The present description relates generally to systems and methods for a sensor system for the detection of target molecules in a sample, and more specifically to compensating for gravitational effects on the detection of target molecules.
Biosensors may allow for the detection of a given specific molecule within a sample, wherein the amount or concentration of said specific molecule is typically small, sometimes in the range of nanograms per milliliter. To detect these molecules, functionalized labels or detection tags, such as enzymes, fluorophores, or magnetic beads, may be utilized. In a magnetic-label biosensor, measuring the presence of certain biochemical agents such as drugs or cardiac markers is based on molecular capture and labeling with magnetic particles or beads. Magnetic attraction of the beads, also referred to as actuation, may increase the performance, e.g., speed, of the biosensor for point-of-care applications. The direction of the magnetic attraction can be either towards the surface where the actual measurement is carried out or away from this surface. In the first case magnetic actuation allows the enhancement of the concentration of magnetic particles near the sensor surface (where the magnetic particles may bind to a corresponding capture element, such as an antibody, on the sensor surface), speeding up the binding process of the magnetic particles at the sensor surface. In the second case, unbound magnetic particles (e.g., magnetic particles that are not bound to a capture element on the sensor surface) are removed from the surface which is called magnetic washing.
In one embodiment, a sensor system includes 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 in the sample container, wherein the detection surface comprises a binding surface, which has been partially functionalized with capture elements that can bind, directly and/or indirectly, the analyte and/or the signal generating elements, wherein the signal generating elements have a spatial distribution profile over the detection surface, wherein the spatial distribution profile has a gradient along a first axis, and wherein the binding surface has an axis of symmetry that is orthogonal to the first axis.
To the accomplishment of the foregoing and related ends, certain illustrative aspects of the system are described herein in connection with the following description and the attached drawings. The features, functions, and advantages that have been discussed can be achieved independently in various embodiments of the present disclosure or may be combined in yet other embodiments, further details of which can be seen with reference to the following description and drawings. The summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of any subject matter described herein.
The following description relates to systems and methods for a sensor system, also referred to as a microfluidic testing system or microelectronic sensor system. The sensor system may be a magnetic sensor system including a sample container having one or more reaction chambers loaded with functionalized magnetic particles, e.g., antibody-labeled magnetic particles, that are configured to bind to a specific target molecule (also referred to herein as an analyte or analyte of interest) such as troponin or B-type natriuretic peptide (BNP). In some examples, the sample container may be loaded with two or more sets of functionalized magnetic particles, where each set is functionalized for a specific analyte. For example, a first set of magnetic particles may be functionalized with an antibody specific to troponin and a second set of magnetic particles may be functionalized with an antibody specific to BNP. Each reaction chamber has a detection surface that is also functionalized, e.g., with the same and/or different antibodies as those bound to the magnetic particles, thereby forming a binding surface on the detection surface. In this way, the magnetic particles may bind to the binding surface via the specific analyte(s), with the number of magnetic particles that bind to the binding surface being a function of the concentration of each analyte.
One or more magnetic elements may be positioned 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 binding surface to expedite binding of the magnetic particle/analyte complexes to the binding surface. The area of the binding surface that binds the magnetic particle/analyte complexes may thus be based on the size and position of the magnetic element, as well any variations in the magnetic field generated by the magnetic element. Typically, the antibodies/capture elements are fixed to the detection surface in discrete regions, such as discrete patches or spots. Further, some sample containers may be configured to detect the concentration of more than one analyte, and thus different capture elements may be present in different binding surface regions.
Accordingly, the positioning of the binding surface regions may be based on the distribution of the magnetic particles, which is in turn based on the magnetic field generated by the magnetic element. For example, if the magnetic field has a highest magnetic flux density at the center of the reaction chamber, the binding surface may be positioned at the center of the reaction chamber. However, gravitational forces also act on the magnetic particles, which may influence the behavior of the magnetic particles during sample testing and thereby lead to result variations. This may particularly be the case when the magnetic particles are concentrated in the sample. Further, while gravitational forces cause an acceleration of the particles towards the center of the Earth, other forces causing acceleration, such as from a moving vehicle, may also cause the same effects. As such, the use of the magnetic sensor system may be limited while the system is in motion, which may limit the point-of-care use environments available. For example, the magnetic sensor system may not be reliably used in an emergency vehicle while the vehicle is in motion and/or positioned on a hill, which may delay patient care.
The effect of gravitational and other forces on the magnetic particles and resultant test unreliability may be exacerbated in sample containers that include different types of capture elements as part of the binding surface to test multiple analytes of interest. For example, when one binding surface region is used for each different analyte of interest, the position of the binding surface regions may be asymmetrical with respect to the geometry of the sample container. In these cases, the influence of gravitational forces on the magnetic particles, particularly when the sample container is not at a flat orientation, may induce variations in the distribution of the magnetic particles, leading to localized areas of higher and lower magnetic particle concentration. When the binding surface layout is asymmetric with respect to the geometry of the sample container, uneven distribution of the magnetic particles may result in one or more binding surface regions being positioned in a region of higher or lower magnetic particle distribution, which may lead to errors in the estimated concentrations of target molecules.
