SYSTEM AND METHOD FOR SIGNAL CALIBRATION IN A SENSOR SYSTEM - Patent application

Abstract

[0003] A method and system for compensating for the effects of gravity and fluid composition in a magnetic biosensor system is provided. In one example, the sensor system includes a sample container configured to receive a sample containing an analyte to be tested, the sample container including a detection surface and a plurality of signal-generating elements within the sample container, the detection surface including a binding surface partially functionalized with capture elements capable of directly and / or indirectly binding to the analyte and / or the plurality of signal-generating elements. The sensor system further includes a memory storing instructions executable by a processor to acquire background data including a sensor signal from one or more background regions of the detection surface, acquire sample data including the sensor signal from the binding surface, and perform correction of the sample data based on the background data.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present specification relates generally to systems and methods for sensor systems for detecting an analyte in a sample, and more particularly to compensating for signal fluctuations that affect the detection of the analyte. [Background technology]

[0002] Biosensors can detect specific target molecules, called analytes, in samples, whose quantities or concentrations are typically low, sometimes in the nanogram per milliliter range. To detect these molecules, functionalized labels or detection tags, such as enzymes, fluorophores, or magnetic beads, are utilized. In magnetically labeled biosensors, the determination of the presence of an analyte (such as a drug or cardiac marker) is based on molecular capture and labeling with magnetic particles or beads. The magnetic beads are disposed within a sample chamber of a sample cartridge. At least a portion of the sensor surface within the sample chamber is prepared for analyte detection. For example, the sensor surface may include one or more regions to which capture elements (e.g., antibodies) configured to bind to the analyte are immobilized. To perform a test, the sample is placed in the cartridge, and any analyte in the sample binds to both the magnetic beads and the capture elements on the binding surface.

[0003] Magnetic attraction of beads, also known as actuation, can improve the performance, e.g., speed, of biosensors in point-of-care applications. The direction of magnetic attraction can be either toward or away from the surface where the actual measurement is performed. In the first case, magnetic actuation can increase the concentration of magnetic particles near the sensor surface (magnetic particles can bind to corresponding capture elements, such as antibodies, on the sensor surface via the analyte) and accelerate the binding process of magnetic particles on the sensor surface. In the second case, unbound magnetic particles (e.g., magnetic particles not bound to capture elements on the sensor surface) are removed from the surface, a process known as magnetic washing. Once magnetic washing is complete, the concentration of analyte in the sample is determined by measuring the number of magnetic beads bound to the capture elements on the sensor surface. For example, a light source is directed toward the area of ​​the sensor surface where the capture elements are immobilized, generating total internal reflection light. The magnetic particles on the sensor surface can scatter and / or absorb the total internal reflection light, which is detected by a detector and used to determine the concentration of target molecules in the sample. Summary of the Invention [Means for solving the problem]

[0004] In one embodiment, the sensor system comprises a sample container configured to receive a sample containing an analyte to be tested, the sample container comprising a detection surface and a plurality of signal generating elements within the sample container, the detection surface comprising a binding surface partially functionalized with capture elements capable of binding directly and / or indirectly to the analyte and / or the plurality of signal generating elements. The sensor system further comprises a memory storing instructions executable by a processor to acquire background data comprising a sensor signal from one or more background regions of the detection surface, acquire sample data comprising the sensor signal from the binding surface, and perform a correction of the sample data based on the background data.

[0005] To the accomplishment of the foregoing and related ends, certain illustrative aspects of systems are described herein in connection with the following description and the annexed drawings. The discussed features, functions, and advantages may be achieved independently in various embodiments of the disclosure or combined in yet other embodiments, further details of which may be found by reference to the following description and drawings. This Summary is provided to introduce in a simplified form a selection of concepts further described below in the Detailed Description. This Summary is not intended to identify key or essential features of any subject matter described herein. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 is a schematic diagram illustrating a general setup of a sensor system according to the present disclosure. [Figure 2] 1A and 1B illustrate schematic diagrams of an exemplary sample cartridge of a sensor system having multiple binding surface areas according to the present disclosure. [Figure 3] 1A and 1B illustrate schematic diagrams of an exemplary sample cartridge of a sensor system having multiple binding surface areas according to the present disclosure. [Figure 4] 1A and 1B illustrate schematic diagrams of an exemplary sample cartridge of a sensor system having multiple binding surface areas according to the present disclosure. [Figure 5] FIG. 5 is a schematic diagram of the exemplary sample cartridge of FIGS. 2-4, with multiple background regions located outside the binding surface region. [Figure 6] FIG. 1 is a schematic diagram illustrating an exemplary distribution of signal generating elements within a sample cartridge according to the present disclosure. [Figure 7] 1 is a flowchart illustrating a method for testing a sample with a sensor system with background correction measured in a background region outside the binding surface region according to the present disclosure. [Figure 8] 10A-10C are graphs showing measured parameters of an analyte using a sensor system with and without background correction performed in accordance with the present disclosure. [Figure 9]10A-10C are graphs showing measured parameters of an analyte using a sensor system with and without background correction performed in accordance with the present disclosure. [Figure 10] 10A-10C are graphs showing measured parameters of an analyte using a sensor system with and without background correction performed in accordance with the present disclosure. [Figure 11] 10A-10C are graphs showing measured parameters of an analyte using a sensor system with and without background correction performed in accordance with the present disclosure. [Figure 12] 10A-10C are graphs showing measured parameters of an analyte using a sensor system with and without background correction performed in accordance with the present disclosure. [Figure 13] FIG. 5 is a schematic diagram of the exemplary sample cartridge of FIGS. 2-4, with multiple background regions located within the binding surface region. [Figure 14] 1 is a flowchart illustrating a method for testing a sample with a sensor system using background correction measured in a background region within a binding surface area according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0007] The following description relates to systems and methods for sensor systems, also referred to as microfluidic test systems or microelectronic sensor systems. The sensor system may be a magnetic sensor system that includes one or more sample containers containing functionalized signal-generating elements, e.g., antibody-labeled magnetic particles, configured to bind to specific target molecules (also referred to herein as analytes or analytes of interest), such as troponin or B-type natriuretic peptide (BNP). Each sample container has a sensor detection surface that is further functionalized with, e.g., the same and / or a different antibody bound to the signal-generating element, to form a binding surface at the detection surface. To measure the concentration of an analyte in a sample, such as blood or saliva, the sample is provided in the sample container, where it is mixed with the signal-generating element. In this manner, the signal-generating element can bind to the sensor binding surface via the analyte, and the number of signal-generating elements that bind to the sensor binding surface is a function of the concentration of the analyte.

[0008] In an example where the sensor system is a magnetic sensor system, the signal-generating elements may be magnetic particles, one or more magnetic elements may be located outside the sample container (e.g., below the sample container), and a magnetic field generated by the one or more magnetic elements may attract the magnetic particles to the sensor binding surface, promoting binding of the magnetic particle / analyte complexes to the sensor binding surface. Thus, the region of the sensor binding surface that binds the magnetic particle / analyte complexes may be based on the size and position of the magnetic elements and the variations in the magnetic field generated by the magnetic elements. Typically, the antibody / capture elements are immobilized on the sensor detection surface in individual regions, such as individual patches or spots. Furthermore, some sample containers are configured to facilitate detection of multiple analyte concentrations, so different capture elements may be present in different binding surface regions. Thus, the positioning of the binding surface region may be based on the magnetic field generated by the magnetic elements. For example, if the magnetic field has the highest magnetic flux density at the center of the sensor detection surface, the binding surface is located at the center of the sensor detection surface. In doing so, the magnetic elements may be concentrated in and near the binding surface region, increasing the signal measured by the detector.

[0009] However, other forces, such as gravity and / or forces generated during movement of the sensor system, may also act on the signal-generating element, which may affect the behavior of the signal-generating element during sample testing, thereby leading to variability in results. Furthermore, the mobility of the signal-generating element is affected by the sample fluid being tested. For example, the viscosity of the sample fluid or the content of other substances in the sample fluid, such as sucrose or proteins, may affect the mobility of the signal-generating element as well as the optical signal generated by the signal-generating element that is measured to determine the concentration of the analyte.

