Devices, systems, and methods for continuous, real-time blood culture measurement

Abstract

To provide devices, systems, and methods for measuring the presence of an analyte of interest in a sample.SOLUTION: Provided herein are devices, systems, and methods for measuring the presence of an analyte of interest in a sample. Certain embodiments of the present disclosure are related to culture measurement systems comprising a culture vial and a sensor, where the sensor is a pH sensor, a responsive label, or an indicator compound incorporated into the culture vial for pH measurement of a sample.SELECTED DRAWING: Figure 4

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 January 23, 2019, which is hereby incorporated by reference in its entirety.

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

[0003] In many fields (e.g., medical, pharmaceutical, and food industries), rapid and accurate determination of microbial contamination within a particular system (e.g., a patient's blood, a batch of drug product, or a food supply) is desirable. Methods have been developed that use sensors containing fluorescent materials in conjunction with indicator materials to indirectly detect microorganisms within a sample through their biological activity. For example, when microorganisms are present in a culture vial, they metabolize nutrients in the culture medium and release carbon dioxide into the sample. The carbon dioxide reacts with a dye to modulate the amount of light absorbed by the sensor within the vial. A photodetector measures the absorption level (e.g., fluorometry), which corresponds to the amount of carbon dioxide released by the microorganisms. Measurement systems employing these methods incorporate a fluorescent sensor or detector to detect fluorescent signals emitted from the container or vial containing the sample and sensor. Software and / or hardware systems are then 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) times, lack of consistency due to temperature fluctuations, complexity of multi-component sensors, and lack of real-time feedback regarding measurement system signal quality. Furthermore, these systems may include components that are difficult to obtain and difficult to incorporate into the measurement vial. Furthermore, these limitations result in sensors that provide inconsistent results from vial to vial. Embodiments of the techniques of the present disclosure eliminate or mitigate at least some of these and / or other shortcomings in blood culture measurement systems. Summary of the Invention [Problem to be solved by the invention]

[0005] Described herein are devices, systems, and methods for measuring properties or characteristics within a sample that undergo changes over time, for example, for measuring pH changes within a sample. [Means for solving the problem]

[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 an interior surface thereof and configured to transmit a signal of the pH measurement. 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 separating the pH sensor from the blood culture vial. In some embodiments, the permeable membrane comprises a polymeric material. In some embodiments, the permeable membrane comprises Nafion, polyurethane, or a cellulosic 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 acquire a signal from the 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 an inner surface thereof and configured to transmit a signal of a pH measurement. 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 separating 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 cellulosic material. In some embodiments, the culture vial is plastic or glass. In some embodiments, the pH sensor includes electrical leads that connect through the blood culture vial to the reader. In some embodiments, the electrical leads pass through a bottom portion of the blood culture vial or a 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 blood culture pH. 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 an interior surface thereof. In some embodiments, the reactive label is configured to emit an absorbance intensity signal corresponding to the 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 it 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 cellulosic material.

[0009] 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 culture vial includes an indicator compound directly incorporated therein. In some embodiments, the indicator compound is a pH-responsive agent configured to be responsive to fluorescent, phosphorescent, 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 covering a portion of the culture vial itself. In some embodiments, the blood culture vial is plastic or glass.

[0010] Some embodiments provided herein relate to a system including a culture vial and one or more detectors configured to measure the intensity of one or more signals emitted 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 an inner surface thereof. In some embodiments, the reactive label is configured to emit an absorbance 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 separating it 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 cellulosic 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 responsive to fluorescent, phosphorescent, 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 covering a portion of the vial. 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 pH in a blood culture sample. In some embodiments, the method includes inoculating a culture vial described herein with the blood culture sample and measuring the pH of the blood culture sample by detecting a pH measurement signal using a system described herein. In some embodiments, the pH measurement signal is obtained by measuring a fluorescent, phosphorescent, or colorimetric signal emitted from a sensor in 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 to a degree of pathogen abundance 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 above or below a sensitivity range. In some embodiments, the method further includes wirelessly transmitting the analytical data to an information management system, a cloud data storage location, or an electronic storage medium (e.g., a hard drive). [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a schematic diagram of a sample measurement system based on fluorescent emissions from carbon dioxide emissions. [Figure 2] 1 is a schematic diagram of a culture measurement system according to an exemplary embodiment of the present disclosure. [Figure 3] 1 is a schematic diagram of a culture measurement system according to an exemplary embodiment of the present disclosure. [Figure 4] 1 is a flow diagram illustrating a process for detecting a signal indicative of the presence of an analyte of interest in the culture medium of a blood sample according to an exemplary embodiment of the present disclosure. [Figure 5] 1 is a graph showing pathogen growth in a blood culture system where a delay in vial introduction confounds accurate readings of pathogen growth. DETAILED DESCRIPTION OF THE INVENTION

[0013] Any feature or combination thereof described herein is included within the present disclosure, unless the features included in any such combination are mutually inconsistent, as will be apparent from the context, from this description, and from the knowledge of one skilled in the art. Furthermore, any feature or combination thereof may be specifically excluded from any embodiment of the present disclosure. For purposes of summarizing the present disclosure, this specification describes certain aspects, advantages, and novel features of the present disclosure. It should, of course, be understood that not all such aspects, advantages, or features need be present in any particular embodiment of the present disclosure.

