Systems and methods for processing analyte signals in GMR-based biomarker detection

Abstract

A signal processing system for detecting a target analyte based on GMR in a tested sample, comprising: a measurement circuit configuration unit, configured to construct a GMR sensor measurement circuit by connecting at least one GMR sensor, and to construct a reference resistor measurement circuit by connecting at least one reference resistor; a magnetic field excitation unit, configured to generate a magnetic field with a frequency of ω 2 The AC magnetic field of the carrier signal is applied to at least one GMR sensor; the carrier signal applying unit is configured to apply a frequency of ω 1 The carrier signal is applied to the GMR sensor measurement circuit, and the frequency ω 1 ,ω 1 +ω 2 and ω 1 ‑ω 2 a carrier voltage applied to a reference resistor measurement circuit; a measurement signal pickup unit coupled to the measurement circuit and configured to collect a reference resistor measurement signal from the reference resistor measurement circuit and a GMR sensor measurement signal from the GMR sensor measurement circuit; and a phase-sensitive resolution unit coupled to the measurement signal pickup unit and configured to analytically resolve a resistance change of the at least one GMR sensor based on both the reference resistor measurement signal from the reference resistor measurement circuit and the GMR sensor measurement signal from the GMR sensor measurement circuit.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is based upon and claims the benefit of U.S. Provisional Patent Application No. 62 / 711,396, filed on July 27, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to systems and methods for processing measurement signals obtained from giant magnetoresistance (GMR) sensor-based analyte detection. In particular, the present disclosure relates to phase-sensitive detection systems and methods for processing measurement signals in GMR-based analyte detection. Background Art

[0004] GMR sensors enable the development of multiplex assays with high sensitivity and low cost in compact systems, thus potentially providing a platform suitable for a wide variety of applications. Prior art has shown the advantages of amplitude modulating the GMR sensor signal to improve the measurement signal-to-noise ratio (SNR), however, depending on the measurement circuit, the relationship between voltage amplitude, phase, and substrate magnetic resistance can be quite complex, so some prior art can simply ignore the phase information, while other prior art may choose to perform DC detection.

[0005] Therefore, there is a need to improve upon conventional methods to derive phase-sensitive measurements of GMR detection signals while maintaining the use of AC measurements. Summary of the invention

[0006] Embodiments herein relate to systems and methods for implementing phase-sensitive measurement and calculation of resistance of magnetoresistive (GMR) sensors used in analyte detection.

[0007] An embodiment of the present disclosure provides a signal processing system for GMR-based detection of a target analyte in a test sample, comprising:

[0008] - a measurement circuit configuration unit configured to construct a GMR sensor measurement circuit by accessing at least one GMR sensor, and to construct a reference resistor measurement circuit by accessing at least one reference resistor;

[0009] - a magnetic field excitation unit configured to apply an AC magnetic field with a frequency of ω2 to the at least one GMR sensor;

[0010] - a carrier signal applying unit configured to apply a carrier signal with a frequency of ω1 to the GMR sensor measuring circuit, and to apply carrier signals with frequencies of ω1, ω1+ω2, ω1-ω2 to the reference resistor measuring circuit;

[0011] a measurement signal pickup unit coupled to the measurement circuit and configured to collect a reference resistor measurement signal from the reference resistor measurement circuit and a GMR sensor measurement signal from the GMR sensor measurement circuit; and

[0012] a phase sensitive resolving unit coupled to the measurement signal pick-off unit and configured to analytically resolve resistance changes of the at least one GMR sensor based both on a reference resistor measurement signal from the reference resistor measurement circuit and on a GMR sensor measurement signal from the GMR sensor measurement circuit.

[0013] Another embodiment provides a signal processing method for GMR-based detection of a target analyte in a test sample, comprising:

[0014] - Obtaining GMR sensor measurement signals, including:

[0015] By connecting at least one GMR sensor, a GMR sensor measurement circuit is constructed, and a carrier signal with a frequency of ω1 is applied to the GMR sensor measurement circuit.

[0016] applying an AC magnetic field having a frequency of ω2 to the at least one GMR sensor, and

[0017] collecting a GMR sensor measurement signal from a GMR sensor measurement circuit;

[0018] - Obtaining a reference resistor measurement signal, comprising:

[0019] A reference resistor measurement circuit is constructed by connecting at least one reference resistor.

[0020] applying carrier signals with frequencies ω1, ω1+ω2, ω1-ω2 to the reference resistor measurement circuit, and

[0021] collecting a reference resistor measurement signal from a reference resistor measurement circuit; and

[0022] - analytically resolving a resistance change of the at least one GMR sensor based on both a reference resistor measurement signal from the reference resistor measurement circuit and a GMR sensor measurement signal from the GMR sensor measurement circuit.

[0023] Other embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description, the accompanying drawings, and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Various embodiments of the present disclosure will be described below with reference to the accompanying drawings, in which:

[0025] Figure 1 is a perspective view of an exemplary cartridge reader unit for use in a system according to an embodiment of the present disclosure;

[0026] Figure 2A is a perspective view of an exemplary cartridge assembly for use in the system according to an embodiment of the present disclosure;

[0027] Figure 2B According to one embodiment of the present invention Figure 2A An exploded view of the cartridge assembly in FIG.

[0028] Figure 2C According to one embodiment of the present invention Figure 2A Schematic diagram of the card box assembly in;

[0029] Figure 2D Shows Figure 2A A cross-sectional view of a cartridge assembly depicting a connection interface between a sample processing card and its sensing and communication substrate;

[0030] Figure 3 is a schematic diagram of a system according to an embodiment of the present disclosure;

[0031] Figure 4 According to one embodiment, when using Figure 3 Steps for performing a method for detecting an analyte in a sample when the system disclosed therein is characterized;

[0032] Figure 5A illustrates an exemplary channel according to some embodiments;

[0033] Figure 5B shows a plurality of channels arranged in a base;

[0034] Figures 6A-6C The structure of a GMR sensor chip is schematically shown, and the chip can be mounted on a card box assembly according to an embodiment of the present disclosure;

[0035] Figure 7 shows a cross-sectional view of a channel on a channel expansion section;

[0036] Fig. 8A shows a more detailed cross-sectional view of a channel having a channel body without a channel enlargement section at the location of a GMR sensor;

[0037] Figure 8B The basic structure and principle of the GMR sensor are shown in principle;

[0038] Fig. 9Ashows an exemplary basic mode in which a GMR sensor operates according to various characterization applications presented herein;

[0039] Fig. 9B Shown with Fig. 9A A process flow chart associated with the sensor structure schematic diagram;

[0040] Fig. 10A Another exemplary basic mode is shown in which a GMR sensor operates according to various characterization applications presented herein;

[0041] Fig. 10B Shown with Fig. 10A A flowchart of the process associated with the sensor structure schematic diagram;

[0042] Fig.11A A sensor structural schematic is shown, which depicts the sensor structural states throughout an exemplary addition process using an analyte detection sandwich antibody strategy;

[0043] Fig. 11B Shown with Fig.11A A flowchart of an exemplary process associated with a schematic diagram of a sensor structure;

[0044] Fig. 12A shows a graph of GMR signal (in ppm) versus time (in seconds) in a test run designed to detect the cardiac biomarker D-dimer;

[0045] Fig. 12B shows the calibration curve for D-dimer (GMR signal in ppm vs. D-dimer concentration) obtained by running samples with varying and fixed D-dimer concentrations;

[0046] Fig.13 The functional block diagram of a card box reader according to an embodiment of the present disclosure is schematically shown;

[0047] Fig.14 is a flowchart of a process of a card cartridge reader according to an embodiment of the present disclosure;

[0048] Fig.15 The functional block diagram of a signal processor according to an embodiment of the present disclosure is schematically shown;

[0049] Fig.16 is a flowchart of a process of a signal processor according to an embodiment of the present disclosure;

[0050] Fig.17 The functional block diagram of a signal processing control unit according to an embodiment of the present disclosure is schematically shown;

[0051] Fig.18is a flowchart of a process of a signal processing control unit according to an embodiment of the present disclosure;

[0052] Fig.19 The functional block diagram of a signal preparation unit according to an embodiment of the present disclosure is schematically shown;

[0053] Fig. 20 is a flowchart of a process of a signal preparation unit according to an embodiment of the present disclosure;

[0054] Fig.21 The functional block diagram of a signal processing unit according to an embodiment of the present disclosure is schematically shown;

[0055] Fig. 22 is a flowchart of a process of a signal processing unit according to an embodiment of the present disclosure;

[0056] Fig.23 An example of a voltage measurement obtained with one possible measurement circuit topology is shown;

[0057] Fig.24A -C shows several available circuit topologies for implementing the present signal processing technique. DETAILED DESCRIPTION

[0058] The present disclosure relates to systems and methods for processing measurement signals obtained from analyte detection using magnetoresistive sensor technology.For purposes of explanation, according to certain embodiments, devices, systems, and features are described with respect to using GMR sensors.

[0059] Depend on Figure 1-4 As can be seen from the following description, the signal processing techniques of the present disclosure can be used in a sample processing system (or "system" as referred to throughout the present disclosure), which can be used to detect the presence of an analyte (or more than one analyte) such as a metal, a biomarker, etc. in a sample. In one embodiment, such a system - in Figure 3 300 - may include: (1) a sample handling system or "cartridge assembly" including a sample preparation microfluidic channel and at least one sensing device (or sensor) for detecting biomarkers in a test sample, and (2) a data processing and display device or "cartridge reader unit" including a processor or controller for processing any detection data of the sensing device of the cartridge assembly and a display for displaying detection events. These two components together comprise the system. In one embodiment, these components may include a variety of features, including but not limited to one or more reagent cartridges, a waste cartridge, and a flow control system, which may be, for example, a pneumatic flow controller.