[0010] As a result of gravity and / or other forces acting on the signal-generating elements and effects on the mobility of the signal-generating elements from the sample fluid, the distribution of the signal-generating elements may not be equal across the binding surface. This uneven signal-generating element distribution can result in unreliable test measurements, especially when more than one type of capture element is present on the sensor binding surface. Furthermore, because the composition of the sample fluid may vary from sample to sample (e.g., some patients may be hyperglycemic and others may be hypoglycemic), the effect of fluid composition on the optical signal of the signal-generating elements may result in test-to-test variability, which may also reduce the reliability of the test.

[0011] Thus, according to embodiments disclosed herein, a sample optical signal acquired during a detection phase of testing a sample with a sensor system to measure the concentration of an analyte in the sample is corrected for a background optical signal acquired during a biochemical reaction phase that may precede the detection phase in which the sample optical signal is acquired. The biochemical reaction phase may include a period in which the magnetic elements of the sensor system are activated to attract magnetic particles to the sensor binding surface, and may occur before a final magnetic wash that repels unbound magnetic beads away from the sensor binding surface. By measuring the signal from the magnetic beads during the biochemical reaction phase in which the magnetic beads are attracted to the sensor binding surface, the combined effects of sample fluid properties and non-uniformity in the magnetic particle distribution, which may affect the sample optical signal response, can be determined and used to directly correct the sample optical signal response (e.g., sample optical signal) measured at the binding surface. Furthermore, the background optical signal is acquired from multiple background regions of the detection surface that do not (at least partially) overlap with the binding surface region. In doing so, the background light signal is not affected by the concentration of the analyte, but it does affect the signal response within the binding surface region during the biochemical reaction step (e.g., during the biochemical reaction step, the signal response increases over time depending on the analyte concentration). However, in some instances, the background region may overlap with the binding surface, and the presence of bound signal-generating elements can be accounted for by subtracting the sample data from the background data.

[0012] FIG. 1 illustrates a schematic diagram of a typical setup for a microelectronic sensor system 100 according to the present disclosure. The system 100 includes a support 11, e.g., made of glass or a transparent plastic such as polystyrene. The support 11 is positioned adjacent to (e.g., below) a sample chamber 2, into which a sample fluid containing a target component to be detected (e.g., a drug, an antibody, DNA, etc.) is supplied. In some examples, the sample chamber 2 may be an interior region of a sample cartridge, and the support 11 may form the bottom surface of the sample cartridge. In other examples, the sample chamber 2 may be an interior region of a microwell plate or other suitable container. The sample further includes a signal-generating element 1, e.g., superparamagnetic beads, which can bind to the target component as a label (for simplicity, only the signal-generating element 1 is shown in FIG. 1 ).

[0013] The interface between the support 11 and the sample chamber 2 is formed by a surface called the detection surface 12. This detection surface 12 is coated with capture elements, e.g., antibodies, that can specifically bind to target components. Further details regarding the coating of the detection surface 12 with capture elements are provided below.

[0014] The sensor system 100 comprises a magnetic field generator 41, e.g., an electromagnet with a coil and core, for controllably generating a magnetic field B in the adjacent space of the detection surface 12 and the sample chamber 2. With the aid of this magnetic field B, the signal-generating element 1 can be manipulated, i.e., magnetized, and (if a gradient magnetic field is used) particularly moved. It is thus possible to attract the signal-generating element 1 to the detection surface 12, for example, to promote binding of the associated target component thereto.

[0015] The sensor system 100 further includes a light source 21, e.g., a laser or light-emitting diode (LED), that generates an incident light beam L1 that transmits into the support 11. The incident light beam L1 reaches the detection surface 12 at an angle greater than the critical angle θc for total internal reflection (TIR) ​​and is therefore totally reflected as an outgoing light beam L2. The outgoing light beam L2 leaves the support 11 through another surface and is detected by a photodetector 31, e.g., a photodiode. The photodetector 31 determines the amount of light in the outgoing light beam L2 (e.g., represented by the light intensity of this light beam across the entire spectrum or in a specific portion of the spectrum). Measurement results are evaluated by an evaluation and recording module 32 coupled to the detector 31, and optionally monitored during an observation period. The module 32 receives input data from the detector 31, processes the input data, and, based on programmed instructions or code corresponding to one or more routines, can output information for display on a display system and / or storage (e.g., in a patient's electronic medical record) in response to the processed input data. In particular, module 32 may be a microcomputer having a microprocessor unit, input / output ports, electronic storage media for executable programs and calibration values, such as read-only memory chips, random access memory, keep-alive memory, and a data bus. The read-only memory of the storage media is programmed with computer-readable data representing instructions executable by the processor to perform methods of controlling the different components of Figure 1, such as those described below with respect to Figures 7 and 13. Furthermore, module 32 is configured (e.g., to execute instructions) to control magnetic field generator 41 to provide a continuous or pulsed magnetic field when commanded, such as by controlling the supply of current to magnetic field generator 41.

[0016] A laser diode (e.g., λ=658 nm) is used as the light source 21. A collimator lens is used to collimate the incident light beam L1, and a pinhole 23, e.g., 0.5 mm, is used to reduce the beam diameter. Accurate measurements require a highly stable light source. However, even with a perfectly stable light source, temperature changes in the laser can cause drift and random variations in the output power.

[0017] To address this issue, the light source may optionally have an integrated incident light monitoring diode 22 for measuring the laser's power level. The (low-pass filtered) output of the monitoring sensor 22 is then coupled to an evaluation module 32, which may divide the (low-pass filtered) optical signal from the detector 31 by the output of the monitoring sensor 22. To improve the signal-to-noise ratio, the resulting signal is time-averaged. This division eliminates the effects of laser power fluctuations, both due to power changes (no regulated power supply required) and temperature drift (no preventative measures such as a Peltier element required).

[0018] In some examples, the final output of the light source 21 is measured. As FIG. 1 roughly illustrates, only a portion of the laser output exits the pinhole 23. Only this portion is used for the actual measurement at the support 11 and is therefore the most direct light source signal. Obviously, this portion is related to the laser's output, as determined, for example, by the integrated monitoring diode 22, but it is subject to mechanical variations or instabilities in the optical path (the laser beam profile is roughly elliptical with a Gaussian distribution, i.e., highly non-uniform). Therefore, it is advantageous to measure the amount of light in the incident light beam L1 after passing through the pinhole 23 and / or, as a result, after passing through other optical components of the light source 21. This can be done in various ways. For example, a parallel glass plate 24 can be positioned at an angle less than 45°, or a beam splitter cube (e.g., 90% transmittance, 10% reflectance) can be inserted into the optical path after the pinhole 23 to deflect a small percentage of the light beam toward a separate incident light monitoring sensor 22'. As another example, a pinhole 23 or small mirrors at the edge of the incident light beam L1 can be used to deflect a small portion of the beam towards the detector.

[0019] 1 includes a second photodetector 31', which is alternatively or additionally used to detect fluorescence emitted by fluorescent particles 1 excited by the evanescent wave of the incident light beam L1. Since this fluorescence is typically emitted isotropically to all sides, the second detector 31' can in principle be positioned anywhere, for example above the detection surface 12. Furthermore, it is of course possible to use the detector 31 for sampling the fluorescence, which is spectrally distinguishable from, for example, the reflected light L2.

[0020] As described above, the sensor system is configured to measure optical signals using total internal reflection (TIR). For example, a light source emits a light beam into a support such that the light beam is totally reflected at an investigation area on the support's detection surface. This "investigation area" may be a sub-area of ​​the detection surface or the entire detection surface, and typically has the shape of a roughly circular spot illuminated by the incident light beam. It should be noted that for total internal reflection to occur, the refractive index of the support must be greater than the refractive index of the material adjacent to the detection surface. This is the case, for example, when the support is made of glass (n=1.6) and the adjacent material is water (n=1.3). It should be further noted that the term "total internal reflection" also includes the case where a portion of the incident light is lost (absorbed, scattered, etc.) during the reflection process, referred to as "frustrated total internal reflection" (fTIR).