Thus, according to embodiments disclosed herein, a sensor system may include a sample container with one or more reaction chambers. The reaction chamber may have a detection surface that is functionalized (e.g., with antibodies) to form a binding surface. The reaction chamber further includes a spatial distribution profile of signal generating elements (e.g., magnetic particles) over the binding surface of the sample container, where the spatial distribution profile includes a gradient having a highest density along or aligned at a given reaction chamber location, such as along a central axis of the sample container and/or reaction chamber. The binding surface may be arranged with a layout that is symmetric with respect to the spatial distribution profile, such as a layout that is symmetric with respect to the central axis (e.g., the central axis is a line symmetry for the binding surface). By doing so, the regions of the binding surface may be positioned so that each region is likely to be exposed to a relatively equal proportion of the signal generating elements. Further, if the sample cartridge is subject to uneven gravitational or other forces that cause an uneven distribution of the signal generating elements, the symmetric layout of the binding surface may ensure that a binding surface region that is exposed to a relatively high proportion of the signal generating elements is balanced by a corresponding, symmetric binding surface region that is exposed to a correspondingly lower proportion of signal generating elements, thereby compensating for any gravitational or other effects causing variations in the signal generating element distribution and reducing signal variations.
The interface between the carrier 11 and the sample chamber 2 is formed by a surface referred to as a detection surface 12. This detection surface 12 may be coated with capture elements, e.g. antibodies, which can specifically bind the target components. Additional details regarding the coating of the detection surface 12 with capture elements is provided below.
The sensor system 100 comprises a magnetic field generator 41, for example an electromagnet with a coil and a core, for controllably generating a magnetic field B at the detection surface 12 and in the adjacent space of the sample chamber 2. With the help of this magnetic field B, the signal generating elements 1 can be manipulated, i.e. be magnetized and particularly be moved (if magnetic fields with gradients are used). Thus it is for example possible to attract signal generating elements 1 to the detection surface 12 in order to accelerate the binding of the associated target component to the detection surface 12.
The sensor system 100 further comprises a light source 21, for example a laser or a light emitting diode (LED), that generates an input light beam L1 which is transmitted into the carrier 11. The input light beam L1 arrives at the detection surface 12 at an angle larger than the critical angle θc of total internal reflection (TIR) and is therefore totally internally reflected as an output light beam L2. The output light beam L2 leaves the carrier 11 through another surface and is detected by a light detector 31, e.g. a photodiode. The light detector 31 determines the amount of light of the output light beam L2 (e.g. expressed by the light intensity of this light beam in the whole spectrum or a certain part of the spectrum). The measurement results are evaluated and optionally monitored over an observation period by an evaluation and recording module 32 that is coupled to the detector 31. Module 32 may receive input data from the detector 31, process the input data, and output information for display on a display system and/or for storage (e.g., in a patient electronic medical record) in response to the processed input data, based on instruction or code programmed therein, corresponding to one or more routines. In particular, module 32 may be a microcomputer, including microprocessor unit, input/output ports, an electronic storage medium for executable programs and calibration values such as a read only memory chip, random access memory, keep alive memory, and a data bus. The storage medium read-only memory can be programmed with computer readable data representing instructions executable by the processor for performing the control methods for different components of
In the light source 21, a commercial (λ=658 nm) laser-diode can be used. A collimator lens may be used to make the input light beam L1 parallel, and a pinhole 23 of e.g. 0.5 mm may be used to reduce the beam diameter. For accurate measurements, a highly stable light source is required. However, even with a perfectly stable power source, temperature changes in the laser can cause drifting and random changes in the output.
To address this issue, the light source may optionally have an integrated input light monitoring diode 22 for measuring the output level of the laser. The (low-pass filtered) output of the monitoring diode 22 can then be coupled to the module 32, which can divide the (low-pass filtered) optical signal from the detector 31 by the output of the monitoring diode 22. For an improved signal-to-noise ratio, the resulting signal may be time-averaged. The division eliminates the effect of laser output fluctuations due to power variations (no stabilized power source needed) as well as temperature drift (no precautions like Peltier elements needed).
In some examples, the final output of the light source 21 may be measured. As
In some examples, sensor system 100 may include a position sensor 35. The position sensor 35 may include an accelerometer, a gyroscope, and/or a geomagnetic sensor. For example, the position sensor may be configured as an inertial movement unit (IMU) including a three-axis or three-degree of freedom (3DOF) position sensor system. This example position sensor system may, for example, include three gyroscopes to indicate or measure a change in orientation of the sensor system within 3D space about three orthogonal axes (e.g., roll, pitch, and yaw). In another example, the IMU may be configured as a six-axis or six-degree of freedom (6DOF) position sensor system. Such a configuration may include three accelerometers and three gyroscopes to indicate or measure a change in location of the sensor system 100 along three orthogonal spatial axes (e.g., x, y, and z) and a change in system orientation about three orthogonal rotation axes (e.g., yaw, pitch, and roll). Output from the position sensor 35 may be sent to the module 32, in order to adjust operation of the sensor system 100 based on the orientation of the sensor system 100, in some examples.