[0060] In general, in order to detect analytes, biomarkers, etc. through the component and output via the cartridge reader unit, the process for preparing the sample in the cartridge assembly is as follows: the original patient sample is loaded into the card, optionally filtered through a filter membrane, after which the negative pressure generated by the pneumatic device outside the card filters the sample into a separated test sample (e.g., plasma). This separated test sample is quantified on the card through the channel geometry. The sample is prepared on the card by interacting with a mixed material (e.g., reagent (which can be wet or dry), buffer and / or washing buffer, beads and / or bead solution, etc.) from a mixed material source (e.g., blister pack, storage cavity, cartridge, well, etc.) before flowing through the sensor / sensing device. The sample preparation channel can be configured so that any number of channels can be stacked vertically on the card, allowing multiple patient samples to be used simultaneously. The same is true for the detection microfluidic device, which can also be stacked vertically. The sample preparation card, which is part of the cartridge assembly, includes: one or more structures that provide functionality selected from the group consisting of: filtering, heating, cooling, mixing, diluting, adding reagents, chromatographic separation, and combinations thereof; and, a device for moving the sample on the sample preparation card. Further description of these features is provided later below.

[0061] Figure 1 300 (see FIG. Figure 3 ) in an example of a cartridge reader unit 100. The cartridge reader unit 100 can be configured to be compact and / or small enough to be used as, for example, a handheld portable device. The cartridge reader unit 100 includes a body or housing 110 having a display 120 and a cartridge receptacle 130 for accommodating a cartridge assembly. The housing 110 can have an ergonomic design to allow for greater comfort when the reader unit 100 is held in the hand of an operator. However, the shape and design of the housing 110 are not intended to be limiting.

[0062] The cartridge reader unit 100 may include an interface 140 and a display 120 for, for example, facilitating user input and / or connecting the cartridge assembly 200 to the unit and / or the sample. According to one embodiment, in conjunction with the disclosed cartridge assembly 200, as part of a process, the system 300 may process, detect, analyze, and generate a report of results, and further display biomarker results, for example, using sensor (magnetoresistive) technology, for multiple detected biomarkers (e.g., five cardiac biomarkers) in a test sample.

[0063] For example, the display 120 may be configured to display information to an operator or user. The display 120 may be provided in the form of an integrated display screen or touch screen (e.g., with tactile or touch feedback), such as an LCD screen or LED screen or any other flat panel display disposed on the housing 110, and (optionally as the case may be) provide an input surface, which may be designed to function as an end-user interface (UI) 140, with which an operator may input commands and / or settings to the unit 100, for example, by touching the display 120 itself with a finger. The size of the display 120 may be variable. Specifically, in one embodiment, the display 120 may be configured to, as part of the end-user interface, display a control panel having keys, buttons, menus and / or keyboard functionality for inputting commands and / or settings for the system 300. In one embodiment, the control panel includes function keys, start and stop buttons, a return or enter button, and a settings button. Additionally and / or alternatively, although Figure 1 Not shown, in one embodiment, the cartridge reader 100 may include any number of physical input devices, including but not limited to buttons and keyboards. In another embodiment, the cartridge reader 100 may be configured to receive input via another device, such as via a direct or wired connection (e.g., connected to a computer (PC or CPU) or processor using a plug and cable) or via a wireless connection. In yet another embodiment, the display 120 may be an integrated screen, or, alternatively, may be an external display system, or may be both. Via the display control unit 120, the test results (e.g., from a reference Figure 3The described cartridge reader 310) can be displayed on an integrated or external display. In yet another embodiment, the user interface 140 can be provided separately from the display 120. For example, if a touch screen UI is not used for the display 120, other input devices can be used as the user interface 140 (e.g., a remote control, keyboard, mouse, buttons, joystick, etc.) and can be associated with the cartridge reader 100 and / or the system 300. Accordingly, it should be understood that the device and / or method for input to the cartridge reader 100 is not intended to be limiting. In one embodiment, all functions of the cartridge reader 100 and / or system 300 can be managed via the display 120 and / or input device, including but not limited to: starting a processing method (e.g., via a start button), selecting and / or changing settings for assays and / or cartridge assembly 200, selecting and / or changing settings related to pneumatics, confirming any reminders for input, viewing steps in a method for processing a test sample, and / or viewing (e.g., via the display 120 and / or user interface 140) test results and values ​​calculated by the GMR sensor and control unit / cartridge reader. The display 120 can visually display information related to the detection of an analyte in a sample. The display 120 can be configured to display the generated test results from the control unit / cartridge reader. In one embodiment, real-time feedback on the test results determined / processed by the cartridge reader unit / controller (by receiving measurements from the sensing device, which are determined as the results of the detected analyte or biomarker) can be displayed on the display 120.

[0064] Optionally, a speaker (not shown) may also be provided as part of the cartridge reader 100 for providing audio output. Any number of sounds may be output, including but not limited to speech and / or alarms. The cartridge reader unit 100 may also include, or optionally include, any number of connectors, such as a LAN connector and a USB connector, and / or other input / output devices associated therewith. The LAN connector and / or the USB connector may be used to connect input devices and / or output devices to the cartridge reader unit 100, including removable memory or drives or other systems.

[0065] According to one embodiment, the cartridge receiver 130 may be an opening in the housing 110 (eg, Figure 12 ), into which a cartridge assembly (e.g., cartridge assembly 200 of FIG. 2 ) may be inserted. In another embodiment, cartridge receptacle 130 may include a tray configured to receive a cartridge assembly therein. Such a tray may be movable relative to housing 110, such as into and out of an opening therein, and thereby receive cartridge assembly 200 and move the cartridge assembly into (and out of) housing 110. In one embodiment, the tray may be a spring-loaded tray configured to releasably lock relative to housing 110. Additional details regarding cartridge reader 100 will be described below with reference to Figure 3 introduce.

[0066] As previously described, the cartridge assembly 200 may be designed to be inserted into the cartridge reader unit 100 so that a sample (eg, blood, urine) may be prepared, processed, and analyzed. Figure 2A-2C An exemplary embodiment of a cartridge assembly 200 according to this embodiment is shown. Certain general features associated with the disclosed cartridge assembly 200 are introduced with reference to these figures. However, as described in more detail below, several different types of cartridge cards and cartridge assemblies can be used with the cartridge reader unit 100 and are therefore provided as part of the system 300. In certain embodiments, the sample processing system or cartridge assembly 200 can take the form of a disposable assembly for performing individual tests. That is, as further understood from the description herein, different cartridge card configurations and / or cartridge assemblies can be used depending on the type of sample and / or analyte to be tested. Figure 2A 2 shows an angled top view of a cartridge assembly 200 according to an embodiment herein. The cartridge assembly 200 includes a sample processing card 210 and a sensing and communication substrate 202 (also referred to as Figure 2B In general, the sample processing card 210 is configured to receive a sample (e.g., via a sample port, such as an injection port, which is also described below) and, once inserted into the cartridge reader unit 100, process the sample and direct the flow of the sample to generate a prepared sample. The card 210 may also have an internal waste chamber ( Figure 2AThe memory chip 275 may be configured to store waste from the sample and / or from the fluid used to prepare the test sample (not shown, but further described below). The memory chip 275 may be read and / or written to and is used to store information related to, for example, cartridge application, sensor calibration, and desired sample processing. In one embodiment, the memory chip 275 is configured to store a pneumatic system protocol, which includes steps and settings for selectively applying pressure to the card 210 of the cartridge assembly 200, thereby achieving sample preparation, which is used to be transferred to a magnetoresistive or magnetoresistive sensor (e.g., a GMR sensor chip 280). The sensor chip can be used to prevent errors in each cartridge assembly 200 inserted into the unit 100 because it includes automation recipes for various assays. The memory chip 275 also includes traceability for the manufacture of each card 210 and / or cartridge assembly 200. The sensing and communication substrate 202 may be configured to establish and maintain communications with the cartridge reader unit 100, and to receive, process, and detect characteristics of the prepared sample. The substrate 202 establishes communication with a controller in the cartridge reader unit 100 so that an analyte can be detected in the prepared sample. The sample processing card 210 is coupled to the sensing and communication substrate 202 (see, e.g., Figure 2B ) are assembled or combined together to form the card box assembly 200. In one embodiment, the adhesive material (see, e.g. Figure 2D ) may optionally be used to bond the card 210 and the substrate 202 to each other. In one embodiment, the substrate 202 may be a laminate layer applied to the sample processing card 210. In one embodiment, the substrate 202 may be designed as a flexible circuit laminated to the sample processing card 210. In another embodiment, the sample processing card 210 may be made of a ceramic material and have circuits, sensors (sensor chips 280), and fluid channels integrated thereon. Alternatively, the card 210 and the substrate 202 may be mechanically aligned and connected together. In one embodiment, a portion of the substrate 202 may extend from an edge or end of the card, for example Figure 2A In another embodiment, as shown. Figure 2B As shown, substrate 2 - 2 may be aligned and / or sized to have edges similar to or smaller than card 210 .