[0014] It is 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 should be construed as covering all modifications, alternatives, and equivalents of these embodiments that may fall within the spirit and scope of the present disclosure. Embodiments of the presently disclosed technology are described herein with respect to blood culture measurement device systems, such as, but not limited to, the BD BACTEC® Blood Culture Device System by Becton, Dickinson and Company. However, it will be understood that embodiments of the presently disclosed technology are not limited to blood culture measurement devices and systems, but may be applied to other types of detection devices and systems.

[0015] Bloodborne pathogen detection is an important function in microbiology laboratories. Blood cultures are essential for identifying pathogens responsible for bacteremia and sepsis. Several automated blood culture systems are currently available. Some systems use fluorescence technology to detect the growth of organisms in blood culture vials. Figure 1 shows a schematic diagram of a currently available measurement system 100. As shown in Figure 1, when microorganisms are present in a culture vial 102, these microorganisms metabolize nutrients in a sample 104 and release carbon dioxide into the sample. A dye sensor 106 in the culture vial 102 reacts with the carbon dioxide, modulating the amount of light absorbed by a fluorescent material in the sensor 106. A light source 108 can be incorporated to emit light to excite the fluorescent material in the sensor 106. A detector 110, such as a photodetector, measures the fluorescence level, which corresponds to the amount of carbon dioxide released by the microorganisms. The system 100 can include an excitation filter 114 or an emission filter 116 to filter wavelengths or wavelength ranges. A processor 112 can be included in the system 100 to process the fluorescence levels to determine the amount or quantity of microbial growth in the sample. Such systems present several limitations, as described herein.

[0016] Device, system, and method embodiments described herein overcome at least some of the limitations and drawbacks of currently available culture measurement systems. In particular, device, system, and method embodiments relate to culture measurement systems having a sensor positioned on the interior surface of a culture vial that directly measures the pH of a sample placed in the culture vial. The sensor can be a pH sensor located within the vial, incorporated into a reactive label located within the vial, or incorporated into the measurement vial material itself. Also provided herein are methods of using the culture measurement systems, for example, for determining pH, determining the presence, variability, or quantity of pathogens, or analyzing analytes in a sample. Additionally, methods of manufacturing the culture measurement devices and systems are provided.

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

[0018] In conventional incubation measurement systems, the output of the measurement system at any particular time is generated based on the ratio of the current detector reading to the initial detector reading taken 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. The detector reading at any time is reading and the initial detector reading is defined as i reading #1 and further define the time at which the initial detector reading was taken as t reading #1 , the variation in the measurement system reported readings presented to the end user can be expressed as: Variation in measurement system reported readings = Δ(i reading / i reading #1 )+Δt reading #1 As shown in this equation, the variation in the measurement system reported readings is expressed as "i reading #1" is any variation in the initial system reading. This variation may reduce the sensitivity of the measurement system. For example, a larger variation in the output measurement may be required to distinguish a variation in the output signal reading from a test sample as being the result of the presence of a microorganism rather than the result of detector variation. 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 measurements of a sample, such as an absolute measurement of pH. Absolute measurements are obtained because the sensor incorporated into 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 mixed into the material used to manufacture the culture vial, optionally at a specified concentration. In some embodiments, the sensor or indicator compound is responsive to excitation or interrogation of fluorescence or phosphorescence by the energy source of the colorimeter system. In some embodiments, the sensor or indicator compound is excited, and the excitation signal corresponds to a property or characteristic of the sample, such as the pH level of the sample. In any of these embodiments, the incorporation of a sensor or indicator compound eliminates the need to take a time-based reference reading or a reading against another reference point, such as a standard analytical reference.

[0019] In conventional culture measurement systems, there is often a delay between the time a sample is drawn and injected into a test vial and the time the vial is placed into the measurement system. In some cases, the inoculated vial is placed into the measurement system several hours or even days later, for example, after a weekend. That is, an initial detector reading may not be obtained for 24 to 72 hours after the vial is inoculated with the sample. The period between when the sample is placed into the vial and when the vial is placed into the measurement device is commonly referred to as the vial introduction delay (DVE). The DVE period may allow for bacterial or other microbial growth prior to the vial's placement into the measurement system. Bacterial or other microbial growth prior to placement into the measurement system may affect the initial detector reading baseline signal and, consequently, the test data normalized using the initial detector reading baseline signal. DVE is shown graphically in Figure 5. As shown in Figure 5, a sample is drawn at an initial time point and then analyzed at a later time point (e.g., analyzed at time 0, referred to as "bottle introduction," meaning placement into the reader). Growth detection occurs following bottle introduction. Growth detection can be reliably analyzed when there is no delay between sampling and bottle introduction. In contrast, delaying bottle introduction from the sampling time results in difficult and uncertain growth detection. During the time between sampling and bottle introduction, pathogens in the sample undergo undetectable pathogen growth. For example, in systems that require relative measurements of fluorescence to detect bacterial growth, this undetectable growth may be due to a lack of detectable fluctuation (e.g., FIG. 5, 24-hour incubation delay at 35°C). 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 ability to set an output signal threshold level from the sensor or indicator compound. In some embodiments, a signal higher than the output signal threshold level provides immediate feedback to the clinician that an excessive amount of pathogen growth has occurred in the test sample, necessitating corrective action of obtaining another test sample.This immediate feedback saves time in detecting delayed vial introduction.

