a detectable signal that varies in proportion to the pH change. Such agents can include, for example, propyl red, p-nitrophenol, azolitmin, chlorophenol red, 3,6-dihydroxyxanthone, alizarin, bromoxylenol blue, M-dinitrobenzoylene urea, bromothymol blue, aurin (rosolic acid), neutral red, cresol red, bromocresol red, bromocresol purple, rosolic acid, nile blue, phenol red, nitroamine, cresol purple, and methyl yellow fluorophore.

[0043] As described herein, the pH-reactive agent in the reactive label 206 undergoes an optical change in response to a change in the analyte, such as a change in the concentration of protons in the sample, thereby indicating the pH. In certain embodiments, a pH-reactive agent that undergoes an optical property change based on a pH change in the culture vial due to a change in the concentration of the analyte in the sample is selected.

[0044] The optical change of the pH-reactive agent can function as an optical filter that excites the pH-reactive agent in the reactive label 206 or changes the amount of light emitted from the pH-reactive agent. Accordingly, a change in the concentration of the analyte of interest in the sample can cause a variation in the signal detected by the detector 210 by changing the optical properties of the pH-reactive agent in the reactive label 206. As a result, the intensity change of the signal detected by the detector 210 can indicate a change in the concentration of the analyte of interest in the sample.

[0045] As an example, in certain embodiments, the system 200 is configured to detect the absence, presence, or quantity variation of pathogens in a sample disposed within the culture vial 202. In embodiments where it is desirable to monitor the absence, presence, or quantity variation of pathogens, the pH-responsive agent of the reactive label 206 is configured to undergo a change in absorbance when the pH varies. When the pathogen grows, CO 2 is exhaled. CO 2 can be mixed with the aqueous culture medium within the vial 202 to produce carbonic acid. The increase in the amount of carbonic acid results in a decrease in pH. When the pH within the vial 202 decreases, the absorbance of the pH-responsive agent decreases, thereby allowing more excitation energy to reach the pH-responsive agent within the reactive label 206, resulting in an increase in the signal emission intensity from the pH-responsive agent. The detector 210 can detect the increase in the signal emission intensity, and this detection can function as an indirect measurement of the increase in CO 2 concentration. As described above, the CO 2 concentration is directly correlated with the growth of the pathogen. Thus, the detection of the increase in signal intensity by the detector 210 can indicate the presence of the pathogen in the sample.

[0046] In certain embodiments, the measurement system 200 can further include a processor configured to perform signal processing to determine the presence of a pathogen based on changes in signal intensity measured by the detector 210. In certain embodiments, the processor can be part of a computer system. Such a computer system can include one or more of a memory, an input, and a display. The memory, which can include both read-only memory (ROM) or both ROM and random access memory (RAM), can be configured to supply instructions and data to the processor. For example, the memory can store one or more modules that store data values that define instructions for configuring the processor to perform signal processing functions. In some embodiments, the computer system is configured to wirelessly transmit this data to a patient, clinician, or researcher by sending data including the test results to a data management system or cloud data storage location, such as, for example, a hospital information management system, a research facility, or a clinical laboratory.

[0047] Some embodiments provided herein relate to culture measurement devices and systems. In some embodiments, the device includes a culture vial that includes an indicator compound incorporated directly into the material of the culture vial. In some embodiments, the indicator compound is configured to be reactive to excitation or interrogation by fluorescence or phosphorescence from an energy source of a colorimeter system. In some embodiments, the excitation is detected by a detector. In some embodiments, the system further includes a detector having a function of detecting excitation from the indicator compound. In some embodiments, the indicator compound is incorporated into the inner surface of the culture vial. For example, the indicator compound can be mixed into the culture vial material (e.g., plastic) prior to the manufacture of the culture vial, such as at a time prior to injection molding of the culture vial. In some embodiments, the indicator compound is incorporated into an inner layer of a plastic culture vial or into a plastic liner layer of a glass culture vial. In some embodiments, the indicator compound is positioned on the inner surface of the culture vial such that it contacts the sample when the sample is placed in the culture vial. In some embodiments, the indicator compound is incorporated into all or a portion of the vial. For example, the indicator compound can be incorporated into the entire culture vial, the bottom portion of the culture vial, one or more walls of the culture vial, or any segment or portion of the culture vial.