[0067] Figure 2CThe features of the cartridge assembly 200 according to one embodiment are schematically shown. As shown, some features may be provided on the sample processing card 210, while other features may be associated with the substrate 202. Generally speaking, in order to accommodate the test sample (e.g., blood, urine) (within the body of the card), the cartridge assembly 200 includes a sample injection port 215, which may be provided at the top of the card 210. In addition, as appropriate, a filter 230 (also referred to herein as a filter membrane), an exhaust port 225, a valve array 230 (or a valve array strip 230), and a pneumatic control port 235 may be provided as part of the card 210. A communication channel 233 is provided in the card 210 to fluidically connect these features of the card 210. The pneumatic control port 235 is part of the pneumatic interface on the cartridge assembly 200, and is used to selectively apply a pressurized fluid (air) to the communication channel 233 of the card (so as to direct the flow of the fluid (air, liquid, test sample, etc.) therein) and / or the valve array 230. Optionally, the card 210 may include different valve control ports 535 connected to designated communication channels 233 for controlling valves in the valve array 230. The card 210 may also have one or more metering chambers 240, gas permeable membranes 245, and mixing channels 250 connected via the communication channels 233 fluidly. The metering chamber is designed to receive at least a test sample therein (directly or filtered) via the communication channels 233. Generally speaking, the sample can be injected into the cartridge assembly 200 via port 215 and processed by filtering by a filter (e.g., filter 220), metering in the metering chamber 240, mixing in the mixing channel 250, heating and / or cooling (optionally), and directed and changed in flow rate via the communication channels 233, pneumatic control ports 235, and valve array 230. For example, the flow of fluid can be controlled using internal microfluidic channels (generally referred to as communication channels 233 throughout this disclosure) and valves, via a pneumatic system (e.g., system 330 in the cartridge reader unit 100, such as Figure 3235) with a pneumatic interface (e.g., on a card 210 having a pneumatic control port 235) or a similar connection portion. According to one embodiment, optional heating of the test specimen and / or mixed material / fluid within the card 210 can be achieved via a heater 259, which can be in the form of a wiring trace having a thermistor and disposed on the upper side of the PCB / substrate 202. According to one embodiment, optional cooling of the test specimen and / or mixed material / fluid within the card 210 can be achieved via a TEC module integrated in the card cartridge assembly 200 (e.g., on the substrate 202), or in another embodiment, via a module integrated within the card cartridge reader unit 100. For example, if a cooling module is provided in the unit 100, it can be pressed against the card cartridge assembly 200 if cooling is required. Processing may also optionally include optionally introducing reagents via optional reagent portions 260 (and / or blister packs) on the card 210, and / or via reagent cartridges in the housing 110 of the cartridge reader unit 100. Reagents may be released or mixed according to the needs of the processing of the sample and the cartridge assembly 200 being analyzed. In addition, optionally optional blister packs 265 may be arranged on the card 210, so that reagents, eluents, cleaning buffers, magnetic nanoparticles, bead solutions or other buffers may be introduced to the sample via the communicating passage 233 during processing. More than one internal waste chamber (also referred to as waste pool or waste reservoir here) 270 may also be optionally arranged on the card 210, so that waste from the sample and reagents may be stored. As discussed below, the output port 255, also referred to as the sensor delivery port or the input port to the sensor, is arranged to output the prepared sample from the card 210 to the GMR sensor chip 280 for detecting the analyte in the test sample. The output port 255 can be fluidically connected to the metering chamber to transfer the test sample and one or more mixed materials to the sensor. Therefore, the sensor can be configured to receive the test sample and the one or more mixed materials via the at least one output port 255. In an embodiment, the input port 257, also referred to as a waste transfer port or an output port from the sensor, is configured to output any fluid or sample from the GMR sensor chip 280 to the waste chamber 270. The waste chamber 270 can be fluidically connected to other functional parts of the card 210 (including, for example, the metering chamber 240, the input port 257, or both at the same time) via the communication channel 233.

[0068] The cartridge assembly 200 has the ability to store, read and / or write data on a memory chip 275, which may be associated with the card 210 or the substrate 202. As previously described, the memory chip 275 may be used to store information related to and / or associated with the cartridge application, sensor calibration, and required sample processing (within the sample processing card), and receive additional information based on the prepared and processed samples. The memory chip 275 may be located on the sample processing card 210 or on the substrate 200.

[0069] As previously described, according to embodiments herein, magnetoresistive sensors may be used to determine analytes (e.g., biomarkers) within a test sample using the systems disclosed herein. Although the specification and drawings refer to the use of a particular type of magnetoresistive sensor, namely a giant magnetoresistive (GMR) sensor, it should be understood that the present disclosure is not limited to a GMR sensor platform. According to certain embodiments, the sensor may be, for example, an anisotropic magnetoresistive (AMR) sensor and / or a magnetic tunnel junction (MTJ) sensor. In embodiments, other types of magnetoresistive sensor technologies may be used. However, for purposes of illustration only, the specification and drawings refer to the use of a GMR sensor as a magnetoresistive sensor.

[0070] The substrate 202 of the cartridge assembly 200 may be or include an electronic interface and / or circuit interface, such as a PCB (printed circuit board), which may have a giant magnetoresistance (GMR) sensor chip 280 and an electrical contact pad 290 (or electrical contact portion) associated therewith. Other components may also be disposed on the substrate 202. According to one embodiment, the GMR sensor chip 280 is at least attached to the substrate 202. The GMR sensor chip 280 may be arranged on and attached to the substrate 202 using, for example, an adhesive. In one embodiment, a liquid adhesive or a tape adhesive may be used between the GMR sensor 280 and the PCB substrate 202. Such a design may require, for example, a bond to the PCB at the bottom and a bond to the processing card at the top. Alternatively, other methods for attaching the GMR sensor chip 280 to the substrate 202 include, but are not limited to, friction fitting the GMR sensor to the PCB, and directly connecting the top of the GMR sensor chip 280 to the sample processing card 210 (e.g., particularly when the substrate 202 is provided in the form of a flexible circuit laminated to (the back of) the sample processing card 210). The GMR sensor chip 280 can be designed to receive a prepared sample from the output port 255 of the sample processing card 210. Thus, the placement of the GMR sensor chip 280 on the substrate can be changed or altered based on the location of the output port 255 on the card 210 (thus, Figure 2BIn one embodiment, for example, the GMR sensor chip 280 is placed on a first side of the substrate 202 (eg, the top side facing the underside of the card 210, such as Figure 2B 202, so as to receive the prepared sample from the output port that outputs on the lower side of the card 210, the contact pads 290 are arranged on the opposite second side of the substrate (for example, on the bottom side or lower side of the substrate 202, so that when the assembly is complete, the contact pads 290 are exposed on the bottom side of the card cartridge assembly 200, so as to be inserted into the card cartridge reader unit 100). The GMR sensor chip 280 may include its own associated contact pads (for example, metal strips or pins), which are electrically connected to the electrical contact pads 290 arranged on its lower side via the electronic connection on the PCB / substrate 202. Therefore, when the card cartridge assembly 200 is inserted into the card cartridge reader 100, the electrical contact pads 290 are configured to serve as an electronic interface and establish an electrical connection, thereby electrically connecting with the electronic device in the card cartridge reader unit 100 (for example, the card cartridge reader 310). Therefore, any sensor in the sensor chip 280 is connected to the electronic device in the card cartridge reader unit 100 through the electrical contact pads 290 and the contact pads of the GMR sensor chip 280.

[0071] Figure 2D An exemplary cross-sectional view of the mating or connection interface of the card 210 and the substrate 202 is shown. Specifically, Figure 2D The interface between the output port 255 on the card 210 and the GMR sensor chip 280 of the substrate 202 is shown according to one embodiment. For example, the figure shows a PCB substrate 202 located below and adjacent to the card 210 according to any embodiment disclosed herein. The substrate 202 can be attached to the bottom surface of the card 210. The card 210 has a channel feature in at least one layer thereof, here marked as a microfluidic channel 433 (which is one of many connecting channels in the card 210), which is designed to guide the test sample processed in the card 210 to the output port 255 directed to the GMR sensor 280. Optionally, an adhesive material can be provided between the layers of the card 210, for example, an adhesive 434A can be provided between the layer of the card having the reagent port 434B and the layer having the channel 433. The substrate 202 contains the GMR sensor chip 280, which is arranged adjacent to the channel 433 and the output port 255 of the card 210.

[0072] Magnetic field (from the reference below Figure 3 The described magnetic field generator 360 (different magnetic field generator 365) can be used to excite the nanomagnetic particles located near the sensor.