[0020] In conventional incubation measurement systems, the initial detector reading baseline signal may be affected by temperature fluctuations in the sensor. Temperature fluctuations around the sensor may be caused by external factors such as insufficient control of the environment surrounding the sensor and / or sensor equipment by the end user, fluctuations in vial temperature after introduction into the system, and air movement through the measurement system. These temperature fluctuations affect the partial pressure of gas in the vial, the rate of gas diffusion at the sensor, the absorption of the pH indicator, and signal emission (such as fluorescent, phosphorescent, or colorimetric emission). Sensor temperature fluctuations may require compensation to provide an accurate reading. In some embodiments, the devices, systems, and methods described herein reduce or eliminate measurement fluctuations due to temperature fluctuations by using a pH sensor that is insensitive to temperature over the temperature range to which the incubation sample is exposed. For example, in some embodiments, the pH sensor has a sensitivity of ±0.5 pH or less at temperatures between 10°C and 50°C. For example, the sensitivity of the pH sensor may vary 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 amounts, or a range of pH changes defined by any two of these values, at temperatures of 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., or 50° C., or a range of temperatures defined by any two of these values. In some embodiments, incorporation of the sensor into the culture vial reduces temperature-dependent variables, thereby improving the accuracy of measurements taken during temperature fluctuations, since an improved pH sensor having only low temperature sensitivity is used rather than conventional complex polymer-based sensors and pH sensors containing pH indicators and fluorescent compounds.

[0021] In conventional culture measurement systems, measurement and data processing techniques can result in delays in detecting the presence of the analyte of interest. Signal fluctuations from noise sources (such as user interference and temperature fluctuations) can appear as biological growth. Algorithms used to process detector data can compensate for these signal fluctuations using moving averages. Using a moving average to smooth the signal can reduce random noise, but it can also delay the detection of signal fluctuations caused by biological growth. Optical blood culture sensor systems must also distinguish impulse noise (such as bottle movement and rough drawer opening and closing) from biological growth; therefore, algorithms processing the detected signal in these systems employ some form of delay to ensure, for example, that measured signal fluctuations are sustained. Such sustained signal fluctuations are more likely to occur when the signal fluctuation is due to biological growth in the blood culture bottle rather than impulse noise. However, this embedded delay can contribute to a longer latency between the time the sample is drawn and the time the blood culture test result is generated. Thus, the signal-to-noise ratio can be high enough to accurately measure samples when analyzed over a period longer than 10 minutes. In contrast, in some embodiments of the devices, systems, and methods described herein, the signal-to-noise ratio for measuring a sample requires only one, two, or three measurements within a time period of less than 5 minutes, e.g., less than 10, 20, 30, 40, 50, or 60 seconds, or less than 1, 2, 3, 4, or 5 minutes, or within a range defined by any two of these values. Thus, in some embodiments, these systems, methods, and devices reduce the time delay to detection due to the absolute measurement of pH and the elimination of calibration. Some embodiments of these systems reduce the incidence of false-negative test readings due to the detection of positive cultures that would not previously be detected due to the time delay to detection. In particular, when the detection time is delayed, the exponential growth portion of the growth curve may already have occurred prior to measurement.

[0022] In conventional culture measurement systems, the sensors used employ multi-component chemical-based formulations that may contain more than 10 components. Any variation in the chemical properties or purity of a single component of the sensor can adversely affect sensor performance. Furthermore, any delay or interruption in the supply of a single component of the sensor can result in a stop in sensor production and, therefore, a delay in the production of culture vials. For example, when a single component is no longer available, manufacturing can be stopped or delayed, thereby adversely affecting product yield. 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 sensor incorporated into the culture vial. In some embodiments, the sensor comprises only one, two, three, or four or fewer components.

[0023] In conventional incubation measurement systems, sensor manufacturing requires the steps of compounding, dispensing, and curing a sensor formulation. Each sensor manufacturing step may reduce the manufacturing consistency of the sensor or reduce the associated performance uniformity. Furthermore, each sensor manufacturing process can result in the production of out-of-tolerance sensors, reducing production yields and increasing product costs. These three manufacturing steps are performed sequentially, and therefore, any variation in each step propagates, resulting in cumulative variations in uniformity between sensors. In some embodiments, the devices, systems, and methods described herein eliminate the drawbacks associated with these sensor manufacturing steps. In particular, in some embodiments, the sensors of the systems and devices described herein do not require the steps of compounding a multi-component chemical system, dispensing such a system into a culture vial, or curing such a 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 manufacturing of chemical formulation-based sensors.

[0024] In conventional culture measurement systems, current normalization techniques fail to provide real-time feedback regarding the signal quality of the measurement system components. This system architecture of the measurement system can result in incorrect measurements. For example, some light source components for exciting fluorescent materials in the sensor can degrade in emission intensity over their useful life. The performance of the optical detector can also degrade. Variations in either the energy emission from the light source components or the sensitivity of the optical detector can cause the measurement system to report inaccurate test data. In some embodiments, the devices, systems, and methods described herein enable emission intensity to serve as a real-time quality indicator for the assay measurement system. If the emission intensity is too high or too low, the sensor measurement instrument can be programmed to automatically ignore the measured assay test vial, or the vial measurement test station can display an intensity outside of a specified value range. For example, the system may include a processor configured to ignore measurement readings that are higher or lower than a certain range, such as measurement readings that are 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x higher than a normally expected reading, or 0.5x, 0.1x, 0.05x, or 0.01x lower than a 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 overcome shortcomings associated with conventional culture measurement systems.

[0026] Culture Measurement Device and System Embodiments Embodiments provided herein relate to culture measurement devices and systems. In some embodiments, the device includes a culture vial containing a sensor. In some embodiments, the system further includes a reader or detector. In some embodiments, the sensor measures the pH of a sample placed in the vial. In some embodiments, the pH measurement correlates to the growth of pathogens in the sample.