[0048] In some embodiments, a culture vial containing an indicator compound further includes a permeable membrane arranged to separate the indicator compound from a sample placed within the culture vial, with the outer surface of the permeable membrane in liquid contact with the sample and the inner surface in contact with the indicator compound, such that the sample is not in direct contact with the indicator compound. In some embodiments, the permeable membrane is configured to allow the passage of certain components, such as ions, while blocking the passage of all other components, so that the indicator compound can have the function of detecting an analyte in the sample without directly contacting the sample. In some embodiments, the permeable membrane protects all or a portion of the inside of the vial.

[0049] In some embodiments, a culture vial containing an indicator compound further includes an impermeable membrane. In some embodiments, the impermeable membrane covers all of the inner surface of the culture vial except for the sensor region, such that the sample can only interact with the sensor region of the culture vial, and only the sensor region can sense an analyte in the sample and emit a detectable signal. The impermeable membrane can include any material that prevents or inhibits the passage of material through the membrane and can include various non-porous plastic or polymer materials.

[0050] In some embodiments, the indicator compound is a pH-responsive agent. For example, the pH-responsive agent can be a compound that emits an absorbance intensity that varies in proportion to the pH of the sample. The absorbance emission can be fluorescence, phosphorescence, or colorimetric light emission. Suitable pH-responsive agents can include pigments, dyes, fluorescent dyes, phosphorescent dyes, chromophore dyes, organic compounds, or inorganic compounds.

[0051] In some embodiments, a change in the absorbance of the indicator compound can be measured using an excitation source and a detector. The excitation source can be a source of fluorescence, phosphorescence, or colorimetric light, such as a light-emitting diode. The detector can be a detector of fluorescence, phosphorescence, or colorimetric light, such as a photomultiplier tube.

[0052] An embodiment of a culture system incorporating an indicator compound is shown in FIG. 3. As shown in FIG. 3, the culture measurement system 300 includes a culture vial 302 and an indicator compound 306. The indicator compound 306 can be incorporated onto the inner surface within the culture vial 302 or can be incorporated within an inner liner that lines the inner surface of the culture vial. A sample 304 is placed within the culture vial 302, and a measured value (such as pH) of the analyte is measured by measuring an absorbance signal using a detector 310. An excitation source 308 excites the indicator compound 306 and excites the absorption of the indicator compound 306. The indicator compound 306 emits an absorbance intensity signal having an intensity that varies in proportion to the pH of the sample 304, and this signal is detected by the detector 310. Excitation and detection of the indicator compound can be performed at any part of the culture vial in which the indicator compound is incorporated, and thus detection does not require that any of the culture vials be performed at a specific location. In contrast, the culture vial described in FIG. 2 requires excitation and sensing of a reactive label placed at an internal location thereof.

[0053] The culture vial 302 is configured to receive a sample 304 such as a blood culture sample. The measurement system 300 is configured to measure the pH of the sample 304 received within the culture vial 302. The pH of the sample varies or fluctuates based on the presence or absence of a pathogen within the sample, and thus the measured value of the pH is correlated with the presence or absence of the pathogen. The culture vial 302 includes an indicator compound 306 that includes a pH-reactive agent. The vial 302 can include a culture fluid that can promote the growth of pathogens therein. The vial 302 can be, for example, a blood culture bottle.

[0054] The excitation source 308 can be activated to emit light of one or more wavelengths or wavelength ranges that excite the pH-reactive agent of the indicator compound 306. In certain embodiments, the excitation source 308 can include one or more light-emitting diodes (LEDs).

[0055] Detector 310 can be configured to detect an absorbance intensity signal emitted by the pH-responsive agent of indicator compound 306 following excitation of indicator compound 306. Detector 310 can be a photomultiplier tube, a silicon photodiode, a PIN silicon diode, a GaAsP photodiode, or any other suitable photodetector. In some embodiments, detector 310 can include a photovoltaic device, a photoresistive device, a photoconductive device, or any other device suitable for detecting the absorbance intensity signal emitted from indicator compound 306. In certain embodiments, one or more detectors 310 can be employed to measure the absorbance intensity signal emitted by indicator compound 306.