[0073] Now refer to Figure 3, other features of the cartridge reader unit 100 are schematically illustrated to further describe how the cartridge reader unit 100 and the cartridge assembly 200 may be configured to work together to provide a system 300 for detecting an analyte in a sample. As described, the cartridge assembly 200 may be inserted into the housing 110 of the cartridge reader unit 100. Generally speaking, the housing 110 of the cartridge reader unit 100 may further include or contain: a processor or control unit 310, also referred to as a "controller" and / or "cartridge reader" 310 throughout this disclosure; a power source 320; a pneumatic system 330; a communication unit 340; a (optional) diagnostic unit 350; a magnetic field generator 360; a memory 370 (or data storage); and, a user interface 140 and / or display 120 thereof. Optionally, a reagent opener (e.g., for opening a reagent source on an inserted cartridge assembly or for introducing a reagent into the cartridge assembly (e.g., if the reagent is not contained within the assembly in a particular reagent portion) may be provided. Figure 3280) may also be provided as part of the cartridge reader unit 100. Once the cartridge assembly 200 is inserted into the housing 110 of the cartridge reader unit 100, and the electrical and pneumatic systems are connected, the cartridge memory chip 275 may be read from the cartridge assembly 200 (e.g., by a cartridge reader 310 / control unit or PCB assembly in the unit 100) to determine the pneumatic system protocol, which contains steps and settings for selectively applying pressure to the card 210 of the cartridge assembly 200, thereby implementing a method for preparing a sample for delivery to a sensor (e.g., a GMR sensor chip 280), so that the sample placed in the assembly 200 can be prepared, processed, and analyzed. The control unit or cartridge reader 310 may control the inputs and outputs required for automation of the process for detecting an analyte in a sample. The cartridge reader 310 may be a real-time controller configured to, among other things, control a giant magnetoresistance (GMR) sensor chip and / or memory chip 275 associated with the cartridge assembly 200 and a pneumatic system 330 within the housing 110 and control from a user interface, for example, to drive a magnetic field generator 360, to send and / or receive signals to and from a sensor chip and / or memory associated with the cartridge assembly 200. In one embodiment, the cartridge reader 310 is provided in the form of a PCB (printed circuit board), which may include additional chips, memories, devices. The cartridge reader 310 may be configured to communicate with and / or control, for example, an internal memory unit, a system operation initializer, a signal preparation unit, a signal preparation unit, a signal processing unit, and / or a data storage device (all not shown in the figure). The cartridge reader 310 may also be configured to send and receive signals via a communication unit 340, so that, for example, a network connection and telemetry (e.g., with a cloud server) can be established, and non-volatile recipes can be implemented. In general, the communication unit 340 allows the cartridge reader unit 100 to send and receive data using wireless or wired techniques. Power may be supplied to the cartridge reader unit 100 via a power source 320 (which may take the form of an internal battery, or via a connector to which an external source (e.g., via a cable and plug) receives power). When activated and / or when the cartridge assembly 200 is mated with the unit 100, the power source 320 is configured to supply power to components of the cartridge reader unit 100. For example, the power source 320 may supply power to a control unit of the cartridge reader 310 as well as to the PCB assembly 560, the magnetic field generator 360, the display 120 and / or the user interface 140, and the pneumatic system 330 (including, for example, any motors, valves, and / or pumps associated therewith). According to one embodiment herein, the power source 320 may be at least one internally mounted battery pack 320.The pneumatic system 330 is used to process and prepare a sample (e.g., blood, urine) placed in the cartridge assembly 200 by moving and directing fluids within and along the sample processing card 210 (e.g., via the pneumatic connection 235, through its channels and connections to direct elastic valves). The pneumatic system 330 can be a system and / or device for moving fluids, which can use, for example, a plunger and / or piston in contact with the fluid. The magnetic field generator 360 can be an external magnetic coil or other field generating device that is installed in the unit 100 or integrated in some way with one or more chips (e.g., sensor chip 280) disposed on a circuit board of the cartridge reader unit 100 or disposed on the cartridge assembly 200. The magnetic field generator 360 is used to excite magnetic nanoparticles near the GMR sensor chip 280 while reading the signal. According to an embodiment, a second magnetic field generator 365, which can be a coil or other field generating device, can be disposed as part of the cartridge reader unit 100 and within the housing 100. For example, according to one embodiment, the second magnetic field generator 365 can be separate and distinct from the magnetic field generator 360. This second magnetic field generator 365 can be configured to generate a non-uniform magnetic field, such that it can apply such a magnetic field to a portion (e.g., top, bottom, side) of the sample processing card 210 of the assembly 200 during sample preparation and processing, such as when moving mixed materials (e.g., buffers and / or magnetic beads from a mixed material source) and testing samples in the card. In one embodiment, the second magnetic field generator 365 is disposed at the opposite end or opposite side of the card cartridge reader unit (e.g., located at the top of the housing 110 of the unit 100), i.e., away from the magnetic field generator 360 used for GMR detection. In one embodiment, the second magnetic field generator 365 is disposed at the opposite end of the card cartridge reader unit compared to the magnetic field generator 360 (e.g., the second magnetic field generator is located at the top of the housing 110 of the unit 100, and the magnetic field generator 360 is disposed at the bottom end of the unit 100 (e.g., near the card cartridge holder 130)). In one embodiment, the total magnetic field used to detect biomarkers includes the applied magnetic field from the magnetic field generator 360 (outside the sensor chip or integrated with the sensor chip) and any disturbances from magnetic nanoparticles near the GMR sensor chip 280. A reagent opener is optionally used to introduce reagents during reading and sample processing of the GMR sensor chip 280 (for example, if the reagents are not contained in a card in a specific reagent portion). As previously introduced, the user interface / display 120 allows the operator to input information, control the process, provide system feedback, and display test results (via an input display screen, which can be a touch screen).

[0074] Figure 44 shows the general steps of a method 400 for performing analyte detection in a sample using the system 300 disclosed herein. In step 410, the system is initialized. For example, initialization of the system may include: powering on the system 300 (including the cartridge reader unit 100), determining configuration information for the system, reading calculations, determining that features (e.g., a magnetic field generator and a carrier signal) are online and ready, etc. In step 415, a complete test sample is added or loaded into the cartridge assembly 200 (e.g., the sample is injected into the cartridge assembly 200, e.g., Figure 2C4. The order of steps 410 and 415 may be varied, i.e., the complete test sample may be added to the assembly 200 before or after system initialization. In step 420, the cartridge assembly 200 is inserted into the cartridge reader unit 100. Optionally, as part of the method 400, user instructions may be input to the cartridge reader unit 100 and / or the system 300 via the user interface / display 120. Then, in step 425, processing of the sample is initiated via the control unit 310. For example, such initiation may include receiving input from an operator or user via the user interface / display 120 and / or a system connected to the reader unit 100. In another embodiment, processing may be automatically initiated by inserting the cartridge assembly 200 into the cartridge reader unit 100 and detecting the presence of the cartridge assembly 200 therein (e.g., via electrical connection between the electrical contact pads 290 on the assembly 200 and the control unit 310, and automatically reading instructions from the memory chip 275). Using pneumatic control instructions (e.g., obtained from the memory chip 275), the sample is processed in step 425 to generate a prepared sample. As generally described above (and further described below), the processing of the sample can depend on the type of sample and / or the type of cartridge assembly 200 inserted into the reader unit 100. In some cases, the processing may include several steps before preparing the sample, including mixing, introducing buffers or reagents, etc. Once the sample is prepared, the prepared sample is sent (e.g., through a channel in the card 210, via the pneumatic system 330 and the pneumatic control of the control unit 310, to the output port 255) to the GMR sensor chip 280. In step 440, the analyte in the prepared sample is detected in the GMR sensor chip 280. Next, in step 445, the signal from the GMR sensor chip 280 is received and processed, for example, via the cartridge reader 310 (control unit, which may include, for example, one or more processors). Once the signal is processed, the test result can be displayed at 450 via, for example, the display 120 / user interface. At 455, the test results are saved. For example, the test results may be saved in a cloud server and / or in an onboard memory chip 275 on the cartridge assembly 200. In an embodiment, any fluid or sample may be directed from the GMR sensor chip 280 to the waste chamber 270 through the input port 257. Thereafter, once all tests have been performed and read by the sensing device / GMR sensor chip 280, the cartridge assembly 200 may be ejected from the cartridge reader unit 100. According to an embodiment, this may be performed automatically, for example, a mechanical device in the housing 110 of the cartridge reader unit may push the assembly 200 out of the housing 110, or this may also be performed manually (with the aid of a button or force), for example, by an operator.

[0075] In one embodiment, the system 300 introduced herein may use a pneumatic control system as disclosed in the international patent application No. PCT / US2019 / ______ (Agent File No. 026462-0504846) entitled “SYSTEM AND METHOD FOR GMR-BASED DETECTION OF BIOMARKERS” and filed on the same day, the entire text of which is incorporated herein by reference.

[0076] In one embodiment, the system 300 introduced herein may use a cartridge assembly as disclosed in international patent application No. PCT / US2019 / ______ (Agent File No. 026462-0504847), entitled “SYSTEM AND METHOD FOR SAMPLE PREPARATION IN GMR-BASED DETECTION OF BIOMARKERS” and filed on the same date, the entire text of which is incorporated herein by reference.

[0077] In one embodiment, the system 300 described herein may detect analytes as disclosed in International Patent Application No. PCT / US2019 / ______ (Agent File No. 026462-0504848), entitled “SYSTEM AND METHOD FOR SENSING ANALYTES IN GMR-BASED DETECTION OF BIOMARKERS” and filed on the same day, which is incorporated herein by reference in its entirety. For example, in one embodiment, the sensing device or GMR sensor chip 280 may include one or more microfluidic channels and a plurality of sensor pads arranged in the one or more microfluidic channels as disclosed in the -0504848 application. In one embodiment, such a channel may optionally include a plurality of GMR sensors arranged in the channel as appropriate. The GMR sensors may all be configured identically to detect an analyte, and this redundancy enables enhanced detection. The GMR sensors may also all be configured differently to detect a variety of different analytes, or configured as a combination of differently configured sensors with some redundancy. The configuration of the channel is not limited. In general, the GMR sensors in the channel may be designed to provide an output (test result) from the GMR sensor chip 280.