[0027] Some embodiments provided herein relate to a culture measurement device including a culture vial including 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 pH measurement to a reader. In some embodiments, the reader is configured to acquire the signal of the pH measurement from the pH sensor. The signal of the pH measurement can be transmitted to the reader wirelessly or through an electrical lead. In embodiments in which the signal is transmitted wirelessly, the pH measurement can be acquired by the pH sensor, and a signal indicative of the pH level, the presence, absence, or fluctuation in the amount of a pathogen, or the level of an analyte is transmitted to the reader. In embodiments in which the signal is transmitted through an electrical lead, the electrical lead can pass through the culture vial, either through a bottom portion of the culture vial or through a septum of the culture vial. The electrical lead can serve as a conduit for transmitting the signal to the reader and can also serve as a conduit for providing 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 provides power to the electrical leads of the pH sensor and receives current readings from the pH sensor. In some embodiments, the pH sensor is configured to be wirelessly powered.

[0028] In some embodiments, a signal indicative of the pH level, the presence, absence, or fluctuation in the amount of pathogens, or the analyte level is transmitted through the electrical leads to a reader. In any of these embodiments, the reader includes a processor capable of correlating the pH level to the quantity or quantity fluctuation of pathogens. In any of these embodiments, the reader includes a display that indicates the measurement results, e.g., the pH level, the quality of the sample, or the presence or quantity of pathogens, to a user. In some embodiments, the reader is configured to wirelessly transmit these data, including the test results, to a data management system or 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 positioned to separate it from a sample disposed 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 coming into direct contact with the pH sensor. In some embodiments, the permeable membrane is configured to allow the passage of certain components, such as ions, but to prevent the passage of all other components, so that the pH sensor can have the ability to detect analytes in the sample without direct contact with the sample, for example, to avoid pH sensor fouling.

[0031] The permeable membrane can comprise any material suitable for allowing permeability of specific ions. In some embodiments, the permeable membrane comprises a polymeric material. Materials that can be used for the permeable membrane 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), polyether ether ketone (PEEK), cellulosic polymer, or polysulfone, or combinations thereof. In some embodiments, the permeable membrane is a bioprotective layer that is selectively permeable, allowing 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 an interior surface thereof. In some embodiments, the system further includes a detector operable to detect a signal from the reactive label. In some embodiments, the reactive label is positioned on the interior surface of the culture vial such that it contacts a sample when the sample is placed in the culture vial.

[0033] In some embodiments, the reactive label comprises a permeable membrane positioned to separate it from a sample disposed in an incubation 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 coming into direct contact with the reactive label. In some embodiments, the permeable membrane is configured to allow the passage of certain components, such as ions, but to prevent the passage of all other components, such that the reactive label has the ability to detect an analyte in a sample without direct contact with the sample.

[0034] In some embodiments, the reactive label comprises a pH-responsive agent. A pH-responsive agent is an agent that responds to a proton flux contacting the reactive label, thereby changing the spectral characteristics of the reactive label. For example, the pH-responsive agent can be a compound that emits an absorbance intensity that varies proportionally with the pH of the sample. The absorbance emission can be a fluorescent, phosphorescent, or colorimetric light emission resulting from excitation or interrogation of the fluorescent or phosphorescent (luminescent) light by an energy source of the colorimeter system. Suitable pH-responsive agents can include pigments, dyes, fluorescent dyes, phosphorescent dyes, chromophoric 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 a fluorescent, phosphorescent, or colorimetric light excitation source, such as a light emitting diode. The detector can be a fluorescent, phosphorescent, or colorimetric light detector, such as a photomultiplier tube.

[0036] An embodiment of an incubation system with a reactive label is shown in Figure 2. As shown in Figure 2, incubation measurement system 200 includes an incubation vial 202 and a reactive label 206. A sample 204 is placed in incubation vial 202, and an analyte measurement (such as pH) is measured at reactive label 206 through a permeable membrane. An excitation source 208 excites reactive label 206, exciting the absorption of a pH-sensitive agent on reactive label 206. The pH-sensitive agent emits an absorbance intensity signal having an intensity that varies proportionally with the pH of sample 204, and this signal is detected by 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 in the culture vial 202. The pH of the sample differs or fluctuates based on the presence or absence of pathogens in the sample, and thus the measured pH value correlates to the presence or absence of the pathogen. The culture vial 202 includes a reactive label 206 that includes a pH-sensitive 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 at one or more wavelengths or ranges of wavelengths that excite the pH-responsive agent of the reactive label 206. In certain embodiments, the excitation source 208 can include one or more light-emitting diodes (LEDs).

[0039] The detector 210 can be configured to detect an absorbance intensity signal emitted by the pH-sensitive agent of the reactive label 206 following excitation of the reactive label 206. The 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, the detector 210 can include a photovoltaic device, a photoresistive device, a photoconductive device, or any other device suitable for detecting an absorbance intensity signal emitted from the reactive label 206. In certain embodiments, one or more detectors 210 can be employed to measure the absorbance intensity signal emitted by the reactive label 206.

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

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

[0042] The pH-responsive agent used in system 200 can be selected based on the emission spectrum of excitation source 208 and / or the specifications of detector 210. In certain embodiments, the pH-responsive agent can include one or more fluorescent, phosphorescent, or colorimetric dyes, or other agents capable of providing a detectable signal that varies proportionally with pH changes. Such agents can include, for example, propyl red, p-nitrophenol, azolitomine, 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, nitramine, cresol purple, and methyl yellow fluorophores.