[0056] System 300 can include one or more excitation filters 314 configured to filter the light from excitation source 308 to supply only light of a specific wavelength or wavelength range to the fluorescent material. For example, in certain embodiments, one or more excitation filters 314 can filter the light to supply a specific wavelength or wavelength range corresponding to the absorption spectrum of the pH-responsive agent to indicator compound 306.

[0057] System 300 can include one or more emission filters configured to filter the light to supply a certain wavelength or wavelength range to the detector. For example, in certain embodiments, one or more emission filters can filter the light to supply a wavelength or wavelength range corresponding to the emission spectrum of the pH-responsive agent to the detector.

[0058] The indicator compound 306 used in system 300 can be selected based on the emission spectrum of the excitation source 308 and / or the specifications of the detector 310. In certain embodiments, the indicator compound 306 can be a fluorescent dye, a phosphorescent dye, or a colorimetric dye, or a pH-responsive agent such as another agent having a function of giving a detectable signal that varies in proportion to a pH change. Such agents can include, for example, propyl red, p-nitrophenol, azolitmin, chlorophenol red, 3,6-dihydroxyxanthone, alizarin, bromoxylenol blue, M-dinitrobenzoylene urea, bromothymol blue, aurin (rosolic acid), neutral red, cresol red, bromocresol red, bromocresol purple, rosolic acid, nile blue, phenol red, nitroamine, cresol purple, and methyl yellow fluorophore.

[0059] As described herein, the indicator compound 306 can undergo an optical change in response to a change in the analyte, such as a change in the concentration of protons in the sample, thereby indicating the pH. In certain embodiments, an indicator compound 306 is selected that undergoes a change in optical properties based on a change in pH within the culture vial due to a change in the concentration of the analyte in the sample.

[0060] The optical change of the indicator compound 306 can function as an optical filter that excites the indicator compound 306 or changes the amount of light emitted from the indicator compound 306. Accordingly, a change in the concentration of the analyte of interest in the sample can result in a variation in the signal detected by the detector 310 by changing the optical properties of the indicator compound 306. As a result, a change in the intensity of the signal detected by the detector 310 can indicate a change in the concentration of the analyte of interest in the sample.

[0061] As an example, in certain embodiments, system 300 is configured to detect the absence, presence, or quantity variation of pathogens in a sample disposed within culture vial 302. In embodiments where it is desirable to monitor the absence, presence, or quantity variation of pathogens, indicator compound 306 is configured to undergo a change in absorbance when the pH varies. When the pathogen grows, CO 2 is exhaled. CO 2 can be mixed with the aqueous culture medium within vial 302 to produce carbonic acid. The increase in the amount of carbonic acid results in a decrease in pH. When the pH within vial 302 decreases, the absorbance of indicator compound 306 decreases, thereby allowing more excitation energy to reach indicator compound 306, resulting in an increase in the signal emission intensity from indicator compound 306. Detector 310 can detect the increase in signal emission intensity, and this detection can function as an indirect measurement of the increase in CO 2 concentration. As described above, the CO 2 concentration is directly correlated with the growth of the pathogen. Thus, the detection of the increase in signal intensity by detector 310 can indicate the presence of the pathogen in the sample.

[0062] In certain embodiments, measurement system 300 can further include a processor configured to perform signal processing to determine the presence of a pathogen based on changes in signal strength measured by detector 310. In certain embodiments, the processor can be part of a computer system. Such a computer system can include one or more of memory, input, and display. Memory, which can include both read-only memory (ROM) or both ROM and random access memory (RAM), can be configured to supply instructions and data to the processor. For example, the memory can store one or more modules that store data values that define instructions for configuring the processor to perform signal processing functions. In some embodiments, the computer system is configured to wirelessly transmit data, including test results, to patients, clinicians, or researchers by sending the data to a data management system or cloud data storage location, such as a hospital information management system, a research facility, or a clinical laboratory.

[0063] In any of the embodiments described herein, the sample is a liquid biological sample, such as a blood sample, a serum sample, a cerebrospinal fluid sample, or other biological sample for which detection of an analyte is desired, a food sample, or an environmental sample, or a culture of any of these samples. In some embodiments, the sample is a blood sample and is analyzed to measure a pathogen by measuring its pH.