[0078] It should be clear that Figure 1 and 2A-2D, the depicted features are representative schematic diagrams of the cartridge reader unit 100 and cartridge assembly 200 as part of the system 300 disclosed herein for detecting an analyte in a sample. Thus, the illustrations are merely illustrative and are not intended to be limiting.

[0079] Now refer to Figure 5A , shows an exemplary channel 500 according to certain embodiments. The channel 500 is shown as a serpentine structure, but this limitation is not required in terms of geometry. The channel 500 includes a plurality of GMR sensors 510 arranged in a channel body 520. The GMR sensors 510 can all be configured identically to detect an analyte, and this redundancy allows for enhanced detection. The GMR sensors 510 can also all be configured differently to detect a variety of different analytes, or be a combination of differently configured sensors with some redundancy. The channel 500 also includes a channel inlet 530, from which any sample, reagent, bead suspension, etc. enters the channel body 520. Flow through the channel body 520 can be facilitated using a positive pressure on the channel inlet 530 or a vacuum applied to the channel outlet 540.

[0080] Figure 5B A plurality of channels 500 are shown arranged within a substrate 550. Each channel 500 features a channel expansion section 560, which is an enlarged area ( Figure 5A , for clarity Figure 5B 560). Without being bound by theory, it is hypothesized that the channel expansion section 560 provides a means for better mixing of materials as they pass through the GMR sensor. A pair of contact pads 570 are arranged around the substrate 550, which serve as electrical conduits between the GMR sensor located in the channel expansion section 560 and the rest of the circuit. The GMR sensor 510 is electrically connected to the contact pads 570 via wiring (not shown).

[0081] Fig. 6A , 6B 6C schematically show the structure of a GMR sensor chip 280, which can be mounted on a cartridge assembly 200 according to an embodiment of the present disclosure. Fig. 6A As shown, the GMR sensor chip 280 includes: at least one channel 610, 620 and 630, which are arranged approximately in the center of the chip; a plurality of GMR sensors 680, which are arranged in the channel; electrical contact pads 640A, 640B, which are arranged at opposite ends of the GMR sensor chip; and metal lines 650, 660, 670A, 670B, 670C, 690A, 690B, 690C, which are coupled to the electrical contact pads 640A, 640B.

[0082] Each of the channels 610, 620, and 630 may have a serpentine shape to allow more sensors to be packaged therein. A plurality of channel expansion sections 685 may be arranged along the channels to accommodate the plurality of GMR sensors. The fluid to be tested flows into and out of the channels 610, 620, and 630 via the channel inlets 615A, 625A, and 635A and the channel outlets 615C, 625B, and 635B, respectively. Although Fig. 6A The GMR sensors 680 are shown arranged in an 8x6 sensor array, with the three channels 610, 620, 630 accommodating 16 sensors each, but other combinations may be used to meet the specific needs of the analytes being detected.

[0083] The electrical contact pads 640A, 640B include a plurality of electrical contact pins. Metal wires 650, 660, 670A, 670B, 670C connect the GMR sensor to corresponding electrical contact pins 645A, 645B, 675. The electrical contact pads 640A, 640B are in turn connected to the electrical contact pads 290 provided on the cartridge assembly 200. When the cartridge assembly 200 is inserted into the cartridge reader 310, an electrical connection is formed between the GMR sensor chip 280 and the cartridge reader 310, thereby making it possible to send a measurement signal from the GMR sensor to the cartridge reader 310.

[0084] Figure 6B More details of the GMR sensors are shown. For example, each GMR sensor may include five GMR strips connected in parallel. On one end, each GMR sensor is connected to one of two common pins (i.e., pin 645A or 645B) through one of the two main metal wires (i.e., wire 650 or 660). The other end of the GMR sensor is connected to a different pin 675 on the electrical contact pad 640A or 640B through a discrete metal wire 670A, 670B, 670C.

[0085] Fig. 6A Also shown are fluid detection wires 690A, 690B, 690C, which are disposed near the channel inlet and / or outlet, each corresponding to one of the channels. The fluid detection function is performed by switches 695A, 695B, 695C disposed in the corresponding fluid detection wires. Figure 6C The structure of switch 695A is shown in greater detail. In response to identifying that a conductive fluid (eg, plasma) is flowing therethrough, switch 695A can couple a conductor 696A on one side to a conductor 696B on the other side to generate a fluid detection signal.

[0086] Fig. 6A The structure and wiring of the GMR sensor chip shown in FIG. 1 is only exemplary. Those skilled in the art will appreciate that other structures and wiring can be used to achieve the same or similar functions. Figure 7 , a cross-sectional view of the channel 700 at the channel expansion section 730 is shown. A GMR sensor 710 is arranged in the channel expansion section 730, and one or more biomolecules 725 are fixed thereto. The fixation of the biomolecules 725 to the GMR sensor 710 is accomplished via conventional surface chemistry (shown in more detail in FIG. 8 ). The biomolecules 725 can be peptides or proteins, DNA, RNA, oligosaccharides, hormones, antibodies, glycoproteins, etc., depending on the nature of the specific assay being performed. Each GMR sensor 710 is connected to a contact pad 770 located outside the channel 700 by a wire 795. In some embodiments, the wire 795 is connected to the GMR sensor 710 at the bottom of the sensor.

[0087] Now refer to Fig. 8A , showing a more detailed cross-sectional view of channel 800. Channel 800 has a channel body 830, which does not have a channel expansion section at the location of GMR sensor 810. Biomolecules 825 are fixed to the sensor via attachment to a biological surface 845. Such biological surface immobilization chemistry is known in the prior art. See, for example, Cha et al. "Immobilization of oriented protein molecules on poly(ethylene glycol)-coated Si(111)" (Proteomics 4:1965-1976, (2004)) and Zellander et al. "Characterization of Pore Structure in Biologically Functional Poly(2-hydroxyethyl methacryltae)-Poly(ethylene glycol)Diacrylate(PHEMA-PEGDA)" (PLOSONE 9(5):e96709, (2014)). In some embodiments, the biological surface 845 comprises a PEG polymer cross-linked with PHEMA. In some embodiments, the cross-linking group is represented by formula (I):

[0088] PA-LG-PA(I)

[0089] Wherein, each PA is photoactivated or metal activated or an activating group, and LG is a linking group. In some embodiments, each PA is the same, and in other embodiments, each PA is different. In some embodiments, the PA is photoactivated or metal activated to form a nitrene intermediate with CH and / or OH insertion ability. See, for example, Chapter 2 "Photogenerated reactive intermediates and their properties" of Laboratory Techniques in Biochemistry and Molecular Biology (Elsevier Press, 12: 8-24 (1983)). In some embodiments, the PA is metal activated to form a carbon ene or carbene intermediate with CH and / or OH insertion ability. See, for example, Doyle et al. "Catalytic Carbene Insertion into CH Bonds" (Chem. Rev. 2: 704-724 (2010)).

[0090] In certain embodiments, each PA is an azide (-N3) moiety and photoactivation generates a nitrene intermediate with CH and / or OH insertion capabilities, thereby facilitating crosslinking of PEG and PHEMA polymers. In certain embodiments, each PA is a diazo (-N2) compound and metal-catalyzed decomposition reaction forms a carbene or carbene intermediate with CH and / or OH insertion capabilities, thereby facilitating crosslinking of PEG and PHEMA polymers. The preparation of both azide and diazo compounds is well known in the art, and in the case of azide compounds, can be obtained by reacting the azidoate N3 - With a suitable organic moiety having a leaving group S N 2 It can be prepared without difficulty by displacement reaction.

[0091] LG in formula (I) can be any organic debris that will support the presence of each PA moiety. It can be a simple C2-C 20 A hydrocarbon chain, which may be straight or branched. The hydrocarbon may include fluorinated variants with any degree of fluorine substitution. In certain embodiments, LG may include aromatic hydrocarbons, including but not limited to benzene, naphthalene, biphenyl, binaphthyl, or aromatic structures with C2-C 20 Thus, in some embodiments, LG can be an alkyl, aromatic or aralkyl structure. In some embodiments, the alkyl linking groups can replace more than one carbon in their chain with oxygen (O) or amine (NR), where R is H or C1-C6 alkyl.

[0092] According to the above examples, the cross-linked PEG-PHEMA structure can be given by formula (II):

[0093] PEG-A-LG-A-PHEMA

[0094] Wherein, PEG is a polyethylene glycol moiety, each A is an attachment atom from the catalytic reaction of an azide or diazo compound, i.e., CH2 or NH, and LG is a linking group as described above.

[0095] exist Fig. 8A 8, the magnetic bead adherent 815 is configured to interact with a biomolecule 825 or an analyte of interest, such as a sandwich structure of antibody-analyte-magnetic bead adherent antibody. Below the biological surface 845 is a further isolation layer 855. The isolation layer 855 can be in direct contact with the GMR sensor 810 and can include, for example, a metal oxide layer. The biological surface layer 845 is in direct contact with the isolation layer 845. The substrate 865 serves as a support for the various components above it - the GMR sensor 810, the isolation layer 855 and the biological surface layer 845. In some embodiments, the substrate 865 is made of silicon wafer.

[0096] Figure 8B The basic structure and principle of a GMR sensor are shown in principle. A typical GMR sensor is composed of a metal multilayer structure having a non-magnetic conductive interlayer sandwiched between two magnetic layers 880A and 880B. The non-magnetic conductive interlayer 890 is often a thin copper film. The magnetic layers 880A and 880B can be made of ferromagnetic alloy materials.