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

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

[0045] As an example, in certain embodiments, system 200 is configured to detect the absence, presence, or quantity fluctuations of pathogens in a sample placed in culture vial 202. In embodiments where it is desirable to monitor the absence, presence, or quantity fluctuations of pathogens, the pH-responsive agent in reactive label 206 is configured to undergo a change in absorbance when the pH fluctuates. As pathogens grow, CO2 is exhaled. CO2 can mix with the aqueous broth in vial 202 to produce carbon dioxide. The increased amount of carbon dioxide results in a decrease in pH. As the pH in vial 202 decreases, the absorbance of the pH-responsive agent decreases, thereby allowing more excitation energy to reach the pH-responsive agent in reactive label 206, resulting in an increase in signal emission intensity from the pH-responsive agent. Detector 210 can detect the increase in signal emission intensity, which can serve as an indirect measurement of an increase in CO2 concentration. As described above, CO2 concentration is directly correlated with pathogen growth. Thus, detection of an increase in signal intensity by detector 210 can indicate the presence of pathogens in the sample.

[0046] In certain embodiments, the measurement system 200 may further include a processor configured to perform signal processing to determine the presence of a pathogen based on changes in signal strength measured by the detector 210. In certain embodiments, the processor may be part of a computer system. Such a computer system may include one or more of a memory, an input, and a display. The memory, which may include read-only memory (ROM) or both ROM and random access memory (RAM), may be configured to provide instructions and data to the processor. For example, the memory may 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 the data, including the test results, to a data management system or cloud data storage location, including, 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 including an indicator compound incorporated directly into the material of the culture vial. In some embodiments, the indicator compound is configured to be responsive to fluorescence or phosphorescence excitation or interrogation by 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 operable to detect excitation from the indicator compound. In some embodiments, the indicator compound is incorporated into the interior 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, e.g., prior to injection molding of the culture vial. In some embodiments, the indicator compound is incorporated into the inner layer of a plastic culture vial or into the plastic liner layer of a glass culture vial. In some embodiments, the indicator compound is positioned on the interior surface of the culture vial so as to contact a 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, the culture vial containing the indicator compound further comprises a permeable membrane positioned to separate the indicator compound from a sample disposed 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 indicator compound, thereby preventing the sample from coming into direct contact with the indicator compound. In some embodiments, the permeable membrane is configured to allow the passage of certain components, such as ions, but prevent the passage of all other components, such that the indicator compound can function to detect analytes in a sample without direct contact with the sample. In some embodiments, the permeable membrane protects all or a portion of the interior of the vial.

[0049] In some embodiments, the culture vial containing the indicator compound further comprises an impermeable membrane. In some embodiments, the impermeable membrane covers all but the sensor area of ​​the interior surface of the culture vial such that the sample can only interact with the sensor area of ​​the culture vial, and only the sensor area can sense the analyte in the sample and emit a detectable signal. The impermeable membrane can comprise any material that prevents or inhibits material from flowing through the membrane, and can include a variety of non-porous plastic or polymeric 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 proportionally with 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, chromophoric dyes, organic compounds, or inorganic compounds.

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

[0052] An embodiment of an incubation system incorporating an indicator compound is shown in FIG. 3. As shown in FIG. 3, incubation measurement system 300 includes an incubation vial 302 and an indicator compound 306. Indicator compound 306 can be incorporated on the interior surface of incubation vial 302 or can be incorporated into an inner liner lining the interior surface of the incubation vial. A sample 304 is placed in incubation vial 302, and an analyte measurement (such as pH) is measured by measuring an absorbance signal using detector 310. An excitation source 308 excites indicator compound 306, causing the indicator compound 306 to absorb. Indicator compound 306 emits an absorbance intensity signal having an intensity that varies proportionally with the pH of sample 304, which is detected by detector 310. The excitation and detection of the indicator compound can occur in any portion of the incubation vial incorporating the indicator compound; therefore, detection does not require any specific location in the incubation vial. In contrast, the culture vial depicted in Figure 2 requires excitation and sensing of reactive labels located at locations within its interior.

[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 in the culture vial 302. The pH of the sample differs or fluctuates based on the presence or absence of pathogens in the sample, and thus, the measured pH is correlated to the presence or absence of the pathogen. The culture vial 302 includes an indicator compound 306 that includes a pH-responsive agent. The vial 302 can contain a culture medium capable of promoting 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 at one or more wavelengths or ranges of wavelengths that excite the pH-responsive agent of the indicator compound 306. In certain embodiments, the excitation source 308 can include one or more light-emitting diodes (LEDs).

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

[0056] The system 300 may include one or more excitation filters 314 configured to filter light from the excitation source 308 so as to provide only a particular wavelength or range of wavelengths of light to the fluorescent material. For example, in certain embodiments, the one or more excitation filters 314 may filter light to provide a particular wavelength or range of wavelengths to the indicator compound 306 that corresponds to the absorption spectrum of a pH-responsive drug.

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

[0058] The indicator compound 306 used in the 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 pH-responsive agent, such as a fluorescent, phosphorescent, or colorimetric dye, or other agent capable of providing a detectable signal that varies proportionally with pH changes. Such agents can include, for example, propyl red, p-nitrophenol, azolitomine, 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 fluorophores.