While
Also shown in
As will be explained in more detail below, the magnetic element 204 may be configured to generate a magnetic field having a gradient, with the highest density of the gradient (e.g., the highest magnetic flux) along a magnetic axis, which in
As shown in
As shown in
Thus, the positioning of the sample cartridge 202 relative to the magnetic element 204 may cause a magnetic field to be generated when the magnetic element 204 is activated (e.g., current is supplied to the coil of the magnetic element 204). The magnetic field may have a gradient with a region of highest magnetic flux density positioned along the center of the sample cartridge, e.g., the central axis 220. In this way, a magnetic field gradient is formed, with the highest density of the gradient located along the central axis 220 and decreasing in each direction away from the central axis 220. After the sample is loaded into the sample cartridge 202, the signal generating elements (e.g., the magnetic particles) are released and mix with the sample. When the magnetic element 204 is activated, the magnetic particles (and any bound analyte) will be pulled to the binding surface 205 by magnetic force, and particularly be pulled toward the central axis 220, where the magnetic particles will interact with the capture elements fixed to the binding surface 205. Thus, the signal generating elements (e.g., the magnetic particles) dispersed in the sample will exhibit a spatial distribution profile over the detection surface 206, where the distribution of the signal generating elements includes a gradient of signal generating element concentration along an orthogonal axis (e.g., orthogonal to the central axis 220), as the signal generating elements may concentrate toward the location of the highest field line density/highest magnetic flux density.
Accordingly, to ensure consistent analyte analysis, particularly when more than one analyte is being tested, the binding element regions may be positioned at or in proximity to the location of the highest field line density/flux density. For example, referring back to
Additionally, the binding surface 205 is arranged in a symmetric manner about the central axis 220. In this way, the central axis 220 may be a line of symmetry for the binding surface 205. The symmetric arrangement of the binding surface 205 includes the binding surface regions being positioned in a symmetric manner. For example, the first region 208, the second region 210, and the third region 212 are positioned symmetrically with the fourth region 214, the fifth region 216, and the sixth region 218, respectively, with respect to the central axis 220 (e.g., a center of the first region 208 is spaced apart from the central axis 220 by an amount that is equal to an amount that a center of the fourth region 214 is spaced apart from the central axis 220). Further, the binding surface 205 may be symmetric with respect to the shape(s) of the binding surface regions. As shown, each binding surface region has the same shape and is the same size (e.g., each region may be a circle having the same diameter), but different regions may have different shapes or be of different sizes as long as the regions maintain symmetry with respect to the central axis 220. For example, the first region 208 may have the same shape as and be the same size as the fourth region 214, the second region 210 may have the same shape as and be the same size as the fifth region 216, and the third region 212 may have the same shape as and be the same size as the sixth region 218. However, the first region 208 may have a different shape and/or be of a different size than the second region 210 or the third region 212, in some examples.
Further still, the binding surface 205 may be symmetric with respect to the type(s) of capture elements included in each region. For example, the first region 208 may include a first antibody fixed to the detection surface 206, such as an anti-troponin antibody. The fourth region 214 may also include the first antibody. However, the second region 210 may include a different, second antibody, if desired, such as an anti-BNP antibody. To maintain the symmetry about the central axis 220, the fifth region 216 may also include the second antibody. In the example shown, the third region 212 may include a third antibody that is different than the first and second antibodies. The sixth region 218 may also include the third antibody.
In this way, the binding surface 205 may be arranged in a symmetric manner with respect to the central axis 220. The symmetry may include symmetry of the size, the shape, and/or the position of each region, and the symmetry may also include symmetry of the type of capture element in each region, e.g., the type of antibody in each region. By arranging the binding surface regions in a symmetric manner with respect to the location of the highest magnetic flux density, signal variations caused by gravitational effects on the sample cartridge (e.g., non-flat orientations of the detection surface 206) may be reduced, which may allow the magnetic sensor system to be used in moving vehicles, while being held in the hand of a user, etc. While the binding surface 205 is described herein as having a line of symmetry that constitutes the central axis 220, in some examples the line of symmetry of the binding surface 205 may be positioned within a threshold range of the central axis 220, such as within a certain distance of the central axis 220 (e.g., within 1 mm of the central axis 220, within 5-10% of an overall width of the detection surface or of the binding surface in a direction orthogonal to the central axis 220, etc.). Further, the line of symmetry may be parallel to the central axis 220, or the line of symmetry may be within a threshold angle of the central axis 220, such as within 5° of the extent of the central axis 220. Further, the binding surface being symmetric with respect to the size, the shape, and/or the position of each region may include the symmetric regions being within a threshold size, shape, or position of each other. For example, two symmetric regions may be considered symmetric with respect to size if a size of one of the regions is within 5-10% of the size of the other region.