[0021] By utilizing fTIR, the detection technique becomes surface-specific, thereby reducing background noise. fTIR generates an evanescent wave in the sample, which exponentially decays with distance from the support surface. When this evanescent wave interacts with another medium, such as signal-generating element 1 in the setup shown in Figure 1, some of the incident light couples to the sample fluid (called "frustrated total internal reflection"), resulting in a decrease in reflected intensity (compared to a clean interface with no interaction, where the reflected intensity would be 100%). Depending on the amount of disturbance, i.e., the amount of signal-generating element at or very close to (within approximately 200 nm of) the detection surface 12 (but not elsewhere in the sample chamber 2), the reflected intensity decreases accordingly. This decrease in intensity is a direct measure of the amount of bound signal-generating element 1 and, therefore, the concentration of target molecules. Comparing the above interaction distance of the evanescent wave, approximately 200 nm, with the typical dimensions of antibodies, target molecules, and magnetic beads, it is clear that background effects are minimal.

[0022] While Figure 1 illustrates a microelectronic sensor system that uses an optical detection system to measure the concentration of an analyte in a sample, other mechanisms for detecting a signal-generating element bound to a sensing surface are possible. For example, the signal-generating element bound to the sensing surface may be detected using magnetoresistance, Hall sensors, coils, optical methods, imaging, fluorescence, chemiluminescence, absorption, scattering, surface plasmon resonance, Raman, acoustic wave detection (e.g., surface acoustic wave, bulk acoustic wave, cantilever, quartz crystal, etc.), electrical detection (e.g., conduction, impedance, amperometry, redox cycling, etc.), etc.

[0023] FIG. 2 schematically illustrates a top view 200 of an exemplary sample cartridge 202 of a sensor system, such as the sample cartridge of the microelectronic sensor system 100 of FIG. 1. The sample cartridge 202 can include multiple walls and a hollow interior, thereby forming a sample chamber 203. The sample chamber 203 is a non-limiting example of the sample chamber 2 of FIG. 1. During a test, a sample (a liquid containing one or more analytes of interest) is introduced into the sample cartridge 202 through an inlet, which may follow the arrows shown in FIG. 2. The sample cartridge 202 includes a binding surface 205 that includes a capture element (e.g., one or more antibodies) coated on the bottom surface of the sample cartridge 202 (the bottom surface of the sample cartridge 202 is also referred to as the detection surface 206). In the illustrated example, the sample cartridge 202 includes six binding surface areas arranged in two rows. The binding surface 205 includes a first region 208, a second region 210, a third region 212 arranged in a first row, and a fourth region 214, a fifth region 216, and a sixth region 218 arranged in a second row. Each binding surface region may include the same capture element. For example, each binding surface region may include an anti-troponin antibody coated on the detection surface 206 at a predetermined concentration. In other examples, one or more binding surface regions may include different capture elements. For example, half of the binding surface region may include an anti-troponin antibody, and the other half of the binding surface region may include an anti-BNP antibody. Portions of the detection surface 206 surrounding and between the binding surface regions may not be functionalized with the capture elements that form / define the binding surface.

[0024] Also shown in Figure 2 is a magnetic element 204 included as part of the sensor system. The magnetic element 204 is a non-limiting example of a magnetic field generator 41 and, as such, may include an electromagnet with a coil and core for controllably generating a magnetic field in the adjacent space of the detection surface 206 and the sample chamber 203.

[0025] The magnetic element 204 is configured to generate a magnetic field having a gradient, with the highest density (e.g., highest magnetic flux) of the gradient extending along the magnetic axis, which in Figure 2 may be the central axis 220 of the sample cartridge 202. In the example shown in Figure 2, the central axis 220 may extend along (e.g., parallel to and aligned with) the longitudinal axis of the magnetic element 204. Additionally, Figure 2 includes a Cartesian coordinate system 250, with the central axis 220 extending along (e.g., parallel to) the X-axis of the coordinate system 250.

[0026] 3 and 4 show different views of the sample cartridge 202. FIG. 3 shows a first side view 300 of the sample cartridge 202, and FIG. 4 shows a second side view 400. Each of FIGS. 3 and 4 includes a Cartesian coordinate system 250. As shown in FIG. 3, the sample cartridge 202 includes a top wall 302, a first side 306, and a second side 308. Each of the first side 306 and the second side 308 extends along the Z axis of the coordinate system 250, which may be parallel to gravity or point in a direction opposite to gravity (e.g., a positive Z direction is upward, away from flat ground). As shown in FIG. 4, the sample cartridge 202 also includes a third side 402 and a fourth side 404. Also shown in FIGS. 3 and 4 is a signal-generation element region 304 where dried, functionalized signal-generation elements (e.g., magnetic beads) are temporarily disposed. As shown, the signal generating element region 304 may be on the interior top surface of the sample cartridge 202 (e.g., the interior surface of the top wall 302), although other locations are possible and / or multiple signal generating element regions are included. When a sample is placed into the sample cartridge 202, the dried functionalized signal generating element is released and mixes with the sample.

[0027] 3, the sample cartridge 202 has a length L1 extending from the first side 306 to the second side 308 along the X-axis of the coordinate system 250. The magnetic element 204 has a length L2 extending along the X-axis parallel to the longitudinal axis of the magnetic element 204. In the illustrated example, the length L2 of the magnetic element 204 may be the same as or longer than the length L1 of the sample cartridge 202.

[0028] As shown in FIG. 4 , the sample cartridge 202 has a width W1 extending along the Y-axis from the third side 402 to the fourth side 404. In some examples, the width W1 of the sample cartridge 202 may be equal to the length L1 of the sample cartridge 202. In other examples, the width W1 may be longer or shorter than the length L1. The magnetic element 204 has a width W2 extending along the Y-axis perpendicular to the longitudinal axis of the magnetic element 204. In the illustrated example, the width W2 of the magnetic element 204 is shorter than the width W1 of the sample cartridge 202. Furthermore, the magnetic element 204 is centered relative to the sample cartridge 202 such that the central longitudinal axis of the magnetic element 204 is aligned with the central axis of the sample cartridge 202, where the central axis of the sample cartridge is located at an equidistant point between the third side 402 and the fourth side 404 and extends from the first side 306 to the second side 308. In this manner, the central longitudinal axis of the magnetic element 204 is located between the two rows of bonding surface areas.

[0029] The magnetic element 204 induces a magnetic field gradient toward the center of the sample cartridge, for example, along the central axis 220. Because the magnetic element 204 has a length L2 that is longer than the length L1 of the sample cartridge 202, the magnetic field gradient may be consistent along the length L1 of the sample cartridge 202 but may vary along the width W1 of the sample cartridge 202. For example, along the central axis 220, the magnetic field may have a highest magnetic flux density along the entire central axis 220 from the first side 306 to the second side 308. However, the magnetic flux density may decrease from the central axis 220 to the third side 402 and from the central axis 220 to the fourth side 404.

[0030] Thus, when the magnetic element 204 is activated (e.g., current is supplied to the coil of the magnetic element 204), a magnetic field is generated. The magnetic field may have a gradient such that the region of highest magnetic flux density is located at the center of the sample cartridge, e.g., along the central axis 220. When a sample is placed in the sample cartridge 202, the signal-generating elements are released and mixed with the sample. When the magnetic element 204 is activated, the signal-generating elements (which may be magnetic particles) and bound analytes are attracted by magnetic force to the detection surface 206, particularly toward the central axis 220, where the signal-generating elements interact with capture elements (e.g., as the binding surface 205) immobilized on the detection surface 206. Thus, the signal-generating elements dispersed in the sample are concentrated at the location of highest magnetic field density / highest magnetic flux density.