[0064] In some embodiments, the culture vial is manufactured and configured for implementation using an existing measurement system. For example, the culture vial can be the same or similar size and shape as an existing culture vial to enable measurement of a sample within an existing measurement platform. In any of the embodiments provided herein, the culture vial is made of a material suitable for measurement of the sample. In some embodiments, the culture vial is glass or plastic. In some embodiments, the culture vial enables optical interrogation of the sample and thus enables an optical signal to pass through the culture vial, for example, enabling the emission of fluorescence, phosphorescence, or colorimetric light.

[0065] Embodiments of a method for detecting a sample Some embodiments provided herein relate to a method for detecting an analyte in a sample. In some embodiments, the method includes inoculating a sample into a culture vial as described in any one or more of the embodiments herein, and measuring the pH of the sample. In some embodiments, the pH of the sample can be measured at a first time point and subsequent time points to provide a measure of the change in pH over time. For example, the pH measurement can be performed using a first time point, a second time point, a third time point, a fourth time point, or more time points. In some embodiments, the pH measurement value is determined immediately after inoculating the sample into the culture vial.

[0066] In some embodiments, a method for detecting an analyte in a sample utilizes, for example, a culture measurement device and system that includes a pH sensor positioned on the inner surface of a blood culture vial as described in one or more of the embodiments above and elsewhere in this specification. In some embodiments, the method includes inoculating a sample into a culture vial with the pH sensor positioned on the inner surface, incubating the sample at a constant temperature for a period of time to allow the pH sensor to equilibrate, and measuring a signal from the pH sensor with a reader. In some embodiments, the reader is configured to obtain a signal from the pH sensor either through an electrical lead or wirelessly. In some embodiments, the reader includes a processor. In certain embodiments, the processor can be part of a computer system. Such a computer system can include one or more of a memory, an input, and a display. The memory, which can include both read-only memory (ROM) or both ROM and random access memory (RAM), can be configured to supply instructions and data to, for example, the processor described above and elsewhere in this specification. For example, the memory can store one or more modules that store data values that define instructions for configuring the processor to perform signal processing functions. In this embodiment, the measured value of pH is determined directly using a pH sensor that can be an ISFET or an ISE.

[0067] In some embodiments, a method for detecting an analyte in a sample utilizes, for example, a culture measurement device and system that includes a reactive label positioned on the inner surface of a culture vial as described in the embodiments above and elsewhere in this specification. In some embodiments, the method includes inoculating a sample into a culture vial having a reactive label positioned on the inner surface, incubating the sample for a period of time to allow the reactive label to equilibrate, exciting the reactive label with an excitation source, and detecting the emitted absorbance intensity signal with a detector. In this embodiment, the measured pH value is determined by measuring the signal intensity that correlates with the pH of the sample. In some embodiments, a decrease in pH results in an increase in signal intensity due to an increase in excitation energy at the reactive label.

[0068] Figure 4 shows an exemplary process 400 for determining the presence of an analyte in a blood culture sample. Process 400 begins at step 410, where a sample is inoculated into a culture vial having a reactive label, such as vial 202 described with respect to FIG. 2. The reactive label can include a pH-reactive agent as described above with reference to FIG. 2.

[0069] After the culture vial is inoculated, process 400 proceeds to step 420, where excitation light at the excitation frequency of the pH-reactive agent is transmitted to the test vial. The excitation frequency can be a frequency or frequency range within the absorption spectrum of the pH-reactive agent. The light can be transmitted by an excitation source, such as excitation source 208 described with respect to FIG. 2.

[0070] After the light is transmitted to the test vial, process 400 moves to step 430, where the intensity of the signal emitted from the test vial is measured. As described herein, a pH-reactive agent can emit an absorption intensity signal due to fluorescence excitation or phosphorescence (luminescence) excitation by the energy source of the colorimeter system or reactivity to interrogation. This signal can be measured by a detector such as detector 210 described with respect to FIG. 2. In certain embodiments, the step of measuring the intensity of the signal at step 430 includes the step of filtering the signal using an emission filter.

[0071] With respect to the detection of the presence of the analyte of interest in the blood culture sample described in the process 400 illustrated in FIG. 4, one of ordinary skill in the art will understand that the methods described herein are not limited to blood culture samples and can be applied to the detection of microorganisms in any culture medium known in the art.