By using the sample cartridge and magnetic element of the present disclosure, the magnetic particle distribution over the binding surface of the sample cartridge 202 can be aligned at a given location, e.g., along the central axis 220. By arranging the binding surface regions to be symmetric with respect to the center of alignment of the magnetic particle distribution, the magnetic sensor system may be configured to prevent signal variations caused by different orientations of the sample cartridge 202.
For example,
Thus, the binding surface of the sample container may arranged so that a center of mass of the spatial distribution profile of the signal generating elements is above the binding surface, rather than to the side of the binding surface. For example, a fraction of signal generating elements from the spatial distribution profile which overlaps the binding surface may be 50% or more, 30% or more, 10% or more, 5% or more. Further, the center of mass of the spatial distribution profile of the signal generating elements distribution mapped on a plane of the binding surface may be within the binding surface. That is, magnetic element and the binding surface may be arranged so that the gradient of signal generating elements that is induced upon activation of the magnetic element is located above and centered over the binding surface. However, the spatial distribution profile may include a second gradient that is centered over a second axis, orthogonal to the central axis 220 described above, during some conditions. For example,
As appreciated from
To achieve the mirror symmetry across both the central axis 220 and the orthogonal axis 702, the third region 212 is arranged symmetric to the first region 208 with respect to the orthogonal axis 702. As such, the third region 212 has the first size, the first shape, and is comprised of the first antibody. Further, the third region 212 is aligned along a common axis (parallel to the X axis) with the first region 208, and the first region 208 and the third region 212 are each spaced apart from the orthogonal axis 702 by the same amount. The fourth region 214 is also arranged symmetric to the first region 208 with respect to the central axis 220. As such, the fourth region 214 has the first size, the first shape, and is comprised of the first antibody. Further, the fourth region 214 is aligned along a common axis (parallel to the Y axis) with the first region 208, and the first region 208 and the fourth region 214 are each spaced apart from the central axis 220 by the same amount. The fifth region 216 is arranged symmetrically with the second region 210 with respect to the central axis 220. As such, the fifth region 216 has the second size, the second shape, and is comprised of the second antibody. Further, the fifth region 216 is aligned along the orthogonal axis 702 with the second region 210, and the second region 210 and the fifth region 216 are each spaced apart from the central axis 220 by the same amount. The sixth region 218 is arranged symmetric to the third region 212 with respect to the central axis 220 and is also arranged symmetric to the fourth region 214 with respect to the orthogonal axis 702. Thus, the sixth region has the first shape, the first size, and is comprised of the first antibody.
In the example shown, the first size may be equal to the second size and the first shape may be the same as the second shape, while the first antibody may be different than the second antibody (e.g., the first antibody may be anti-troponin and the second antibody may be anti-BNP). However, other shapes, sizes, and antibody arrangements are possible as long as the symmetry across both the central axis 220 and the orthogonal axis 702 is maintained. For example, the second size may be larger than the first size (e.g., the diameter of the circles may be larger for the second and fifth capture element spots) and/or the second shape may be different than the first shape (e.g., the second shape may be a square rather than a circle).
When the binding surface is arranged in a symmetric manner to have a first line of symmetry that extends along and is aligned with a magnetic axis and a second line of symmetry that is orthogonal to the magnetic axis (and where both the magnetic axis and the orthogonal axis are lines of symmetry for the geometry of the reaction chamber), any changes in orientation of the sample cartridge that result in localized high concentrations of magnetic particles may be compensated for. For example, if the sample cartridge 202 shown in
Additionally, as shown in
Each sample cartridge may include a binding surface. For example, the first sample cartridge 1002 may include a first binding surface 1008 and the second sample cartridge 1004 may include a second binding surface 1010. Each binding surface may be similar to the binding surface described above, e.g., include one or more regions each having a capture element fixed to the detection surface of the sample cartridge.
The first binding surface 1008 and the second binding surface 1010 may be arranged to have collective symmetry across the central axis 1012 and an orthogonal axis 1014 positioned equidistant from the first sample cartridge 1002 and the second sample cartridge 1004. For example, as shown, three different types of antibodies are present in the binding surfaces, with a first antibody (schematically depicted in striped lines) arranged in a first column of the first binding surface 1008 and a last column of the second binding surface 1010, a second antibody (schematically depicted in dots) arranged in each middle column of the binding surfaces, and a third antibody (schematically depicted in cross-hatched lines) arranged in a last column of the binding surface 1008 and a first column of the second binding surface 1010. The binding surface regions may be symmetric in size and shape across each of the central axis 1012 and the orthogonal axis 1014.