[0031] Thus, to ensure consistent analyte analysis, particularly when multiple analytes are being tested, binding surface 205 is located at or near the location of the highest magnetic field density / flux density. For example, referring back to FIG. 2 , binding surface 205 is positioned proximate to central axis 220 (e.g., each region is positioned above the magnetic elements and within a threshold distance from central axis 220). In this way, when signal-generating elements are concentrated at detection surface 206 via the magnetic field generated by the magnetic elements, the signal-generating elements will be concentrated at or along binding surface 205, thereby increasing the likelihood that any magnetic particle / analyte complexes will interact with and bind to the appropriate antibodies forming binding surface 205.

[0032] In the example shown in Figures 2-4, the sample cartridge 202 includes six binding surface areas located on a single magnetic element whose magnetic axis is aligned with the central axis of the sample cartridge 202; however, other configurations are possible without departing from the scope of the present disclosure. For example, more or fewer binding surface areas may be included, such as a single binding surface area, two binding surface areas, or three binding surface areas. The binding surface areas may be arranged differently than shown in Figures 2-4, such as in a single row, three rows, or a circular arrangement. The sensor system may, in some examples, include multiple magnetic elements. Furthermore, in some examples, the magnetic element may generate a magnetic field with the highest magnetic flux density centered around a single point rather than along an axis.

[0033] The sample cartridge 202 is configured to be positioned within a sensor system, such as the sensor system of FIG. 1. The sample cartridge 202 contains reagents for conducting a test, for example, to measure the concentration of an analyte in a sample. The reagents can include functionalized magnetic particles (e.g., magnetic particles including an analyte-specific capture element, such as a signal-generating element included in the signal-generating element region 304) and a binding surface 205, and can further include buffer or other reagents. A sample, such as blood or saliva, is introduced into the sample chamber of the sample cartridge, where it mixes with the magnetic particles and the capture element bound to the detection surface 206. Once the sample is introduced into the sample chamber and the signal-generating element is dispersed, the biochemical reaction phase of the test begins. During the biochemical reaction phase, analytes (e.g., troponin) in the sample bind to the functionalized signal-generating elements and / or the binding surface. During the biochemical reaction phase, the analyte molecules can be in four states: unbound, bound only to the signal-generating element, bound only to the binding surface, or bound to both the binding surface and the signal-generating element. To facilitate the process of the analyte reaching a fourth state (where the analyte is bound to both the binding surface and the signal generating element), the magnetic element is activated to generate a magnetic field that actively draws the signal generating element closer to the binding surface of the sample cartridge.

[0034] After a threshold amount of time has elapsed, the biochemical reaction phase is stopped by applying a magnetic field that draws unbound signal-generating elements (e.g., signal-generating elements not bound to the binding surface via the analyte and / or capture element) away from the binding surface. This magnetic wash initiates the detection phase, at which point an optical field is used to obtain a measurement of the number of signal-generating elements remaining on the binding surface (due to their binding to the binding surface). The optical signals measured during the detection phase, referred to herein as sample data, are then compared with predetermined calibration information obtained from a tag on the sample cartridge, such as an RFID tag, to calculate the analyte concentration. Typically, the optical signals used to calculate the analyte concentration are obtained from specific, predetermined measurement regions of interest (ROIs) on the binding surface. These measurement ROIs may be subsets of the binding surface, e.g., rectangular regions overlapping the area of ​​the binding surface. Alternatively, each measurement ROI may encompass the entire area of ​​the respective binding surface region, or a region that includes both the respective binding surface region and some area outside the respective binding surface region.

[0035] The above-described testing process can result in variations in the optical signal detected at each measurement ROI and / or between tests due to non-uniformity in signal-generating element distribution and / or differences in sample fluid parameters, such as viscosity. For example, a first patient being tested for analyte concentration (e.g., troponin) may submit a sample (e.g., blood) with a higher blood glucose level than a sample from a second patient. Because the optical properties of the signal-generating element are affected by the material composition of the signal-generating element and the fluid surrounding it, the higher blood glucose level will cause the signal-generating element in the sample from the first patient to have different optical properties than the signal-generating element in the sample from the second patient. Thus, test results between the first and second patients may differ due to the blood glucose levels of the patients' blood samples, in addition to the varying levels of analyte. Furthermore, in some instances, patient samples may exhibit different fluid viscosities, which can affect the mobility of the signal-generating element during testing, resulting in test variability.

[0036] To address the above-mentioned problems of non-uniform distribution of signal-generating elements and different sample fluid properties, background data is acquired during the biochemical reaction phase of the test (e.g., before applying a magnetic field to remove unbound magnetic particles from the binding surface) or at another appropriate time point in the test, and used to correct the sample data acquired during the detection phase. The background data can include optical signals acquired when bound and unbound magnetic particles are present on the binding surface, and thus are acquired when a magnetic field is applied to actively attract the magnetic particles to the binding surface, but can also be acquired when no magnetic field is applied.

[0037] However, to further improve correction of sample data with background data, the background data may include measurements of the optical signal from only unbound signal-generating elements, since the concentration of analyte affects the binding of the signal-generating elements to the binding surface, and therefore the background data is obtained from a background region that does not overlap the binding surface.

[0038] FIG. 5 shows another schematic diagram 500 of the sample cartridge 202, including the location of multiple background regions 502. In the illustrated example, the multiple background regions 502 are arranged to surround each individual binding surface region, thus arranged in a first column 504, a second column 506, and a third column 508. In some examples, each column can include four background regions, for a total of 12 background regions. In the illustrated example, the first column 504 includes background regions numbered 1 through 4 (from left to right), the second column 506 includes background regions numbered 5 through 8, and the third column 508 includes background regions numbered 9 through 12. As described above, background regions are areas of the detection surface 206 where optical signals are detected to generate background data; it should be understood that no capture elements are immobilized on the detection surface in the background regions. In some examples, the four corner background regions (shown by dashed lines in FIG. 5) can be omitted. As used herein, the term "background region" may refer to a region (which may be circular, rectangular, or another suitable shape) of the detection surface of a sample cartridge where a sensor signal (e.g., an optical signal) is measured to generate background data used to correct sample data, which is used to determine the concentration of one or more analytes in the sample. In some examples, the background region may fully or partially overlap with the binding surface. In other examples, the background region may not overlap with the binding surface. As described herein, the sensor signal measured in the background region may include optical or other types of signals (e.g., magnetic) generated by signal-generating elements (which may be magnetic particles or other types of particles or beads that can be detected optically or otherwise) bound to the detection surface (e.g., in regions where the detection surface is coated with one or more capture elements) and / or not bound to the detection surface. In examples where fTIR is used to generate and measure optical signals, optical signals output by signal-generating elements within a threshold range (e.g., within 100 nm) of the detection surface are measured, while signal-generating elements outside the threshold range are not detected.

[0039] 6 shows an exemplary image 600 of a sample cartridge 602 during a biochemical reaction stage in which, after a sample is introduced into the sample cartridge, a signal generating element 640 mixes with the sample and is attracted to a binding surface 605 on the detection surface 603 of the sample cartridge. The sample cartridge 602 is a non-limiting example of the sample cartridge 202 described above, and thus includes an inlet 604 at one end of the detection surface 603 and a pinning 606 at the other opposite end of the detection surface 603. The binding surface 605 includes six individual regions of capture elements immobilized on the detection surface 603, which are arranged in two rows, including a first region 608, a second region 610, a third region 612, a fourth region 614, a fifth region 616, and a sixth region 618. Each region of the binding surface 605 is represented by a rectangle, which may indicate a measurement ROI (e.g., where an optical signal from magnetic particles at the binding surface is detected). However, other shapes for the capture elements and / or the area of ​​the measurement ROI are possible without departing from the scope of this disclosure.

[0040] 6 further illustrates the location of a plurality of background regions, which are arranged in three columns as shown. The first (top) column of background regions includes a first background region 620 and a second background region 622. The second (center) column of background regions includes a third background region 624, a fourth background region 626, a fifth background region 628, and a sixth background region 630. The third (bottom) column of background regions includes a seventh background region 632 and an eighth background region 634.