[0097] The resistance of the metal multilayer structure varies with the relative magnetization directions of the magnetic layers 880A and 880B. Figure 8B ) results in lower resistance, while antiparallel magnetization (as shown in the right half of Figure 8B The magnetization direction can be controlled by an externally applied magnetic field. Therefore, the metal multilayer structure shows a change in its resistance according to the external magnetic field.

[0098] GMR sensors have a sensitivity that exceeds that of anisotropic magnetoresistance (AMR) or Hall sensors. This property makes it possible to detect stray fields from nanoscale magnetic materials. For example, stray fields from magnetic nanoparticles attached to the sensor surface will change the magnetization of the magnetic layer and thus change the resistance of the GMR sensor. Therefore, changes in the number of magnetic nanoparticles attached to the GMR sensor per unit area can be reflected in changes in the resistance value of the GMR sensor.

[0099] Now refer to Fig. 9A and 10A, showing two exemplary basic modes in which the GMR sensor operates according to the various characterization applications presented herein. Fig. 9A In the illustrated first mode, at the start of the assay, magnetic beads 915 are loaded into proximity with the GMR sensor via the biological surface 965 (see Fig. 8A , 810). During the assay, the presence of the interrogated analyte causes the magnetic beads 915 to move away from the biological surface 965 (and, therefore, from the GMR sensor); this mode is a so-called subtraction mode because the magnetic beads are removed from the vicinity of the sensor surface. Fig. 10A The second major mode of operation typically employed in an assay is the addition mode. In such an assay, when the analyte being interrogated is present, there is a net increase in the number of beads 1015 present in the vicinity of the GMR sensor (see Fig. 8A , 810). Each mode - additive or subtractive - relies on a change in the number of beads (915, 1015) near the sensor surface, thereby changing the resistance of the GMR sensor system. The change in resistance is measured and the concentration of the analyte being interrogated can be quantitatively determined.

[0100] Back to Fig. 9A , shows a sensor structure diagram, which gives the sensor structure throughout the exemplary subtraction process. At the beginning of the process, the system is in state 900a, wherein the GMR sensor arranges multiple molecules (typically biomolecules) 925 with associated magnetic beads 915 on its biological surface 965. The volume on the biological surface 965 may be dry or have solvent at the beginning. In the case of dryness, the detection process may include a solvent priming process performed with, for example, a buffer solution. After the introduction of the analyte, the system presents the form of state 900b, wherein some magnetic beads 915 have been removed from the molecules 915 in proportion to the analyte concentration. The changes in states 900a and 900b provide a measurable change in resistance, which allows the analyte of interest to be quantified. In certain embodiments, the analyte can simply directly remove the beads from the molecules 925. In other embodiments, the analyte may chemically react with the molecule 925 to cleave a portion of the molecule attached to the bead 915 , thereby releasing the bead 915 along the cleaved portion of the molecule 925 .

[0101] In an embodiment, the biological surface 965 comprises a polymer. A specific polymer may be selected to promote covalent attachment of the molecule 925 to the biological surface 965. In other embodiments, the molecule 925 may be associated with the biological surface 965 via an electrostatic reaction. The polymer coating may be selected or modified to use, for example, conventional attachment chemistries for covalently anchoring biological molecules. Attachment chemistries include any chemical moiety comprising an organic functional group handle, such organic functional group handles including, but not limited to, amines, alcohols, carboxylic acids, and thiol groups. Covalent attachment chemistries include, but are not limited to, the formation of esters, amides, thioesters, and imines (which may be subsequently subjected to a reduction reaction, i.e., reductive amination). The biological surface 965 may comprise a surface modifier, such as a surfactant, including, but not limited to, anionic surfactants, cationic surfactants, and zwitterionic surfactants.

[0102] In an embodiment, the magnetic beads 915 can be nanoparticles, including spherical nanoparticles. Such nanoparticles can have an effective diameter in the range of about 2 to about 50 nanometers (nm), or about 5 to about 20nm, or about 5 to about 10nm. In an embodiment, the magnetic beads 915 can be coated to promote covalent attachment to the molecules 925. In other embodiments, the magnetic beads 915 can be coated to promote electrostatic association with the molecules 925. The magnetic beads 915 can be differently labeled and / or coated to promote multiple detection schemes. In such an embodiment, the differential labeling and / or coating is configured so that different beads interact with different molecules arranged on different GMR sensors or a single sensor, wherein the different molecules are spatially organized to produce addressable signals.

[0103] Fig. 9B Shown with Fig. 9A Process flow 901 associated with the sensor structure scheme of the present invention. The process begins at 920 by injecting the sample into the cartridge assembly. The sample can then be processed by any necessary steps (e.g., filtration, dilution and / or chemical modification) at step 930. The order of these pre-processing steps can depend on the nature of the sample and the analyte to be detected. Movement in the system can be controlled pneumatically. Step 940 involves sending the processed sample to the GMR sensor at a specific flow rate for the object. Such a flow rate can be selected to reflect the kinetics of the chemical process on the surface of the GMR sensor. Step 950 provides readings from the GMR sensor reflecting changes in the concentration of magnetic beads on the surface of the GMR sensor. These readings allow detection of resistance changes in step 960. Finally, step 970 provides calculation of the detection results based on the resistance changes.

[0104] Now refer to Fig. 10A, shows a diagram of the sensor structure that illustrates the sensor structure throughout an exemplary addition process. At the beginning of the process, the system is in state 1000a, wherein the GMR sensor has a plurality of molecules (typically biological molecules) 1025 arranged on its biological surface 1065. The plurality of molecules 1025 are selected to adhere to the queried analyte 1090, as shown in the second state 1000b. The queried analyte 1095 is configured to adhere to the magnetic beads 1015. In some embodiments, the queried analyte 1095 is associated with the beads before passing through the biological surface 1065. For example, this can occur during pretreatment of the sample being tested. (In other embodiments, the queried analyte 1095 may first pass through the biological surface, and then, after the analyte adheres to the biological surface 1065, the queried analyte 1095 is modified with the magnetic beads 1015, as described below with reference to Fig.17 A). In some embodiments, a given analyte 1095 to be queried may need to be chemically modified prior to attachment to the magnetic particles 1015. In some embodiments, the magnetic beads 1015 may be modified to interact with the analyte 1095 to be queried. The ability to quantify the analyte is provided by the change in measured resistance from state 1000a (wherein the magnetic beads 1015 are not present) to state 1000b (wherein the magnetic beads 1015 are associated with the chemical surface 1065).

[0105] Fig. 10B Shown with Fig. 10A An exemplary process flow 1001 associated with a sensor structure scheme of the present invention is shown. The process begins at 1020 by injecting a sample into a cartridge assembly. Then, the sample can be processed by any necessary steps (e.g., filtering, diluting and / or chemical modification) at step 1030. The order of these pre-processing steps can depend on the nature of the sample and the analyte to be detected. Movement in the system can be controlled pneumatically. Step 1040 involves sending the processed sample to the reaction chamber, and then, at step 1050, beads are introduced into the reaction chamber to modify the analyte to be queried. As introduced above, such modifications can be performed directly on the sensor surface rather than in the reaction chamber. In step 1060, the modified sample is sent to the GMR sensor at an object flow rate. Such a flow rate can be selected to reflect the kinetics of the chemical process on the GMR sensor surface. Step 1070 provides a reading from the GMR sensor reflecting the change in the concentration of magnetic beads on the GMR sensor surface. These readings allow the detection of resistance changes in step 1080. Finally, step 1090 provides a detection result calculated based on the resistance change.

[0106] Now refer to Fig.11A, wherein a sensor structure diagram is shown, which shows sensor structure states 1100a-d throughout an exemplary addition process (state 1100b) using a sandwich antibody strategy for detecting an analyte 1195. At the beginning of the process, the system is in state 1100a, wherein the GMR sensor has a plurality of antibodies 1125 disposed on its biosurface 1165. Then, as shown in state 1100b, the analyte 1195 passes over the biosurface 1165, allowing the analyte 1195 to adhere to the antibody 1125. Next, as shown in state 1100c, the analyte 1195 is modified by adhering to a second antibody 1135, on which a covalently linked biotin moiety (B) is disposed. Then, a magnetic bead 1115 modified with streptavidin (S) is added, thereby allowing a strong biotin-streptavidin association to provide state 1100d. In certain embodiments, the streptavidin is provided as a coating on the magnetic bead 1115.

[0107] Fig. 11B Shown with Fig.11A An exemplary process flow 1101 associated with a sensor structure scheme of the present invention is shown. The process begins at 1110 by injecting a sample into the cartridge assembly. The sample can then be processed at step 1120 by any necessary steps (e.g., filtration, dilution, and / or the like). The order of these pre-processing steps will depend on the nature of the sample and the analyte to be detected. Movement in the system can be controlled pneumatically. In step 1130, the processed sample is sent to the GMR sensor at a specific flow rate. Such a flow rate can be selected to reflect the kinetics of the chemical process between the antibody attached to the biological surface and the analyte on the surface of the GMR sensor. Next, step 1140 introduces a biotinylated antibody (Ab) into the GMR sensor. This creates a "sandwich" structure of the analyte between the two antibodies. In step 1150, beads coated with streptavidin are introduced into the GMR sensor, which can now interact with the biotin-attached antibody. Step 1160 provides for obtaining readings from the GMR sensor reflecting changes in the concentration of magnetic beads on the GMR sensor surface. These readings allow the detection of resistance changes in step 1170. Finally, step 1180 provides a detection result calculated based on the resistance change.