[0072] In some embodiments, a method for detecting an analyte in a sample includes, for example, a culture measurement device and system that includes a culture vial that includes an indicator compound incorporated on the inner surface of the culture vial as described in the embodiments above and elsewhere in this specification. In some embodiments, the method includes inoculating a sample into a culture vial in which the indicator compound is incorporated on the inner surface, incubating the sample at a constant temperature for a period of time to allow the indicator compound to equilibrate, exciting the indicator compound with an excitation source, and detecting an absorption intensity signal at a detector. In this embodiment, the measured pH value is determined by measuring the signal intensity that correlates with the pH of the sample. In some embodiments, a decrease in pH results in an increase in signal intensity due to an increase in excitation energy in the indicator compound.

[0073] In any of the embodiments of the method for detecting an analyte, when the pathogen grows, CO 2 is exhaled. CO 2can be mixed with the aqueous culture medium in the culture vial to produce carbonic acid. The increase in the amount of carbonic acid results in a decrease in pH. The decrease in pH is measured using the method described herein, and thus, the detection of pH correlates with the degree of the presence of pathogens in the sample.

[0074] In any of the embodiments of the method for detecting a specimen, the equilibration of the sensor (pH sensor, reactive label, or indicator compound) occurs over a period of time including an amount of time in the range defined by 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 60 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, or 60 minutes, or any two of these times. The second or subsequent measurement value can be obtained at a second time following the first measurement time. The second or subsequent measurement can be performed 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, or 60 minutes after the first measurement, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 10 hours, 12 hours, 15 hours, 18 hours, 21 hours, or 24 hours after the first measurement, or at a point in time in the range defined by any two of these values. The subsequent time points can also be employed during a period advantageous for determining the presence of pathogens in the sample.

[0075] Embodiments of a method for manufacturing a culture measurement device and system Some of the embodiments provided herein relate to a method of manufacturing any one or more of the devices and systems of the embodiments described herein. In some embodiments, a culture vial is obtained, and a pH sensor is incorporated into the inner surface of the culture vial such that the pH sensor is immersed in the sample when, for example, a sample is inoculated into the culture vial of one or more of the above-described embodiments and elsewhere in this specification. In some embodiments, the culture vial includes a port for the electrical leads of the pH sensor to pass through the culture vial. In some embodiments, the port is positioned in the immediate vicinity of the location of the pH sensor at the bottom portion of the culture vial. In some embodiments, the port is positioned within a septum that closes the culture vial.

[0076] In some embodiments, for example, as described in one or more of the above embodiments and elsewhere in this specification, a culture vial with a reactive label disposed therein is manufactured. In some embodiments, the reactive label is positioned on the inner surface of the culture vial. In some embodiments, the reactive label includes a permeable membrane that functions as a bioprotective layer between it and the sample in the culture vial. In some embodiments, the reactive label is adhered to the inner surface of the culture vial by an adhesive such as a double-sided tape or other biocompatible adhesive.

[0077] In some embodiments, for example, as described in one or more of the above embodiments and elsewhere in this specification, a culture vial with an indicator compound incorporated therein is manufactured. In some embodiments, the indicator compound is mixed with the culture vial material prior to the manufacture of the culture vial such that the indicator compound forms an integral component of the culture vial during the manufacture of the culture vial. In some embodiments, the culture vial is a plastic culture vial and is formed using injection molding techniques. In some embodiments, the culture vial is a glass culture vial and the indicator compound is incorporated into a plastic layer that lines the inner surface of the glass culture vial. The indicator compound can be incorporated into the plastic layer by mixing the indicator compound with the plastic layer material prior to the formulation of the plastic layer. In some embodiments, the indicator compound is incorporated into all or a portion of the culture vial. For example, the indicator compound can be incorporated only within the entire culture vial or a portion thereof, such as within the bottom portion of the culture vial, within one or more walls of the culture vial, or within a divided portion or region of the culture vial. In some embodiments, the culture vial having the indicator compound further includes a permeable membrane that covers all or a portion of its interior and functions as a bioprotective layer between the indicator compound and a sample within the culture vial. In some embodiments, the culture vial having the indicator compound further includes an impermeable membrane that covers all or a portion of its interior. The region where the impermeable membrane is absent is the sensor region, which is the region where the sample can interact with the indicator compound incorporated within the culture vial.