As described above, the binding surface 205 is described herein as having one or more additional lines of symmetry that constitute the orthogonal axis 702 and/or an axis between two reaction chambers, but in some examples the lines of symmetry of the binding surface 205 may be positioned within a threshold range of the respective axis, such as within a certain distance of the axis (e.g., within 1 mm of the axis, within 5-10% of an overall width of the detection surface or of the binding surface in a direction orthogonal to the axis, etc.). Further, the lines of symmetry may be parallel to the respective axis, or the lines of symmetry may extend within a threshold angle of the axis, such as within 5° of the extent of the axis.
In some examples, two or more magnetic elements may be included in proximity to a sample cartridge, which may result in two or more areas of highest magnetic force and thus two or more gradients of signal generating elements (e.g., magnetic particles). In such examples, the binding surface regions may be arranged in two or more groups so as to overlap/align with each area of highest magnetic force, and each group may be arranged symmetrically with respect to a respective area. For example,
The binding surface may include regions arranged into two groups, e.g., a first row and a second row. The first row of binding surface regions may be arranged along a first magnetic axis 1105 that comprises an axis of highest magnetic flux density generated by the first magnetic element 1104. The second row of binding surface regions may be arranged along a second magnetic axis 1107 that comprises an axis of highest magnetic flux density generated by the second magnetic element 1106. The first row of binding surface regions may be arranged symmetrically with respect to the first magnetic axis 1105 and the second row of binding surface regions may be arranged symmetrically with respect to the second magnetic axis 1107.
As shown in
As a result, and as shown in
While a sample cartridge configured to be positioned in a sensor device or sensor system has been described herein, it is to be appreciated that the sample cartridge may be any suitable container that is coated with two or more binding surface regions on a detection surface thereof and configured to house a sample mixed with signal generating elements, such as magnetic particles. For example, the sample cartridge may not be enclosed as described herein but may instead lack a top wall, or the sample cartridge may be in the form a plate including one or more wells. As such, the sample cartridge(s) described above with respect to
At 1304, method 1300 determines if a request has been received to measure the concentration of one or more analytes in the sample. The request may be received via user input entered to the sensor system (e.g., user selection of a “start” button on a user interface of the sensor system). If a request has not been received, method 1300 returns and continues to monitor for a sample measurement request being received.
If a request to measure the sample has been received, method 1300 proceeds to 1306 to optionally determine the orientation of the detection surface of the sample container. If present in the sensor system, a position sensor (such as position sensor 35) may output information usable to determine an orientation of the sensor system and hence the sample cartridge. The orientation may be determined relative to a direction of gravity. For example, based on the output of the position sensor, the sensor system may determine if the detection surface (which in a default, flat orientation may extend in a horizontal plane perpendicular to gravity and parallel to flat ground) is flat or if the detection surface is tilted with respect to gravity. The output of the position sensor may further be used to determine the axis and direction of the tilt. In some examples, the output from the position sensor may be used to determine if the sensor system and hence the sample cartridge is accelerating.
At 1308, one or more magnetic elements of the sensor system are activated in order to attract the signal generating elements, which may be magnetic particles, 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 with a gradient centered along a single magnetic axis or a single point, or the one or more magnetic elements may include two or more magnetic elements, such as first magnetic element 1104 and second magnetic element 1106, that generate multiple magnetic fields with gradients centered along multiple magnetic axes or points. The magnetic element(s) may be activated to generate a continuous or a pulsed magnetic field. Further, in some examples, the generated magnetic field may be pulsed or modulated so as to perform one or more magnetic washes after pulling the magnetic particles to the binding surface.
The magnetic particles are pulled to the binding surface so that the magnetic particles have a distribution at the binding surface that is centered along the magnetic axis (or axes when more than magnetic element is present) or the magnetic point(s) and have a gradient that extends along an axis orthogonal to the magnetic axis. Because the binding surface includes a plurality of regions arranged symmetrically with respect to the magnetic axis or point, the magnetic particles may distribute in an equal manner with respect to the binding surface, and thus signal variations due to inhomogenous magnetic particle distribution may be reduced or avoided.
At 1310, method 1300 optionally determines if the detection surface is tilted, based on the orientation of the sample cartridge determined at 1306 (e.g., based on the output of the positon sensor). If the detection surface is tilted, method 1300 proceeds to 1312 to optionally compensate for the tilted orientation of the detection surface. In one example, compensating for the tilted orientation may include adjusting the magnetic field strength generated by one or more of the magnetic elements based on the orientation of the binding surface, as indicated at 1314. Adjusting the magnetic field strength may include adjusting the magnetic field strength when the binding surface is tilted along an orthogonal axis, at least in some examples. The orthogonal axis may be perpendicular to the magnetic axis of the magnetic element. For example, referring to
In some examples, as indicated at 1316, compensating for the tilted orientation may include mathematically compensating for the detection surface tilt during the processing of the detection unit output to determine the concentration of one or more analytes, as explained in more detail below. For example, the signal that is detected from the signal generating elements may be weighted for some binding surface regions relative to other binding surface regions based on the orientation, e.g., the signal from a binding surface region that is lower to ground than another binding surface region may be given a lower weight than the signal from the other binding surface region.