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

[0060] The optical change in indicator compound 306 can act as an optical filter that excites or changes the amount of light emitted from indicator compound 306. Accordingly, changes in the concentration of the analyte of interest in the sample can result in a variation in the signal detected by detector 310 by changing the optical properties of indicator compound 306. As a result, changes in the intensity of the signal detected by detector 310 can indicate changes 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 fluctuations of a pathogen in a sample disposed in culture vial 302. In embodiments where it is desirable to monitor the absence, presence, or quantity fluctuations of a pathogen, indicator compound 306 is configured to undergo a change in absorbance when pH fluctuates. As pathogens grow, CO2 is exhaled. CO2 can mix with the aqueous culture medium in vial 302 to produce carbon dioxide. The increased amount of carbon dioxide results in a decrease in pH. As the pH in 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 signal emission intensity from indicator compound 306. Detector 310 can detect the increase in signal emission intensity, which can serve as an indirect measurement of an increase in CO2 concentration. As described above, CO2 concentration is directly correlated with pathogen growth. Thus, detection of an increase in signal intensity by detector 310 can indicate the presence of a pathogen in the sample.

[0062] In certain embodiments, the measurement system 300 may further include a processor configured to perform signal processing to determine the presence of a pathogen based on changes in signal strength measured by the detector 310. In certain embodiments, the processor may be part of a computer system. Such a computer system may include one or more of a memory, an input, and a display. The memory, which may include read-only memory (ROM) or both ROM and random access memory (RAM), may be configured to provide instructions and data to the processor. For example, the memory may 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 the data, including the test results, to a data management system or cloud data storage location, including, for example, 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, serum sample, cerebrospinal fluid sample, or other biological sample in which detection of an analyte is desired, a food sample, or an environmental sample, or a culture medium of any of these samples. In some embodiments, the sample is a blood sample, and is analyzed to determine pathogens 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 the sample within an existing measurement platform. In any of the embodiments provided herein, the culture vial is 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 allows for optical interrogation of the sample, thus allowing an optical signal to pass through the culture vial, e.g., fluorescence, phosphorescence, colorimetric light emission.

[0065] Embodiments of methods for detecting an analyte Some embodiments provided herein relate to methods for detecting an analyte in a sample. In some embodiments, the method includes inoculating the sample into a culture vial 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 at subsequent time points to provide a measure of pH change over time. For example, pH measurements 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 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 a culture measurement device and system including a pH sensor positioned on the interior surface of a blood culture vial, e.g., as described above and in one or more of the embodiments elsewhere herein. In some embodiments, the method includes inoculating a culture vial having a pH sensor positioned on the interior surface with the sample, incubating the sample for a period of time to allow the pH sensor to equilibrate, and measuring a signal from the pH sensor in a reader. In some embodiments, the reader is configured to obtain the signal from the pH sensor 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 read-only memory (ROM) or both ROM and random access memory (RAM), can be configured to provide instructions and data to the processor, e.g., as described above and elsewhere herein. 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 pH measurement is determined directly using a pH sensor, which can be an ISFET or an ISE.

[0067] In some embodiments, a method for detecting an analyte in a sample utilizes a culture measurement device and system including a reactive label positioned on the inner surface of a culture vial, for example, as described above and in embodiments elsewhere herein. In some embodiments, the method includes inoculating the 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 at a detector. In this embodiment, a measurement of pH is determined by measuring a signal intensity that correlates to 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] 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 the 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-sensitive agent, as described above with reference to FIG. 2.

[0069] After the culture vial is inoculated, process 400 moves to step 420, where excitation light at the excitation frequency of the pH-responsive agent is transmitted to the test vial. The excitation frequency can be a frequency or range of frequencies that is within the absorption spectrum of the pH-responsive 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-responsive agent can emit an absorption intensity signal due to responsiveness to fluorescent or phosphorescent (luminescent) excitation or interrogation by an energy source of the colorimeter system. This signal can be measured by a detector, such as detector 210 described with respect to FIG. 2. In certain embodiments, measuring the intensity of the signal in step 430 includes filtering the signal with an emission filter.

[0071] Although detection of the presence of an analyte of interest in a blood culture sample has been described with respect to process 400 illustrated in FIG. 4, one skilled in the art will understand that the methods described herein are not limited to blood culture samples, but may be applicable 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 utilizes an incubation measurement device and system including an incubation vial containing an indicator compound incorporated on the interior surface of the incubation vial, for example, as described above and in embodiments elsewhere herein. In some embodiments, the method includes inoculating the sample into the incubation vial having the indicator compound incorporated on the interior surface, incubating the sample for a period of time to allow the indicator compound to equilibrate, exciting the indicator compound with an excitation source, and detecting an absorbance intensity signal at a detector. In this embodiment, a measurement of pH is determined by measuring the signal intensity, which correlates to 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 indicator compound.

[0073] In any of the embodiments of the method for detecting an analyte, as the pathogen grows, CO2 is exhaled. The CO2 can mix with the aqueous broth in the culture vial to produce carbon dioxide. The increased amount of carbon dioxide results in a decrease in pH. The decrease in pH is measured using the methods described herein, and thus, the detection of pH correlates with the degree of pathogen presence in the sample.

[0074] In any of the embodiments of the method for detecting an analyte, equilibration of the sensor (pH sensor, reactive label, or indicator compound) occurs over a period of time including 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 a range of time defined by any two of these values. A second or subsequent measurement can be taken at a second time following the first measurement. The second or subsequent measurement can be taken at 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, or 60 minutes, 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 time point within a range defined by any two of these values. Subsequent time points may also be employed in a time period favorable for determining the presence of pathogens in the sample.