[0078] In any of the embodiments for manufacturing a culture measurement device and system, a particular (e.g., regardless of which of the above-described embodiments and any of the pH sensors, reactive labels, or indicator compounds described elsewhere in this specification are included) culture vial can be manufactured for use within an existing measurement system. For example, the culture vial can be sized and shaped the same as or similar to an existing culture vial so that it can be seamlessly incorporated into an existing measurement system. In some embodiments, the culture vial is manufactured to be the same as or similar to a BD BACTEC® blood culture system vial manufactured by Becton, Dickinson and Company so that the sample therein can be measured using the BD BACTEC® system.

[0079] The embodiments disclosed herein provide devices, systems, and methods for measuring an analyte in a sample using a pH sensor, a reactive label, or an indicator compound to determine the pH of the sample. Those skilled in the art will recognize that these embodiments can be implemented in hardware, software, firmware, or any combination thereof.

[0080] In addition to the advantages described above, embodiments of the devices, systems, and methods described herein can be advantageously implemented without changing the consumable components within current blood culture measurement systems. For example, the implementation of the techniques of the present disclosure can be carried out without changing the form of the assay bottle containing contents consisting of a culture fluid or a nutrient solution.

[0081] It will be further understood that embodiments of the techniques of the present disclosure are not limited to blood culture measurement devices and systems, but can be applied to other types of optical detection devices or systems.

[0082] The functions and configurations of the reader, detector, or processor described in this specification can be stored on a processor-readable medium or a computer-readable medium as one or more instructions. The term "computer-readable medium" means any available medium that can be accessed by a computer or a processor. By way of example and not limitation, such media can include RAM, ROM, EEPROM, flash memory, CD-ROM, or other optical disk storage, magnetic disk storage, or other magnetic storage devices, or any other medium that can be used to store the desired program code in the form of instructions or data structures and that is accessible by a computer. As used herein, a disk includes a compact disk (CD), a laser disk, an optical disk, a digital versatile disk (DVD), a floppy disk, and a Blu-ray (registered trademark) disk. Usually, a disk magnetically replicates data, and a disk optically replicates data using a laser. It should be noted that a computer-readable medium can be tangible and non-transitory. The term "computer program product" means a combination of a computer device or a processor and code or instructions (e.g., a "program") that can be executed, processed, or calculated by them. As used herein, the term "code" can mean software, instructions, code, or data that is executable by a computer device or a processor.

[0083] In any one or more embodiments of a device, system, or method, a measured pH value can be wirelessly transmitted to system components for analysis of such data to derive a bacterial growth curve. In some embodiments, the transmission of pH analysis data is sent to a central centralized system such as an information system or a cloud repository or a laboratory so that a researcher, patient, or clinician can access the analysis.

[0084] Software or instructions can be transmitted through a transmission medium. For example, when software is transmitted from a website, server, or other remote information source using coaxial cable, fiber optic cable, twisted pair, digital subscriber line (DSL), or wireless technologies such as infrared, radio waves, and microwaves, the coaxial cable, fiber optic cable, twisted pair, DSL, or wireless technologies such as infrared, radio waves, and microwaves are included within the definition of the transmission medium.

[0085] The methods disclosed herein include one or more steps or actions for providing the described methods. The steps and / or actions of the method can be interchanged with each other without departing from the scope of the disclosure of the present invention. In other words, the order and / or use of specific steps and / or actions can be modified without departing from the scope of the disclosure of the present invention, provided that a specific order of steps or actions is not required for the proper operation of the described method.

[0086] The term "determine" encompasses a wide range of actions and thus "determine" can include, for example, calculating, computing, processing, deriving, investigating, referring (e.g., referring within a table, database, or another data structure), and ascertaining. Similarly, "determine" can include, for example, receiving (e.g., receiving information) and accessing (e.g., accessing data in a memory). Further, "determine" can include, for example, resolving, selecting, choosing, and establishing.