If method 1300 determines that the detection surface is not tilted, method 1300 proceeds to 1320 to maintain default parameters, which may include maintaining equal magnetic field strengths, e.g., each magnetic element may be controlled to generate a magnetic field of the same strength, and/or weighting the signals from each binding surface equally (or at least not weighting the signals based on the orientation of the detection surface). While compensation for device orientation is described with respect to
At 1318, the sample is measured even if the sensor system is moving or tilted, by activating one or more light sources, such as light source 21, and obtaining detector data from one or more detectors, such as detector 31. In some examples, the light source(s) may be activated and detector data obtained during the binding of the magnetic particles to the binding surface and washing, or the light source(s) may be activated and detector data obtained only once binding and washing is complete. In some examples, the light source may be configured so that the signal generating elements are detected using frustrated total internal reflectance (fTIR). Further, the light source and detection unit may be configured such that only signal generating elements within a certain threshold distance of the detection surface are measured, such as within 100 nm of the detection surface. As such, when referring to the spatial distribution of the signal generating elements herein, the distribution may be limited to only those signal generating elements that are within 100 nm (or another suitable distance, such as 200 nm) of the detection surface. The obtained detector data may be processed to determine a concentration of one or more analytes of interest in the sample, and the determined concentration(s) or concentration signal(s) may be output for display and/or saved in memory. For example, the concentration of the analyte may be computed using a calibration curve to convert the measured amount of bound signal generating elements into a concentration of the analyte. The calibration curve (or formula, or equation) may be stored in the memory of the sensor system (e.g., the evaluation and recording module 32), and the values/parameters for the calibration curve or formula may be stored onto an RFID tag of the sensor system. The calibration parameters (e.g., the calibration curve or formula, including constants of the formula) may be determined after manufacturing by testing a series of cartridges with reference samples, e.g., samples containing different concentrations of analyte, distributed over the reportable range for the test. The test data is then subsequently analyzed by fitting (e.g., a least squares regression) the data using a mathematical formula. The resulting fit parameters are then written onto the RFID tag of the device. Method 1300 then ends.
Thus, a sensor system, such as the sensor system described above, may include a measurement device to measure an amount of bound signal generating elements and compute a concentration of an analyte in a sample. The bound signal generating elements may be signal generating elements (e.g., magnetic particles) that are bound to a capture element coated on a detection surface of a sample cartridge containing the sample, either directly or indirectly via the analyte. As described herein, the capture elements may be coated on the detection surface in a symmetric layout with respect to a gradient of the signal generating elements, to thereby form a binding surface on the detection surface. The arrangement of the binding surface (e.g., the symmetric arrangement with at least one axis of symmetry that is orthogonal to an axis defining the gradient of the signal generating elements), wherein the at least one axis of symmetry of the binding surface together with the gradient causes a number of signal generating elements of the plurality of signal generating elements that overlap the binding surface to remain constant in the presence of external forces such as gravity. In some examples, the amount of bound signal generating elements are measured by the measurement device using fTIR. Further, an orientation of the sample cartridge may be measured and used to mathematically compensate for the measured amount of bound signal generating elements when computing the concentration of the analyte.
The technical effect of symmetrically arranging a binding surface with respect to a gradient of signal generating elements of a sample cartridge of a sensor system is that signal variations induced by uneven gravitational effects may be reduced, particularly when more than one analyte is being tested.