[0041] The dark dots / lines in Figure 6 represent signal-generating elements 640. The distribution of signal-generating elements during the biochemical reaction phase varies across the detection surface 603. For example, due to the configuration of the magnetic elements (not shown in Figure 6), the signal-generating elements 640 are concentrated along the central region of the detection surface, with no (or few) signal-generating elements present along the detection surface near the top (e.g., including pinning 606) or bottom (e.g., including inlet 604) of the sample cartridge. A background region is positioned to exclude these zero-density regions and further surrounds the binding surface region.

[0042] In the example shown in FIG. 6, the signal-generating elements exhibit an uneven distribution. For example, there are more signal-generating elements on the left and right sides of the sample cartridge 602 than in the center of the sample cartridge 602. Therefore, the optical signal acquired during the detection phase may be stronger in the left and right regions of the binding surface than in the center of the sample cartridge. Therefore, background data can be used to correct the sample data. For example, the optical signals measured in the background regions surrounding the first region 608 (e.g., background regions 620, 624, and 626) are combined (e.g., averaged) and used to correct the sample data acquired in the first region 608. In another example, the optical signals measured in each background region are combined to form an entire background data set that is used to correct the sample data acquired in each region of the binding surface. In this way, the optical signal measured during the biochemical reaction phase is considered a calibration measurement of the optical signal capacity of a particular test and is therefore used to correct the sample data. In doing so, variations in the concentration of signal-generating elements or fluid properties such as refractive index or viscosity are compensated for.

[0043] While this specification describes a sample cartridge configured to be positioned in a sensor device or sensor system, it should be understood that the sample cartridge may be any suitable container configured to contain a sample coated with one or more capture elements to form its binding surface and mixed with a signal generating element. For example, the sample cartridge may not be sealed as described herein and instead lack a top wall, or the sample cartridge may be in the form of a plate containing one or more wells. As such, the sample cartridge described above with respect to Figures 2-6 may be referred to as a sample container, which may include a cartridge, plate, multiwell plate, or virtually any other structure capable of containing a sample and having a binding surface as described herein.

[0044] FIG. 7 is a flowchart illustrating a method 700 for testing a sample using a sensor system, such as sensor system 100, that includes applying background correction using background data collected in multiple background regions (such as the multiple background regions shown in FIGS. 5 and / or 6) that do not overlap any regions of the binding surface. Method 700 is performed, at least in part, by a computing system, such as evaluation and recording module 32 of sensor system 100, according to processor-executed instructions stored in its memory. At 702, a sample is received in a sample chamber of the sensor system. The sample may include a bodily fluid, such as blood or saliva, which is mixed with a reagent, buffer, water, or the like. The sample is introduced through a sample inlet and allowed to flow into the sample chamber. The sample chamber may comprise the interior of a sample container, such as sample cartridge 202. Thus, the sample may be mixed with a signal-generating element (such as magnetic particles) within the sample chamber. The sample container may include one or more capture elements coated on a detection surface of the sample container, thereby forming a binding surface.

[0045] At 704, a baseline measurement is optionally obtained. Obtaining the baseline measurement may include activating one or more light sources of the sensor system and detecting the resulting optical signal with one or more detectors of the sensor system. The baseline measurement is obtained before the initiation of a biochemical reaction step, for example, before activating magnetic elements of the sensor system. At 706, one or more magnetic elements of the sensor system are activated to attract the signal-generating element to the binding surface of the sample cartridge. The one or more magnetic elements may include one or more magnetic elements, such as magnetic element 204, that generate a magnetic field about a magnetic axis or a single point. The magnetic elements are activated to generate a continuous or pulsed magnetic field according to a predetermined actuation protocol.

[0046] At 708, during a biochemical reaction phase in which one or more magnetic elements are actuated according to an actuation protocol, one or more light sources, such as light source 21, of the sensor system are activated, and detector data is acquired from one or more detectors, such as detector 31, measuring optical signals in each background region of the sample container to generate background data. For example, a light source positioned to direct light into the background region is activated, and the resulting optical signals are measured by a corresponding detector. The collection of background data, at least in some examples, may be timed to correspond to an actuation period in which a magnetic field is applied to attract the signal-generating element to the binding surface. Optical signals may be acquired at one or more discrete time points during the biochemical reaction phase, or the optical signals may be acquired continuously during the biochemical reaction phase. In some examples, the optical signals may be acquired using FTIR-based detection. In such examples, only (magnetic) particles in close proximity to the detection surface, e.g., typically within an evanescent wave penetrating about 100 nm into the sample chamber, are detected. Furthermore, when using a pulsed magnetic field, the magnetic particles are not in proximity to the detection surface for the entire duration of the pulse (when the magnetic field is turned off for hundreds of milliseconds or even seconds), and therefore the measured signal corresponds to the effective time that the particles are at the detection surface (and can only then bind to the binding surface).

[0047] In 710, during the detection phase, which begins after at least one magnetic wash is performed (e.g., the magnetic wash includes applying a magnetic field to repel unbound signal-generating elements away from the binding surface of the sample container), one or more light sources are activated, and detector data is acquired to measure optical signals at each region of the binding surface to generate sample data. For example, light sources positioned to direct light toward the binding surface are activated, and the resulting optical signals are measured by corresponding detectors. In some examples, sample data collection is performed only after the biochemical reaction phase is completed. In other examples, sample data can be collected at multiple time points during an interruption of the biochemical reaction phase. For example, the biochemical reaction phase can be paused to collect a first sample data set (after performing a magnetic wash) and then resume the biochemical reaction phase. The biochemical reaction phase is then terminated, and a second sample data set is collected (after performing another magnetic wash). By collecting sample data at one or more time points before the biochemical reaction phase is completed, for example, signal saturation due to high analyte concentrations is avoided by measuring the optical signal before the biochemical reaction is completed. The optical signals may be acquired at one or more discrete time points during the detection phase, or the optical signals may be acquired continuously during the detection phase. The timing at which the optical signals are acquired may be based on the desired signal-to-noise ratio of the signal (e.g., a signal acquired closer to saturation of the binding surface may have a higher signal-to-noise ratio) and / or the desired speed at which the test is performed. Additionally, the optical signals acquired to generate sample data, as well as the background optical signals, are acquired using fTIR.

[0048] At 712, method 700 determines whether the optical signal measured from each background region is a non-zero signal. For example, the signal response detected from each background region during background data collection can be analyzed to confirm that each region recorded a positive, non-zero value from the output of the corresponding detector. Given the density of magnetic particles, it is expected that at least some signal will be measured from each background region. If no signal is detected from one or more background regions (e.g., a zero value or within a threshold range of zero), this may indicate the presence of air bubbles or that the sample does not completely fill the sample container, which can compromise the test results. Thus, if one or more background regions record a zero signal or a signal within a threshold range of zero (e.g., the answer at 712 is "No"), method 700 proceeds to 720, where it displays and / or stores a notice that the current test is invalid and / or the analyte concentration cannot be determined, and then method 700 returns.

[0049] However, if each background region has a positive, non-zero signal (e.g., answer "yes" at 712), method 700 proceeds to 714, where the background data and sample data are corrected, optionally based on the reference measurements obtained at 704. For example, the reference measurements can be subtracted from each of the background data and sample data. In doing so, other variations that may affect the optical signal (e.g., output from the light source) can be compensated for. At 716, the sample data is corrected based on the background data. As previously described, background data from one or more background regions adjacent to or surrounding a region of the binding surface can be combined and used to correct the sample data for that region of the binding surface. In another example, background data from all background regions can be combined and used collectively to correct the sample data from each region of the binding surface. Correcting the sample data based on the background data can include dividing the sample data by the background data. In another example, various functions, such as a relationship between the sample data and the background data established during calibration (where the relationship is linear, power function, exponential, etc.), are applied to correct the sample data using the background data.

[0050] In some examples, the background data can be weighted so that optical signals acquired from some background regions are given a greater weight than optical signals acquired from other background regions. For example, referring to FIG. 6, optical signals from the background regions in the second (center) row (background regions 624, 626, 628, and 630) are given a lesser weight than optical signals from the background regions in the first (top) and third (bottom) rows. After weighting, the optical signals can be combined (e.g., summed or averaged) to generate background data. Giving a smaller weight to the background regions in the center row can compensate for the tendency of signal-generating elements to concentrate along the center of the sample cartridge, where magnetic flux density is highest.