[0075] Embodiments of methods for manufacturing culture measurement devices and systems Some embodiments provided herein relate to methods of manufacturing any one or more of the device and system embodiments described herein. In some embodiments, a culture vial is obtained and a pH sensor is incorporated into the interior surface of the culture vial such that when a sample is inoculated into the culture vial, for example, as described in one or more of the above embodiments and elsewhere herein, the pH sensor is immersed in the sample. In some embodiments, the culture vial includes a port through which the electrical lead of the pH sensor passes through the culture vial. In some embodiments, the port is located in a bottom portion of the culture vial, immediately adjacent to the location of the pH sensor. In some embodiments, the port is located in a septum that closes the culture vial.

[0076] In some embodiments, a culture vial is manufactured having a reactive label disposed therein, e.g., as described in one or more of the above embodiments and elsewhere herein. In some embodiments, the reactive label is positioned on the interior surface of the culture vial. In some embodiments, the reactive label includes a permeable membrane that serves as a bioprotective layer between the reactive label and the sample in the culture vial. In some embodiments, the reactive label is adhered to the interior surface of the culture vial by an adhesive, such as a double-layer tape or other biocompatible adhesive.

[0077] In some embodiments, a culture vial is manufactured having an indicator compound incorporated into its interior surface, e.g., as described in one or more of the above-described embodiments and elsewhere herein. In some embodiments, the indicator compound is mixed with the culture vial material prior to manufacture of the culture vial, such that the indicator compound forms an integral component of the culture vial during manufacture. 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 lining the interior 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 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 into the entire culture vial or only a portion thereof, e.g., the bottom portion of the culture vial, one or more walls of the culture vial, or a separate portion or region of the culture vial. In some embodiments, the culture vial with the indicator compound further comprises a permeable membrane that covers all or a portion of its interior and acts as a bioprotective layer between the indicator compound and the sample in the culture vial. In some embodiments, the culture vial with the indicator compound further comprises an impermeable membrane that covers all or a portion of its interior. The area without the impermeable membrane is the sensor area, where the sample can interact with the indicator compound incorporated within the culture vial.

[0078] In any of the embodiments for manufacturing culture measurement devices and systems, a particular culture vial (e.g., whether including a pH sensor, reactive label, or indicator compound described in one or more of the above embodiments and elsewhere herein) can be manufactured for use within an existing measurement system. For example, the culture vial can be the same as or similar in size and shape to an existing culture vial so that it can be seamlessly integrated 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 samples therein can be measured using the BD BACTEC® system.

[0079] The implementations disclosed herein provide devices, systems, and methods for measuring analytes in a sample using a pH sensor, reactive label, or 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 benefits discussed above, embodiments of the devices, systems, and methods described herein can be advantageously implemented without modifying consumable components within current blood culture measurement systems. For example, implementation of the techniques of the present disclosure can be implemented without changing the nature of the assay bottles containing the culture or nutrient solution contents.

[0081] It will be further understood that embodiments of the presently disclosed technology are not limited to blood culture measurement devices and systems, but may be applied to other types of optical detection devices or systems.

[0082] The functions and configurations of a reader, detector, or processor described herein can be stored as one or more instructions on a processor-readable or computer-readable medium. The term "computer-readable medium" refers to any available medium accessible by a computer or 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 usable for storing desired program code in the form of instructions or data structures or accessible by a computer. As used herein, a disk includes a compact disk (CD), laser disk, optical disk, digital versatile disk (DVD), floppy disk, and Blu-ray® disk; disks typically replicate data magnetically, while disks replicate data optically using a laser. It should be noted that a computer-readable medium can be tangible and non-transitory. The term "computer program product" refers to a combination of a computing device or processor and code or instructions (e.g., a "program") that can be executed, processed, or computed by the computing device or processor. As used herein, the term "code" may mean software, instructions, code, or data that is executable by a computing device or processor.

[0083] In one or more embodiments of any of the devices, systems, or methods, pH value measurements can be wirelessly transmitted to system components for analysis of such data to derive bacterial growth curves. In some embodiments, transmission of pH analysis data is transmitted to a centralized system or laboratory, such as an information system or cloud repository, so that the analysis is accessible to researchers, patients, or clinicians.

[0084] Software or instructions may be transmitted over a transmission medium. For example, if the software is transmitted from a website, a 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 transmission media.

[0085] The methods disclosed herein include one or more steps or actions to provide the described method. Method steps and / or actions may be interchanged with one another without departing from the scope of the present disclosure. In other words, unless a specific order of steps or actions is required for the proper operation of the described method, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the present disclosure.

[0086] The term "determining" encompasses a wide range of actions, and thus "determining" can include calculating, operating, processing, deriving, examining, referencing (e.g., referencing in a table, database, or another data structure), and ascertaining, etc. Similarly, "determining" can include accepting (e.g., accepting information) and accessing (e.g., accessing data in a memory), etc. Additionally, "determining" can include resolving, selecting, choosing, establishing, etc.

[0087] In the foregoing description, specific details have been presented to provide a thorough understanding of the examples. However, those skilled in the art will appreciate that the examples may be practiced without these specific details. For example, electrical components / devices may be shown in block diagrams in order not to obscure the examples with unnecessary detail. In other instances, such components, other structures, and techniques may be shown in detail to more fully explain the examples.