The disclosure also provides support for 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 in the sample container, wherein the detection surface comprises a binding surface, which has been partially functionalized with capture elements that can bind, directly and/or indirectly, the analyte and/or the plurality of signal generating elements, wherein the plurality of signal generating elements have a spatial distribution profile over the detection surface, wherein the spatial distribution profile has a gradient along a first axis, and wherein the binding surface has an axis of symmetry that is orthogonal to the first axis. In a first example of the system, the sample container has at least one axis of symmetry, which also constitutes the axis of symmetry of the binding surface. In a second example of the system, optionally including the first example, the axis of symmetry of the binding surface is a first axis of symmetry, wherein the binding surface has a second axis of symmetry orthogonal to the first axis, wherein the sample container has two axes of symmetry, orthogonal to each other, which also constitute the first and second axes of symmetry of the binding surface. In a third example of the system, optionally including one or both of the first and second examples, the system further comprises: a magnetic field generation component, able to generate a magnetic gradient within the sample container. In a fourth example of the system, optionally including one or more or each of the first through third examples, the magnetic gradient within the sample container causes the plurality of signal generating elements to move towards the first axis of symmetry of the binding surface. In a fifth example of the system, optionally including one or more or each of the first through fourth examples, the second axis of symmetry of the binding surface together with the magnetic gradient causes a number of signal generating elements of the plurality of signal generating elements overlapping the binding surface to remain constant in the presence of external forces such as gravity. In a sixth example of the system, optionally including one or more or each of the first through fifth examples, the spatial distribution profile of the plurality of signal generating elements also has a second gradient along a second axis which is orthogonal to said first axis. In a seventh example of the system, optionally including one or more or each of the first through sixth examples, the binding surface is also symmetric along a third axis that is orthogonal to said second axis. In an eighth example of the system, optionally including one or more or each of the first through seventh examples, the gradient in the spatial distribution profile of the plurality of signal generating elements is such that that the spatial distribution profile has a maximum concentration and then decreases in both directions along the first axis. In a ninth example of the system, optionally including one or more or each of the first through eighth examples, a center of mass of the spatial distribution profile of the plurality of signal generating elements is above the binding surface. In a tenth example of the system, optionally including one or more or each of the first through ninth examples, a fraction of the spatial distribution profile which overlaps the binding surface is 50%/o or more, 30% or more, 10% or more, or 5% or more. In an eleventh example of the system, optionally including one or more or each of the first through tenth examples, the system further comprises: a measurement device to measure an amount of bound signal generating elements and compute a concentration of the analyte. In a twelfth example of the system, optionally including one or more or each of the first through eleventh examples, the concentration of the analyte is computed using a calibration curve to convert the measured amount of bound signal generating elements into a concentration of the analyte. In a thirteenth example of the system, optionally including one or more or each of the first through twelfth examples, the amount of bound signal generating elements are measured by the measurement device using fTIR. In a fourteenth example of the system, optionally including one or more or each of the first through thirteenth examples, the spatial distribution profile of the plurality of signal generating elements only includes signal generating elements within 100 nm of the detection surface. In a fifteenth example of the system, optionally including one or more or each of the first through fourteenth examples, an orientation of the sample cartridge is measured and used to mathematically compensate for the measured amount of bound signal generating elements when computing the concentration of the analyte. In a sixteenth example of the system, optionally including one or more or each of the first through fifteenth examples, the binding surface includes a first region which has been functionalized with a first type of capture element and a second region which has been functionalized with a second type of capture element, wherein the first capture element can bind, directly and/or indirectly, the analyte, and the second capture element can bind, directly and/or indirectly, a second, different analyte.
In another example of the system, optionally including one or more or each of the previously described examples, the system may be used to carry out a method including receiving a sample containing an analyte to be tested in a sample container of the sensor system, the sample container including a detection surface and a plurality of signal generating elements in the sample container, wherein the detection surface comprises a binding surface, which has been partially functionalized with capture elements that can bind, directly and/or indirectly, the analyte and/or the plurality of signal generating elements; generating a spatial distribution profile of the plurality of signal generating elements over the detection surface, wherein the spatial distribution profile has a gradient along a first axis, wherein the binding surface has an axis of symmetry that is orthogonal to the first axis; and measuring an amount of bound signal generating elements bound to the binding surface and computing a concentration of the analyte in the sample based on the amount of bound signal generating elements.
In another representation, a magnetic sensor system includes a first sample cartridge configured to receive a first sample to be tested, a second sample cartridge configured to receive the first sample or a second sample to be tested; at least one electromagnetic unit configured to produce a magnetic field at a first binding surface of the first sample cartridge and at a second binding surface of the second sample cartridge, the magnetic field having a magnetic field gradient with a highest density of magnetic field lines along a first axis; and wherein the first binding surface and the second binding surface are arranged in a symmetric manner with respect to the first axis and a second axis, orthogonal to the first axis.
In another representation, a sample cartridge for a magnetic sensor system includes a plurality of walls forming a sample chamber configured to receive a sample to be tested and a plurality of capture element spots arranged on a detection surface of the sample cartridge in a symmetric manner with respect to a first axis, where the first axis is configured to align with a magnetic axis of a magnetic element of the magnetic sensor system when the sample cartridge is loaded in the magnetic sensor system. The magnetic element is configured to produce a magnetic field at the binding surface of the sample cartridge, the magnetic field having a magnetic field gradient with a highest density of magnetic field lines along the magnetic axis.