[0051] At 718, the corrected sample data is stored and / or displayed on a display of the sensor system. The corrected sample data is used to determine the concentration of one or more analytes of interest in the sample, or the determined concentration or concentration signal is output for display and / or saved in memory. For example, the computing system can access a relationship between the corrected sample data and the analyte concentration (e.g., from an RFID tag on the sample container, from a relationship stored in memory, etc.) and determine the analyte concentration based on the corrected sample data and the relationship. For example, the analyte concentration can be calculated using a calibration curve to convert the measured amount of bound signal-generating element to the analyte concentration. The calibration curve (or calculation, or equation) is stored in memory of the sensor system (e.g., evaluation and recording module 32), and the values / parameters of the calibration curve or equation are stored on the RFID tag of the sensor system. The calibration parameters (e.g., the equation including the constants of the calibration curve or equation) are determined after manufacture by testing a series of cartridges with reference samples, e.g., samples containing different concentrations of analyte distributed across the reportable range of the test. The test data is then analyzed by fitting the data with a mathematical formula (e.g., least squares regression). The resulting fitting parameters are then written to the device's RFID tag. Method 700 then ends.

[0052] Figures 8-10 are example graphs illustrating the effect of background correction described above with respect to Figure 7. For each graph, sample data and / or background data were obtained for multiple, varied samples from different patients, each spiked with a different amount of analyte, here troponin-I. The samples were measured using a sensor system such as the sensor system of Figure 1. The sample container used to measure the samples may be the sample cartridge of Figures 2-6, which, in the illustrated example, may include a binding surface arranged in six distinct regions, as shown in Figure 2, with each region of the binding surface containing an anti-troponin antibody. In the illustrated example, six samples were measured, each measured 15 times. For each sample measurement, the troponin concentration was determined during the respective detection phase. Additionally, for each sample measurement, background data was obtained in each background region during the biochemical reaction phase, as described in more detail below.

[0053] FIG. 8 shows a graph 800 of measured troponin concentrations as a function of the average optical signal measured during the biochemical reaction phase (also referred to as the binding phase) for each sample. Thus, the y-axis of graph 800 is the measured troponin-I concentration (cTnI) in ng / L, and the x-axis shows the average optical signal acquired during the biochemical reaction phase (which is normalized to a reference measurement and is therefore a percentage of the reference measurement). Graph 800 in FIG. 8 shows measured troponin concentrations based on the optical signal acquired during the detection phase, without background correction. Each of the measured troponin concentrations for a given sample (e.g., 13 to 15 measured troponin concentrations) was plotted as a function of the average optical signal during the biochemical reaction phase for that measurement. For example, line 802 is a line of best fit of the 13 measured troponin concentrations for the first sample during the respective detection phase as a function of the average optical signal measured during the biochemical reaction phase for that given sample. Each individual troponin concentration measurement for the first sample is shown in FIG. 8 as a plus sign plotted as a function of the average optical signal measured during the biochemical reaction phase. As can be seen from graph 800, the measured troponin concentration increases as the average optical signal detected during the biochemical reaction phase increases, as indicated by the increasing slope of line 802 and the remainder of the tested samples (each tested sample is shown as a best-fit line with corresponding individual measurements shown as various symbols). The correlation between the measured analyte concentration and the optical signal illustrates potential coefficient of variation (CV) effects. In other words, each sample has a known troponin concentration to be measured during each measurement. However, test-to-test variability in magnetic particle binding (e.g., due to non-uniform particle distribution, sample fluid properties, etc.) can result in artificially low or artificially high troponin concentration measurements. For example, the measured troponin concentration in the first sample exhibits a relatively high level of variation, ranging from approximately 15 ng / L to 20 ng / L.

[0054] FIG. 9 shows a graph 900 of measured troponin concentrations for multiple samples as a function of the optical signal measured during the biochemical reaction phase for each sample, with background correction applied. Thus, the y-axis of graph 900 is the measured troponin-1 concentration (cTnl) in ng / L, and the x-axis shows the optical signal acquired during the biochemical reaction phase. The samples measured to generate graph 900 are the same as those measured to generate graph 800, but in graph 900, the measured troponin concentrations were determined based on optical signals acquired during the detection phase, with the optical signals corrected using the background correction described herein (e.g., as described above with respect to FIG. 7). The specific background correction applied to generate graph 900 involved measuring the optical signal in the background region shown in FIG. 6. The optical signals from the background region in the first column and the background region in the third column were weighted relative to the optical signal in the second column of the background region. The total weighting for the background regions was (from left to right, top to bottom) factors of 2, 2, 1, 1, 1, 1, 2, and 2. The optical signals measured from multiple regions of the binding surface (e.g., sample data) were divided by the optical signals measured in the background regions during the biochemical reaction phase (e.g., background data) and multiplied by a factor of 37.5 (which was the average optical signal across the background data).

[0055] As can be seen in FIG. 9 , the observed correlation between the measured analyte concentration and the optical signal decreased for each sample. For example, line 902 shows a best-fit line of the measured troponin concentration for a first sample as a function of the averaged, corrected optical signal measured during the biochemical reaction phase of a given sample (corresponding to the sample measured to generate line 802). Line 902 shows the decreasing correlation between the measured analyte concentration and the optical signal during the biochemical reaction phase. Thus, correcting the sample data with background data indicative of overall magnetic particle binding accounts for test-to-test variability in magnetic particle binding, improving the accuracy and reproducibility of troponin concentration measurements.

[0056] The limit of quantitation (LoQ) 10% coefficient of variation (CV) (LoQ10%CV) was calculated and plotted for the uncorrected and corrected troponin concentration measurements, as shown in Figure 10. Graph 1000 in Figure 10 shows the LoQ10%CV of measured troponin concentrations (ng / L) for two troponins (native and NIST-developed reference troponin), uncorrected and corrected as described above. As can be seen from Figure 10, background correction reduces the LoQ for each troponin.

[0057] FIG. 11 shows a graph 1100 illustrating the effect on CV using different combinations of background regions. The different combinations of background regions shown in FIG. 11 include all background regions (e.g., the first, second, and third columns shown in FIG. 6 ), only the background region in the second column, only the background regions in the first and third columns, only the two central background regions (background regions numbered 626 and 628 in FIG. 6 ), and only a single background region in the second column (background region numbered 624 in FIG. 6 ). Each combination of background regions showed an effect on CV. For example, measuring the optical signal from each background region showed an 18% reduction in CV (row marked “All”). Additionally, in some combinations, the background regions were also weighted such that the background region in the second column was weighted by a factor of 1 and the background regions in the first and third columns were weighted by a factor of 4. This weighting showed an improvement in the CV effect compared to unweighted background correction; for example, an 18% reduction in CV improved to a 21% reduction in CV. Graph 1100 also shows that the background regions near the pinning and sample vessel entrance (eg, the background regions in the first and third rows) contribute most to the corrected CV improvement.

[0058] The improvement in measured troponin concentration CV and LoQ10% CV with background correction was tested on additional batches of sample containers, as shown by graph 1200 in Figure 12. Although the batches may differ in casein concentration, bloodhousing, or other factors, all tested batches contained six anti-troponin antibody spots. Graph 1200 shows that while the effect of background correction on LoQ10% CV varied from batch to batch, background correction showed a decrease in LoQ for each batch except batch 1, thereby demonstrating high reproducibility in the effect of background correction.

[0059] FIG. 13 illustrates another background region layout used to obtain background data for correcting sample data to perform background correction and reduce test-to-test variability in analyte concentration measurements. In FIG. 13, a schematic diagram 1300 of a sample cartridge 202 is shown, including the locations of multiple background regions 1302. In the example shown in FIG. 13, the multiple background regions 1302 are positioned so that each background region overlaps a corresponding region of the binding surface. For example, the first background region 1304 is co-located with the first region 208, and each of the remaining background regions is co-located with a different region of the binding surface (such that six background regions are included, one for each region of the binding surface functionalized to contain a capture element). It should be understood that the background regions are regions of the detection surface 206 where an optical signal is detected during the biochemical reaction phase, as described above.