[0108] Fig.11A and 11B The protocol was implemented using cardiac biomarkers, and proof of concept results were obtained in Fig. 12A - shown in C. Fig. 12AA graph of the GMR signal (in ppm) over time (in seconds) in a test run designed to detect the cardiac biomarker D-dimer is shown. To generate this data, a biosurface was prepared by printing a D-dimer capture antibody using 2nL of a 1mg / mL D-dimer antibody in a PBS buffer with 0.05% sodium azide. To test for possible cross-reactivity, two combinations of capture antibodies were printed using 2nL of a 1mg / mL troponin I antibody solution in a PBS buffer with 0.05% sodium azide, and the biosurface was also functionalized with a troponin I capture antibody. In addition, two other controls were printed on the biosurface. The first was a negative control prepared by printing 2nL of a 0.5% BSA solution in a PBS buffer with 0.05% sodium azide, and the second was a positive control prepared by printing 2nL of 1mg / mL biotin coupled to mouse immunoglobulin in a PBS buffer with 0.05% sodium azide. The printed sensor was loaded into a cardiac test cartridge and configured to use the Fig.11A and 11B The "sandwich" test introduced in .

[0109] In the sample test, 120 microliters of plasma or whole blood are loaded into the sample well in the cartridge. A membrane filter is used to remove blood cells as the sample is pulled from the sample well into the flow channel. 40 microliters of plasma (or the plasma portion of whole blood) flows into the metering channel, where a deposited powder containing antibody / biotin conjugate, blocking agent, and mouse immunoglobulin dissolves into the sample solution. When flowing through the sensor area, the analyte, antibody / biotin conjugate and the antibody immobilized on the sensor surface form an antibody-analyte-biotinylated antibody sandwich. The flow rate is modulated depending on the test. For troponin I, the sample is allowed to flow through the sensor for 20 minutes at a flow rate of 1 microliter / minute. For D-dimer, the sample is allowed to flow for 5 minutes at a flow rate of 4 microliters / minute. After the sample flows, streptavidin-coated magnetic beads are introduced, which allow adhesion to the sensor surface where the biotinylated antibody is attached. The GMR sensor measures the attached magnetic beads, which is proportional to the concentration of the analyte in the sample. The bead solution was flowed through the sensor at a flow rate of 4 to 10 μl / min for 5 minutes. The signal was read from the peak within 300 seconds after the beads began to adhere.

[0110] like Fig. 12AAs shown in the curve graph, the negative control printed with only BSA does not adhere to D-dimer, so the signal remains close to the baseline as expected. The positive control with biotinylated mice shows sufficient bead adhesion as expected. The curve graph of the real sample of human D-dimer at 666.6ng / mL shows a peak detection signal of about 750ppm, which shows that D-dimer was successfully detected in the real sample. There is almost no cross-reactivity with the two adherent troponin I capture antibodies (not clearly shown because these lines are very close to the lines of the negative control).

[0111] Fig. 12B A D-dimer calibration curve is shown (GMR signal in ppm vs. D-dimer concentration) by running samples with varying and fixed D-dimer concentrations. The calibration curve allows calculation of concentrations for future unknown samples containing D-dimer as the analyte of interest. Fig. 12C A similar graph in is provided for the cardiac biomarker troponin I. Together these results demonstrate the feasibility of measuring D-dimer and creatinine protein I in blood or plasma samples from experimental subjects.

[0112] Fig.13 FIG. 3 is a functional block diagram of a card box reader 310 according to an embodiment of the present disclosure. Fig.13 As shown, the cartridge reader 310 can be roughly divided into a sample preparation control part and a signal processing part. The memory reading unit 1310 and the sample preparation control unit 1320 constitute the sample preparation control part. The memory reading unit 1310 is adapted to read the information stored in the memory chip 275 on the cartridge assembly 200 when receiving a signal indicating that the cartridge assembly 200 has been inserted into the cartridge reader 310. The sample preparation control unit 1320 is configured to generate pneumatic control signals based on the information read from the memory chip 275 and send them to the pneumatic system 330. In some embodiments, when the cartridge assembly 200 is identified to be inserted into the cartridge reader 310, an indication signal may be generated by the cartridge assembly 200 and sent to the memory reading unit 1310 to notify the insertion event. Alternatively, in other embodiments, such an indication signal may be generated by other components on the cartridge reader 310 and sent to the memory reading unit 1310.

[0113] The signal processing function of the cartridge reader 310 is mainly performed by the signal processor 1330. The signal processor 1330 is suitable for controlling electrical components, preparing and collecting signals, processing, displaying, storing and relaying test results to external systems. For example, the signal processor 1330 operates to generate a control signal for controlling the magnetic field generator 360 so that a magnetic field excitation is applied to the GMR sensor in the cartridge assembly 200. After receiving a measurement signal from the GMR sensor in the cartridge assembly 200 and from at least one reference resistor arranged on the cartridge assembly 200 and / or the signal processor 1330, the signal processor 1330 processes the measurement signal to obtain a test result of the analyte detection. The test result is displayed on an integrated or external display via the display control unit 120. In addition, the signal processor 1330 is coupled to the user interface 140 for receiving instructions from the user. In addition, in some embodiments, the signal processor 1330 is coupled to the communication unit 340 and / or coupled to the diagnostic unit 350, so that diagnosis and evaluation can be made possible only by the test results or in combination with other externally available data.

[0114] Fig.14 FIG. 4 is a flow chart of a process of a card box reader 310 according to an embodiment of the present disclosure. Fig.14 As shown, the cartridge reader 310 begins its operation in step 1410 by initializing the operating mode based on the system configuration file and / or the instructions input by the user via the user interface 140. Next, the process waits for a signal indicating that the cartridge assembly 200 has been inserted into the cartridge reader 310 in step 1420. This signal may be generated by the cartridge assembly 200 or by the cartridge reader 310 when the insertion is recognized. In response to receiving such a signal, in step 1430, the cartridge reader 310 reads the memory chip 275 on the cartridge assembly 200. Next, in step 1440, the cartridge reader 310 generates a control signal based on the read information and sends it to the pneumatic system 330 for pneumatic control of preparing the sample to be tested. In step 1450, the cartridge reader 310 prepares measurement signals on the GMR sensor and on the at least one reference resistor, and receives such signals. Then, in step 1460, the cartridge reader 310 processes the received measurement signals to generate a test result. Finally, in step 1470, the cartridge reader 310 sends the generated test results to the display control unit 120 for display to the user.

[0115] Fig.15 FIG. 1 is a schematic diagram showing a functional block diagram of a signal processor 1330 according to an embodiment of the present disclosure. Fig.15As shown, the signal processor 1330 includes a system operation initializer 1510, a configuration file 1520, a signal processing control unit 1530, a signal preparation unit 1540, a signal processing unit 1550, and an optional data storage 1560. The system operation initializer 1510 is configured to set the system operation environment and initialize the functions of the signal processor 1330, especially the functions of the signal processing control unit 530, based on the system configuration information read from the configuration file 1520 and / or the instructions received via the user interface 140. The signal processing control unit 1530 operates to generate control signals for controlling the signal preparation unit 1540 and the signal processing unit 1550. It also operates to control the display of the detection results on the display via the display control unit 120, and to control the data communication between the signal processing control unit 1550 and the communication unit 340 and / or the diagnosis unit 350. The signal preparation unit 1540 is configured to, under the control of the signal processing control unit 1530, prepare the measurement circuit, excite the AC magnetic field applied to the GMR sensor, generate a carrier signal applied to the measurement circuit, collect the measurement signal from the measurement circuit, and feed the measurement signal to the signal processing unit 1550 after amplification and analog-to-digital conversion. The signal processing unit 1550 is configured to process the received measurement signal by analytically solving the detection result and send the detection result to the signal processing control unit 1530. In addition, in some embodiments, the result data can be stored in the optional data storage 1560.

[0116] Fig.16 FIG. 1 is a flowchart of a process of the signal processor 1330 according to an embodiment of the present disclosure. Fig.16 As shown, the system operating environment is initialized by reading system configuration information from a configuration file and / or receiving user instructions via the user interface 140, and the process starts at step 1610. Then, at step 1620, a series of control signals are generated by the signal processing control unit 1530 to manage the operation of the signal preparation unit 1540 and the signal processing unit 1550. In step 1630, the measurement circuit is built by the signal preparation unit 1540 based on the control signal from the signal processing control unit 1530 to prepare the measurement signal from the GMR sensor and from at least one reference resistor. Then, in step 1640, the prepared measurement signal is processed by the signal processing unit 1550 to resolve the test result of the analyte detection. Finally, in step 1650, the generated test result is sent from the signal processing unit 1550 to the display control unit 120 for display to the user.

[0117] Fig.17 The functional block diagram of the signal processing control unit 1530 according to an embodiment of the present disclosure is shown in principle. Fig.17As shown, the signal processing control unit 1530 includes a multiplexer control signal generator 1710, a multiplexer control signal output unit 1720, a D / A converter control signal generator 1730, a D / A converter control signal output unit 1740, and a resolution and I / O control unit 1750. Based on information related to the system configuration and / or input via the user interface 140, the multiplexer control signal generator 1710 generates a control signal for one or more multiplexers in the signal preparation unit 1540 and sends it to the multiplexer through the multiplexer control signal output unit 1720. The D / A converter control signal generator 1730 and the D / A converter control signal output unit 1740 are responsible for generating and sending control signals to one or more D / A converters in the signal preparation unit 1540. The resolution and I / O control unit 1750 manages the measurement signal processing performed by the signal preparation unit 1550, receives the processing results, and sends them to the display control unit 120. Optionally, the solution and I / O control unit 1750 also serves as an interface with the communication unit 340 and with the diagnosis unit 350 .