In another representation, a method for a magnetic sensor system includes adjusting a field strength of one or more magnetic elements of the magnetic sensor system based on orientation of a binding surface of a sample container of the magnetic sensor system. In a first example of the method, the magnetic sensor system includes a first magnetic element and a second magnetic element and the binding surface extends across a first plane, and wherein adjusting the field strength comprises: if an entirety of the first plane is perpendicular to gravity, adjusting the field strength so that the first and second magnetic elements generate equal field strengths; and if the first plane is tilted with respect to gravity, adjusting the field strength of one or both of the first and second magnetic elements so that the first and second magnetic elements generate unequal field strengths. In a second example of the method, optionally including the first example, adjusting the field strength of one or both of the first and second magnetic elements so that the first and second magnetic elements generate unequal field strengths comprises generating an overall magnetic field gradient at the binding surface that increases in magnetic flux density in a direction opposite of gravity. In a third example of the method, optionally including one or both of the first and second examples, adjusting the field strength comprises adjusting the field strength to pull a plurality of magnetic particles mixed with a sample loaded in the sample container to the binding surface of the sample container along a magnetic axis, the magnetic axis forming a line of symmetry for the binding surface. In a fourth example of the method, optionally including one or more or each of the first through third examples, the binding surface includes a first capture element region specific to a first analyte and a second capture element region specific to a second analyte. In a fifth example of the method, optionally including one or more or each of the first through fourth examples, the field strength is adjusted in response to a request to measure the sample loaded into the sample container. In a sixth example of the method, optionally including one or more or each of the first through fifth examples, the method further includes measuring the sample by directing light onto the binding surface and detecting light reflected from the binding surface.
In another representation, a magnetic sensor system includes a sample container configured to receive a sample to be tested, the sample container comprising a reaction chamber comprising a binding surface that can bind magnetic particles directly or via an analyte from the sample; and a magnetic element configured to produce a magnetic field at the binding surface of the sample container, the magnetic field having a magnetic field gradient with a highest density along a first axis that crosses through the reaction chamber, wherein the binding surface is arranged in a symmetric manner with respect to the first axis. In a first example of the system, the binding surface is defined by two or more regions, where a first capture element is present in a first region of the at least two regions and a second capture element is present in a second region of the at least two regions, and wherein the first region and the second region are arranged on a same side of the first axis. In a second example of the system, optionally including the first example, the binding surface is defined by a first region arranged on a first side of the fist axis and a second region arranged on a second, opposite side of the first axis, and the first region is symmetric to the second region with respect to a size, a shape, a position, and a type of capture element present in each of the first region and the second region. In a third example of the system, optionally including one or both of the first and second examples, the binding surface is arranged in a symmetric manner with respect to a second axis, orthogonal to the first axis, wherein the second axis crosses a center of mass of the one or more reaction chambers. In a fourth example of the system, optionally including one or more or each of the first through third examples, the first axis is parallel to a longitudinal axis of the magnetic element. In a fifth example of the system, optionally including one or more or each of the first through fourth examples, the system further includes a plurality of functionalized magnetic particles arranged in the sample container. In a sixth example of the system, optionally including one or more or each of the first through fifth examples, the system further includes a detection unit for detecting functionalized magnetic particles bound to the binding surface and a processing unit configured to compute a concentration of the analyte based on output from the detection unit. In a seventh example of the system, optionally including one or more or each of the first through sixth examples, the reaction chamber is a first reaction chamber and the binding surface is a first binding surface, and wherein the sample container comprises a second reaction chamber having a second binding surface arranged in a symmetric manner with respect to the first axis. In an eighth example of the system, optionally including one or more or each of the first through seventh examples, the first binding surface is symmetric to the second binding surface with respect to a second axis, orthogonal to the first axis, the second axis positioned intermediate the first reaction chamber and the second reaction chamber.
In another representation, a method for a magnetic sensor system includes receiving a sample to be tested in a sample container of the magnetic sensor system, the sample container including a reaction chamber having a binding surface including a first region comprising a first capture element specific to a first analyte and a second region comprising a second capture element specific to a second analyte; activating a magnetic element of the magnetic sensor system positioned below the sample container to pull a plurality of magnetic particles mixed with the sample to the binding surface of the sample container along a magnetic axis, the magnetic axis forming a line of symmetry for the binding surface; and measuring a concentration of the first analyte and the second analyte in the sample, where one or both of the activation of the magnetic element and the measuring are performed while the magnetic sensor system is in motion and/or positioned at a non-flat orientation with respect to gravity. In a first example of the method, the magnetic sensor system is positioned in a vehicle and the magnetic element is activated and/or the measuring is performed while the vehicle is in motion and/or while the vehicle is positioned on an incline or a decline. In a second example of the method, optionally including the first example, measuring the concentration of the first analyte and the second analyte comprises directing light onto the binding surface and detecting light reflected from the binding surface.
References to “one embodiment” or “an embodiment” do not necessarily refer to the same embodiment, although they may. Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” Words using the singular or plural number also include the plural or singular number respectively, unless expressly limited to a single one or multiple ones. Additionally, the words “herein,” “above,” “below” and words of similar import, when used in this application, refer to this application as a whole and not to any particular portions of this application. When the claims use the word “or” in reference to a list of two or more items, that word covers all of the following 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.
Filing Document | Filing Date | Country | Kind |
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PCT/EP2021/084964 | 12/9/2021 | WO |
Number | Date | Country | |
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63127384 | Dec 2020 | US |