[0060] When the background region is located as shown in Figure 13, the optical signal measured during the biochemical reaction stage includes signals from both bound and unbound magnetic particles. Therefore, the signal from only the unbound magnetic particles is obtained by using the optical signal acquired when the biochemical reaction stage is completed (and is used as background data to correct the sample data as described above). For example, the optical signal after the biochemical reaction stage is completed (e.g., the optical signal acquired during the detection stage) is subtracted from the optical signal acquired during the biochemical reaction stage to obtain background data.

[0061] FIG. 14 is a flowchart illustrating a method 1400 for testing a sample using a sensor system, such as sensor system 100, that includes applying background correction using background data collected at multiple background regions, each overlapping a respective binding surface region (such as the multiple background regions shown in FIG. 13). Method 1400 is performed, at least in part, by a computing system, such as evaluation and recording module 32 of sensor system 100, according to instructions stored in its memory. At 1402, a sample is received in a sample chamber of the sensor system. The sample may include a bodily fluid, such as blood or saliva, which is mixed with a reagent, buffer, water, or the like. The sample is introduced through a sample inlet and allowed to flow into the sample chamber. The sample chamber may comprise the interior of a sample container, such as sample cartridge 202. Thus, the sample may be mixed with a signal-generating element (such as magnetic particles) within the sample chamber. The sample container may include one or more capture elements coated on a detection surface of the sample container, thereby forming a binding surface.

[0062] At 1404, a baseline measurement is optionally obtained. Obtaining the baseline measurement may include activating one or more light sources of the sensor system and detecting a resulting optical signal with one or more detectors of the sensor system. The baseline measurement is obtained before the initiation of a biochemical reaction step, for example, before activating magnetic elements of the sensor system. At 1406, one or more magnetic elements of the sensor system are activated to attract the signal-generating element to the binding surface of the sample cartridge. The one or more magnetic elements may include one or more magnetic elements, such as magnetic element 204, that generate a magnetic field centered on a magnetic axis or a single point. The magnetic elements are activated to generate a continuous or pulsed magnetic field according to a predetermined actuation protocol.

[0063] At 1408, during a biochemical reaction phase in which one or more magnetic elements are actuated according to an actuation protocol, one or more light sources of the sensor system, such as light source 21, are activated, and detector data is acquired from one or more detectors, such as detector 31, measuring the optical signal in each background region of the sample vessel to generate background data. For example, a light source positioned to direct light at the background region is activated, and the resulting optical signal is measured by a corresponding detector. The collection of background data may, in at least some examples, be timed to correspond to an actuation period in which a magnetic field is applied to attract the signal-generating elements to the binding surface.

[0064] In 1410, during a detection phase that begins after at least one magnetic wash is performed (e.g., the magnetic wash includes applying a magnetic field to repel unbound magnetic particles away from the binding surface of the sample vessel), one or more light sources are activated, and detector data is acquired to measure the optical signal at each region of the binding surface to generate sample data. For example, a light source positioned to direct light toward the binding surface is activated, and the resulting optical signal is measured by a corresponding detector. In some examples, sample data collection is performed only after the biochemical reaction phase is completed. In other examples, sample data can be collected at multiple time points during an interruption of the biochemical reaction phase. For example, the biochemical reaction phase can be paused so that a first sample data set is collected (after magnetic wash) and then the biochemical reaction phase can be resumed. The biochemical reaction phase is then terminated, and a second sample data set is collected (after another magnetic wash). By collecting sample data at one or more time points before the biochemical reaction phase is completed, for example, signal saturation due to high analyte concentrations is avoided by measuring the optical signal before the biochemical reaction is completed.

[0065] In 1412, the background data and sample data are corrected, optionally based on the reference measurements obtained in 1404. For example, the reference measurements can be subtracted from each of the background data and sample data. In doing so, other variables that may affect the optical signal (e.g., output from the light source) can be compensated for. In 1414, the sample data is subtracted from the background data to generate corrected background data. As explained above, the optical signal measured during the biochemical reaction stage includes signals from both bound and unbound signal-generating elements because the optical signal is measured at the capture element spot (because the background region overlaps with the binding surface). Therefore, the signal from only the unbound signal-generating element is obtained by removing the optical signal obtained when the biochemical reaction stage is completed (which represents the optical signal from only the bound signal-generating element). The corrected background data may include separate corrected background data sets for each background region, or the background data may be combined and the combined sample data subtracted from the combined background data.

[0066] At 1416, the sample data is corrected based on the corrected background data. Correcting the sample data based on the corrected background data can include dividing the sample data by the corrected background data. In other examples, various functions are applied to correct the sample data using the background data, such as a relationship between the sample data and the background data established during calibration (the relationship being linear, power function, exponential function, etc.).

[0067] At 1418, the corrected sample data is stored and / or displayed on a display of the sensor system. The corrected sample data is used to determine the concentration of one or more analytes of interest in the sample, similar to the process described above with respect to Figure 7, and the determined concentrations or concentration signals are output for display and / or stored in memory. Method 1400 then ends.

[0068] While the methods described above with respect to Figures 7 and 14 involve background correction using optical signals acquired at individual regions, the methods discussed herein may instead rely on images of the entire detection surface of the sample vessel. For example, images of the entire sample chamber / detection surface are acquired and stored in memory during both the biochemical reaction and detection phases of the test. Once the detection phase is complete, signals can be extracted from the stored images to obtain background data (e.g., signals from unbound magnetic beads during the biochemical reaction phase) and sample data (e.g., signals from bound beads after the biochemical reaction has stopped).

[0069] Thus, by measuring the sensor signal from the signal-generating elements during the magnetic attraction phase, the combined effects of sample characteristics and nonuniformity in the distribution of signal-generating elements (and possibly other causes) that affect the signal response are measured and used to directly correct the signal response of the binding surface. By using signal responses from signal-generating elements outside the binding surface area (e.g., so that background data is acquired in one or more areas of the detection surface that are not functionalized with capture elements), background correction can affect the signal response within the binding surface even during the magnetic attraction phase (e.g., during this phase, the signal response increases over time depending on the analyte concentration), but is not affected by the concentration of the analyte being tested. Another advantage of the background correction described herein is that the signal measured outside the binding surface during the biochemical reaction (when the magnetic particles are on the binding surface) can be used as a confirmation of the correction function of the reaction. For example, if the reaction chamber is not completely filled with liquid and instead contains an air inclusion, a signal near zero will be measured at the location of the air inclusion, indicating that the signal-generating elements cannot reach this region of the detection surface. This information can then be used to invalidate the test and prevent erroneous test results.

[0070] The technical effect of correcting sample data indicating the number of signal-generating elements bound to the binding surface based on background data indicating the number of unbound signal-generating elements is to compensate for the effects of gravity and fluid composition on the analyte concentration determined based on the sample data, thereby reducing test-to-test variability.