[0088] This specification includes headings to aid in locating various sections for reference. These headings are not intended to limit the scope of the concepts described therein. Such concepts may have applicability throughout the entire specification.

[0089] It should also be noted that the above examples may be described as processes depicted as flowcharts, flow diagrams, finite state diagrams, structure diagrams, or block diagrams. While a flow diagram may describe operations as sequential processes, many of these operations may be performed in parallel or simultaneously, and processes may be repeated. Additionally, the order of operations may be rearranged. A process terminates when the operation is completed. A process may correspond to a method, a function, a procedure, a subroutine, a subprogram, etc. When a process corresponds to a software function, the termination corresponds to the function returning to the calling function or the main function.

[0090] The foregoing description of implementations of the present disclosure is provided to enable any person skilled in the art to make or use embodiments of the present disclosure. Various modifications to these implementations will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other implementations without departing from the spirit or scope of the present disclosure. Thus, the present disclosure is not intended to be limited to the implementations shown herein but is to be accorded the widest scope consistent with these principles and novel features disclosed herein.

Claims

1. 1. A culture vial for measuring blood culture pH, comprising: a pH sensor positioned on an interior surface of the blood culture vial and configured to transmit a signal of a pH measurement; a culture vial containing

2. 2. The culture vial of claim 1, wherein the pH sensor is an ion-specific field effect transistor (ISFET) or an ion-selective electrode.

3. 3. The culture vial of claim 1, further comprising a permeable membrane layer separating the pH sensor from the contents of the blood culture vial.

4. The culture vial of claim 3 , wherein the permeable membrane comprises a polymeric material.

5. 5. The culture vial of claim 3 or 4, wherein the permeable membrane comprises Nafion, polyurethane, or a cellulosic material.

6. 6. The culture vial of claim 1, wherein the blood culture vial is made of plastic or glass.

7. A blood culture vial according to any one of claims 1 to 6; a reader configured to acquire the signal from the pH sensor; Including, the system.

8. 8. The system of claim 7, wherein the pH sensor includes an electrical lead that passes through the blood culture vial and connects to the reader.

9. 9. The system of claim 8, wherein the electrical leads pass through a bottom portion of the blood culture vial or through a septum of the blood culture vial.

10. The system of claim 7 , wherein the pH sensor is configured to communicate wirelessly with the reader.

11. The system of claim 10 , wherein the reader is configured to wirelessly transmit analytical data to an information management system or a cloud data storage location.

12. The system of claim 7 , wherein the pH sensor is configured to be wirelessly powered.

13. 1. A blood culture vial for measuring blood culture pH, comprising: a reactive label positioned on an interior surface of the blood culture vial and configured to emit an absorbance intensity signal corresponding to a pH measurement; blood culture vials, including

14. 14. The culture vial of claim 13, wherein the reactive label comprises a pH-responsive agent.

15. 15. The culture vial of claim 14, wherein the pH-responsive agent is fluorescent, phosphorescent, or colorimetric.

16. 16. The culture vial of any one of claims 13 to 15, wherein the reactive label comprises a permeable membrane that separates the reactive label from the contents of the blood culture vial.

17. 17. The culture vial of claim 16, wherein the permeable membrane comprises a polymeric material.

18. 18. The culture vial of claim 16 or 17, wherein the permeable membrane comprises Nafion, polyurethane, or a cellulosic material.

19. 1. A blood culture vial for measuring blood culture pH, comprising: an indicator compound incorporated directly into the blood culture vial; blood culture vials, including

20. 20. The culture vial of claim 19, wherein the indicator compound is a pH-responsive agent configured to be responsive to fluorescent, phosphorescent, or colorimetric excitation.

21. 21. The culture vial of claim 19 or 20, wherein the indicator compound is a pigment, a dye, an organic compound, or an inorganic compound.

22. 22. The culture vial of any one of claims 19 to 21, comprising an impermeable membrane covering a portion of the interior of the culture vial.

23. 23. The culture vial of any one of claims 13 to 22, wherein the blood culture vial is plastic or glass.

24. A culture vial according to any one of claims 13 to 23; one or more detectors configured to measure the intensity of one or more signals emitted from the pH-responsive agent after exposure to the interrogating energy source; Including, the system.

25. 25. The system of claim 24, further comprising a wireless transmitter configured to wirelessly transmit the analytical data to an information management system or a cloud data storage location.

26. 1. A method for measuring pH in a blood culture sample, comprising: inoculating a blood culture vial according to any one of claims 1 to 6 or 13 to 23 with a blood culture sample in a blood culture system according to any one of claims 7 to 12 or 24 or 25; measuring the pH of the blood culture sample by detecting a pH measurement signal; A method comprising:

27. 27. The method of claim 26, wherein the pH measurement signal is obtained by measuring a fluorescent, phosphorescent, or colorimetric signal emitted from a sensor in the blood culture vial.

28. 28. The method of claim 26 or 27, further comprising measuring the pH of the blood culture sample at a second or subsequent time point.

29. 27. The method of claim 26, wherein the measured pH of the blood culture sample correlates with a degree of pathogen burden within the blood culture sample.

30. 30. The method of claim 29, wherein the pathogen is a bacterium or a fungus.

31. 31. A method according to any one of claims 26 to 30, wherein the system includes a processor configured to ignore measurements above or below a sensitivity range.

32. 32. The method of any one of claims 26 to 31, further comprising wirelessly transmitting the analytical data to an information management system or a cloud data storage location.

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