[0087] In the above description, specific details have been presented for a thorough understanding of the examples. However, those skilled in the art will understand that these examples can be practiced without these specific details. For example, electrical components / devices may be shown in block diagrams so as not to obscure these examples with unnecessary details. In other cases, such components, other structures, and technologies may be shown in detail to explain these examples more fully.

[0088] This specification includes headings for reference purposes and to assist in finding various sections. These headings are not intended to limit the scope of the concepts described therein. Such concepts can have applicability throughout this specification.

[0089] It should also be noted that the above examples can be described as processes shown as flowcharts, flow diagrams, finite state diagrams, structural diagrams, or block diagrams. Flowcharts can describe operations as sequential processes, but many of these operations can be performed in parallel or simultaneously, and the processes can be repeated. Further, the order of operations can be rearranged. A process is terminated when its operations are completed. A process can correspond to a method, function, procedure, subroutine, subprogram, etc. When a process corresponds to a software function, its termination corresponds to the return of the function to the calling function or main function.

[0090] The above description of the implementation of the disclosure of the present invention has been presented to enable any person skilled in the art to make or use the embodiments of the disclosure of the present invention. Various modifications to these implementations will be immediately apparent to those skilled in the art, and the general principles defined herein can be applied to other implementations without departing from the spirit or scope of the disclosure of the present invention. Accordingly, the disclosure of the present invention is not limited to the implementations shown herein, but is intended to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

Claim 1: A culture vial for measuring the culture pH, comprising: a pH sensor positioned on the inner surface of the culture vial and configured to transmit a signal of the measured pH value; the pH sensor being an ion-specific field effect transistor or an ion-selective electrode; i) the pH sensor includes an electrical lead configured to be connected to a reader configured to obtain the signal from the pH sensor through the culture vial, or ii) the pH sensor is configured to wirelessly communicate with a reader configured to obtain the signal from the pH sensor; a culture vial. Claim 2 The culture vial according to claim 1, further comprising a permeable membrane layer that separates the pH sensor from the contents of the culture vial. Claim 3 The permeable membrane includes a polymer material, and / or the permeable membrane includes Nafion, polyurethane, or a cellulose-based material; the culture vial according to claim 2. Claim 4 The culture vial according to any one of claims 1 to 3, wherein the culture vial is made of plastic or glass. Claim 5 The culture vial according to any one of claims 1 to 4, wherein the electrical lead passes through the bottom portion of the culture vial or through the partition wall of the culture vial. Claim 6 The culture vial according to any one of claims 1 to 4, wherein the pH sensor is configured to wirelessly communicate with the reader. Claim 7 The culture vial according to any one of claims 1 to 6, wherein the pH sensor is configured to be wirelessly powered. Claim 8: The culture vial according to any one of claims 1 to 7, wherein the culture vial is a blood culture vial containing a culture solution that promotes the growth of pathogens present in a blood sample. Claim 9 A system comprising the culture vial or blood culture vial according to any one of claims 1 to 8, and the reader configured to obtain the signal from the pH sensor. Claim 10: The system according to claim 9, wherein the reader is configured to analyze the signal from the pH sensor to generate analysis data, and the reader is configured to wirelessly transmit the analysis data to an information management system or a cloud data storage location. Claim 11: A method for measuring the pH in a culture sample, comprising: ​ Inoculating a culture sample into the culture vial according to any one of claims 1 to 8, and placing the culture vial in the culture system according to claim 9 or 10; Measuring the pH of the culture sample by detecting a signal of the measured pH value; A method comprising.

12. The method according to claim 11, further comprising measuring the pH of the culture sample at a second or subsequent time point.

13. The method according to claim 11 or 12, wherein the measured pH of the culture sample correlates with the degree of the amount of pathogens in the culture sample.

14. The method according to claim 13, wherein the pathogen is a bacterium or a fungus.

15. The method according to any one of claims 11 to 14, wherein the system includes a processor configured to ignore measurement values higher or lower than a sensitivity range.

16. The method according to any one of claims 11 to 15, further comprising wirelessly transmitting analysis data to an information management system or a cloud data storage location.

17. The culture vial is a blood culture vial containing a culture solution that promotes the growth of pathogens present in a blood sample, and the sample is a blood sample. The method according to any one of claims 11 to 16.

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