[0071] The present disclosure also provides support for a sensor system, the sensor system including a sample container configured to receive a sample containing an analyte to be tested, the sample container including a detection surface and multiple signal-generating elements within the sample container, the detection surface including a binding surface partially functionalized with capture elements capable of directly and / or indirectly binding to the analyte and / or the multiple signal-generating elements, the sensor system further including a memory storing instructions executable by a processor to acquire background data including a sensor signal from one or more background regions of the detection surface, acquire sample data including the sensor signal from the binding surface, and perform correction of the sample data based on the background data. In a first example of the system, the one or more background regions of the detection surface are each positioned so as to at least partially not overlap with the binding surface. In a second example of the system (possibly including the first example), the system further includes a magnetic element, the magnetic element being activated to generate a magnetic field that attracts the multiple signal-generating elements to the binding surface while the background data is being acquired, and the magnetic element being not activated to generate a magnetic field or the magnetic element being activated to keep unbound signal-generating elements away from the binding surface while the sample data is being acquired. In a third example of the system (optionally including one or both of the first and second examples), at least some of the plurality of signal-generating elements comprise a capture element capable of binding to an analyte. In a fourth example of the system (optionally including one or more or each of the first through third examples), the instructions are executable to weight the sensor signal from at least one background region differently from at least one other background region. In a fifth example of the system (optionally including one or more or each of the first through fourth examples), the binding surface comprises a plurality of individual regions, each region of the binding surface functionalized with a capture element, and each of the one or more background regions of the detection surface are positioned such that they do not overlap with the plurality of individual regions of the binding surface such that each background region is not functionalized with a capture element.In a sixth example of the system (possibly including one or more or each of the first through fifth examples), the plurality of individual regions of the binding surface are disposed in a first row of regions and a second row of regions, and the one or more background regions of the detection surface include a plurality of background regions disposed in a first row of background regions, a second row of background regions, and a third row of background regions. In a seventh example of the system (possibly including one or more or each of the first through sixth examples), the first row of background regions are disposed proximate to the pinning of the sample container, the third row of background regions are disposed proximate to the inlet of the sample container, the second row of background regions are disposed intermediate the first row of background regions and the third row of background regions, and the sensor signals of the one or more background regions are weighted such that the sensor signals from the first row of background regions and the third row of background regions are given a greater weight than the sensor signal from the second row of background regions. In an eighth example of the system (possibly including one or more or each of the first through seventh examples), each background region of the detection surface overlaps with a respective region of the binding surface. In a ninth example of the system (possibly including one or more or each of the first through eighth examples), the instructions are executable to subtract the sample data from the background data to generate corrected background data, and correcting the sample data based on the background data includes correcting the sample data based on the corrected background data. In a tenth example of the system (possibly including one or more or each of the first through ninth examples), the instructions are executable to determine a concentration of an analyte in the sample based on the corrected sample data. In an eleventh example of the system (possibly including one or more or each of the first through tenth examples), the instructions are executable to determine an analyte concentration in the sample based on the corrected sample data in response to obtaining a positive, non-zero optical signal from each of the one or more background regions, and to output a notification indicating that the concentration of the analyte cannot be determined in response to not obtaining a positive, non-zero optical signal from each of the one or more background regions.

[0072] The present disclosure also provides support for a method for a sensor system, the method including: measuring a sensor signal at one or more background regions of a detection surface of the sample container to generate background data during testing of a sample containing an analyte contained in a sample container of the sensor system; measuring the sensor signal at a binding surface of the sample container to generate sample data, the binding surface including one or more regions of the detection surface functionalized with capture elements capable of directly and / or indirectly binding to the analyte and / or multiple signal-generating elements of the sample container; and outputting the analyte concentration in the sample based on the sample data and the background data. In a first example of the method, the sensor signal at the one or more background regions is measured while the multiple signal-generating elements are attracted to the binding surface, and the sensor signal at the binding surface is measured while the multiple signal-generating elements are not attracted to the binding surface. In a second example of the method (which optionally includes the first example), the sensor signal includes an optical signal measured using frustrated total internal reflection.

[0073] References to "one embodiment" or "an embodiment" do not necessarily refer to the same embodiment, although they may. Throughout this specification and claims, words such as "comprise," "comprising," and the like are to be construed in an inclusive sense, i.e., "including, but not limited to," as opposed to an exclusive or exhaustive sense, unless the context clearly dictates otherwise. Words using the singular or plural also include the plural or singular, respectively, unless expressly limited to the singular or plural. Additionally, the words "herein," "above," "below," and similar words, when used in this application, refer to this application as a whole and not to any particular portions of this application. When a claim uses the word "or" in connection with a list of two or more items, this word encompasses all interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list, unless expressly limited to one or the other.

Claims

1. 1. A sensor system comprising: a sample container configured to receive a sample containing an analyte to be tested, the sample container comprising: a detection surface; and a plurality of signal generating elements within the sample vessel, the detection surface comprising a binding surface partially functionalized with capture elements capable of directly and / or indirectly binding to the analyte and / or the plurality of signal generating elements; The sensor system further comprises: acquiring background data including sensor signals from one or more background regions of the sensing surface; acquiring sample data including a sensor signal from the binding surface; a memory storing instructions executable by a processor to perform a correction of the sample data based on the background data; the binding surface includes a plurality of individual regions, the plurality of individual regions of the binding surface being disposed in a first row of regions and a second row of regions, and the one or more background regions of the detection surface include a plurality of background regions disposed in the first row of background regions, the second row of background regions, and the third row of background regions; the background region of the first row is located adjacent to the pinning of the sample container, the background region of the third row is located adjacent to the inlet of the sample container, the background region of the second row is located intermediate the background region of the first row and the background region of the third row, and the sensor signals of the one or more background regions are weighted such that the sensor signals from the background region of the first row and the background region of the third row are given a greater weight than the sensor signal from the background region of the second row; The sensor system.

2. The sensor system of claim 1 , wherein each of the one or more background regions of the detection surface is positioned so as to at least partially not overlap the binding surface.

3. and a magnetic element, wherein the magnetic element is activated to generate a magnetic field that attracts the plurality of signal-generating elements to the binding surface while the background data is being acquired, the magnetic element comprising:

3. The sensor system of claim 1, wherein the magnetic element is not activated to generate a magnetic field while sample data is being acquired, or the magnetic element is activated to keep unbound signal generating elements away from the binding surface.

4. The sensor system of any one of claims 1 to 3, wherein at least some of the plurality of signal-generating elements comprise a capture element capable of binding to an analyte.

5. The sensor system of any one of claims 1 to 4, wherein the instructions are executable to weight the sensor signal from at least one background region differently than at least one other background region.

6. A sensor system described in any one of claims 1 to 5, wherein each region of the binding surface is functionalized with a capture element, and wherein one or more background regions of the detection surface are each positioned so as not to overlap with multiple individual regions of the binding surface, such that each background region is not functionalized with a capture element.

7. The sensor system of any one of claims 1 to 6, wherein each background region of the detection surface overlaps with a respective region of the binding surface.

8. 8. The sensor system of claim 1, wherein the instructions are executable to subtract the sample data from the background data to generate corrected background data, and wherein correcting the sample data based on the background data comprises correcting the sample data based on the corrected background data.

9. The sensor system of any one of claims 1 to 8, wherein the instructions are executable to determine an analyte concentration in the sample based on the corrected sample data.

10. 10. The sensor system of claim 1, wherein the instructions are executable to: determine a concentration of the analyte in the sample based on the corrected sample data in response to obtaining a positive, non-zero optical signal from each of the one or more background regions; and to output a notification indicating that the concentration of the analyte cannot be determined in response to not obtaining a positive, non-zero optical signal from each of the one or more background regions.

11. 1. A method for a sensor system comprising: measuring a sensor signal at one or more background areas of a sensing surface of the sample container during testing of the sample containing the analyte contained in the sample container of the sensor system to generate background data; measuring a sensor signal at a binding surface of the sample container to generate sample data, the binding surface including one or more regions of the detection surface functionalized with capture elements capable of directly and / or indirectly binding to the analyte and / or a plurality of signal generating elements of the sample container; outputting the concentration of the analyte in the sample based on the sample data and the background data; Including, the plurality of individual regions of the binding surface are disposed in a first row of regions and a second row of regions, and the one or more background regions of the detection surface include a plurality of background regions disposed in a first row of background regions, a second row of background regions, and a third row of background regions; The background region of the first row is located adjacent to the pinning of the sample container, the background region of the third row is located adjacent to the inlet of the sample container, the background region of the second row is located intermediate the background region of the first row and the background region of the third row, and the sensor signals of one or more background regions are detected by the background region of the first row and the background region of the third row. the signal from the sensor is weighted so that it is given a greater weight than the signal from the sensor from the The method.

12. 12. The method of claim 11, wherein the sensor signal in one or more background areas is measured while the plurality of signal-generating elements are attracted to the binding surface, and the sensor signal at the binding surface is measured while the plurality of signal-generating elements are not attracted to the binding surface.

13. The method of claim 11 or 12, wherein the sensor signal comprises an optical signal measured using frustrated total internal reflection.

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