[0118] Fig.18 1 is a flow chart of a process of the signal processing control unit 1530 according to an embodiment of the present disclosure. The process starts at step 1810 by generating a multiplexer control signal in the multiplexer control signal generator 1710 based on information read from a configuration file and / or a user instruction received from the user interface 140. In step 1820, the generated control signal is sent to at least one multiplexer in the signal preparation unit 1540 to configure the measurement circuit structure. In step 1830, a D / A converter control signal is generated by the D / A converter control signal generator 1730 based on the configuration information and / or the user instruction, and is sent to at least one D / A converter in the signal preparation unit 1540 in step 1840. Next, in step 1850, based on the configuration information and / or the user instruction, the solution and I / O control unit 750 controls the signal processing of the measurement signal by the signal processing unit 1550. After the signal processing is completed, in step 1860, the solution and I / O control unit 1750 receives the test result from the signal processing unit 1550. Next, in step 1870, the solution and I / O control unit 1750 sends the received test results to the display control unit 120 for display on an integrated or external display. The order of steps 1810-1820 and 1830-1840 can be changed, that is, the control of the multiplexer can be before or after the control of the D / A converter, or they can be performed simultaneously.

[0119] Fig.19 The functional block diagram of the signal preparation unit 1540 according to an embodiment of the present disclosure is shown in principle. Fig.19As shown, the signal preparation unit 1540 includes a carrier signal generating part, a magnetic field excitation part, a circuit configuration part, a signal pickup part and a clock synchronization part. For ease of explanation, Fig.19 Also shown are the magnetic field generator 360 and the GMR sensor in the cartridge assembly 200 , although they are not components of the signal preparation unit 1540 .

[0120] The carrier signal generation section includes a D / A converter 1910, a carrier signal generator 1920, and a carrier signal buffer 1930. The D / A converter 1910 is configured to receive a control signal from the D / A converter control signal output unit 1740 of the signal processing control unit 1530, and to generate a carrier signal generation parameter based on the received control signal. The carrier signal generator 1920 is configured to generate an AC carrier signal for the measurement circuit based on the carrier signal generation parameter from the D / A converter 1910. The carrier signal buffer 1930 is coupled between the carrier signal generator 1920 and the measurement circuit so that the carrier signal generator 1920 presents a very low impedance output compared to the higher impedance of the measurement circuit. Optionally, a filter can be arranged on the carrier signal input to the measurement circuit to remove potential harmonics.

[0121] Although the AC voltage signal Fig.19 , which is shown as a carrier signal applied to the measurement circuit. Depending on the structure of the measurement circuit, the carrier signal can be an AC current signal, a DC voltage signal or a DC current signal.

[0122] The magnetic field excitation part includes a D / A converter 1910 and a magnetic field driver 1940. Based on the control signal received from the D / A converter control signal output unit 1740 of the signal processing control unit 1530, the D / A converter 1910 generates a magnetic field generation parameter. The magnetic field driver 1940 is configured to drive the magnetic field generator 360 based on the magnetic field generation parameter, thereby applying an AC magnetic field to the GMR sensor. Fig.19 The carrier signal generating section and the magnetic field excitation section shown share a common D / A converter, but they may use separate D / A converters to generate the carrier signal control parameters and the magnetic field excitation control parameters.

[0123] The circuit configuration part includes at least one multiplexer 1950 and at least one reference resistor 1955. When the card cartridge assembly 200 is inserted into the card cartridge reader 310, an electrical connection is formed between the electrical contact pads 640A, 640B of the GMR sensor chip 280 on the card cartridge assembly 200 and the signal preparation unit 1540 of the card cartridge reader 310 via the electrical contact pads 290 provided on the card cartridge assembly 200. Based on the multiplexer control signal received from the signal processing control unit 1530, the at least one multiplexer 1950 is connected to more than one GMR sensor or more than one reference resistor to configure a suitable measurement circuit.

[0124] In some embodiments, the multiplexer 1950 and the reference resistor 1955 are disposed on the cartridge reader 310 for cost advantages. Alternatively, in other embodiments, they may be disposed on the cartridge assembly 200 to obtain a number of performance advantages, such as reduced trace length between the multiplexer and the GMR sensor, a reduced number of connections from the cartridge assembly 200 to the cartridge reader 310, etc. Alternatively, the multiplexer and the reference resistor may be disposed on both the cartridge reader 310 and the cartridge assembly 200.

[0125] The signal pickup portion (also referred to as a "differential voltage probe" or "voltage probe") includes a measurement signal buffer 1960, a differential amplifier 1970, and an A / D converter. The measurement signal buffer 1960 is coupled between the multiplexer 1950 and the differential amplifier 1970, and is used to make the measurement circuit present a relatively high impedance at the input of the differential amplifier 1970. The differential amplifier 1970 operates to capture the time series of voltage observations from the measurement circuit and sends the amplified measurement signal to the A / D converter 1980. The A / D converter 1980 is configured to send the analog-to-digital converted measurement signal to the signal processing unit 1550. Optionally, a filter can be used on the differential amplifier 1970 and / or the A / D converter 1980 to remove harmonics.

[0126] Preferably, in some embodiments, a clock synchronizer 1990 is used to provide synchronization between the carrier signal generation section, the magnetic field excitation section, and the signal pickup section. Specifically, the generation of the carrier signal generation parameters and the magnetic field generation parameters by the D / A converter 1910 is clocked by the same source as the A / D converter 1980, i.e., by the clock synchronizer 1990.

[0127] Fig. 20 FIG. 1 is a flowchart of a process of the signal preparation unit 1540 according to an embodiment of the present disclosure. Fig. 20As shown, the process starts in step 2010 by receiving a multiplexer control signal from the signal processing control unit 1530. Next, in step 2015, the multiplexer 1950 in the signal preparation unit 1540 configures the measurement circuit based on the received multiplexer control signal by connecting a specific GMR sensor and / or a reference resistor. In step 2220, the signal preparation unit 1540 receives a D / A converter control signal from the signal processing control unit 1530. Based on the D / A converter control signal, in step 2025, the D / A converter 1910 in the signal preparation unit 1540 generates a carrier signal generation parameter. Next, in step 2230, a carrier signal is generated based on the generated carrier signal generation parameter, and is buffered and applied to the measurement circuit configured in step 2015. In step 2035, the D / A converter 1910 in the signal preparation unit 1540 generates a magnetic field generation parameter based on the D / A converter control signal. Next, in step 2040, a magnetic field is generated by the magnetic field generator driver 1940 based on the magnetic field generation parameter excitation and applied to the GMR sensor via the magnetic field generator 360. In step 2045, the measurement signal collected on the configured measurement circuit is buffered and then amplified by the differential amplifier 1970 in the signal preparation unit 1540. In step 2050, the amplified measurement signal is converted into a digital signal by the A / D converter 1980 in the signal preparation unit 1540. Finally, in step 2055, the converted digital signal is sent to the signal processing unit 1730 for further processing. The order of steps 2025-2030 and 2035-2040 can be changed, that is, generating the magnetic field excitation can be before or after generating the carrier signal, or they can be performed simultaneously.

[0128] Fig.21 The functional block diagram of the signal processing unit 1550 according to an embodiment of the present disclosure is shown in principle. Fig.21 As shown, the signal processing unit 1550 includes a reference signal generator 2110 , a multiplier 2120 , an integrator 2130 , an integration timing controller 2140 and a closed-form solution unit 2150 .

[0129] The reference signal generator 2110 is configured to receive a control signal from the solution and I / O control unit 1750 of the signal processing control unit 1530, generate in-phase and quadrature (rotated 90 degrees) sinusoidal reference signals at all frequencies of interest based on the received control signal, and send the generated reference signals to the multiplier 2120. The multiplier 2120 is configured to receive the measurement signal from the A / D converter 1980 of the signal preparation unit 1540, multiply the measurement signal by the reference signal from the reference signal generator 2110, so as to generate in-phase products and quadrature products at each frequency of interest for each measurement signal. The in-phase products and quadrature products are sent to the integrator 2130. The integrator 2130 is configured to accumulate these products under the control of the integration timing controller 2140, and send the accumulation to the closed-form solution unit 2150. The closed-form solver 2150 is adapted to solve for the received cumulative GMR sensor resistance and magnetoresistance quantities that are phase accurate and unaffected by the frequency, amplitude or phase of the applied carrier signal or the amplitude or phase response of the circuit supplying the signal.

[0130] Fig. 22 FIG. 1 is a flowchart of a process of the signal processing unit 1550 according to an embodiment of the present disclosure. Fig. 22 As shown, the process starts in step 2210 by receiving a control signal from the solution and I / O control unit 1750 of the signal processing control unit 1530. In step 2215, based on the control signal, in-phase and quadrature reference signals at all frequencies of interest are generated in the signal processing unit 1550. Then, in step 2220, the reference resistor measurement signal is received from the signal preparation unit 1540. In step 2225, the reference resistor measurement signal is multiplied by the in-phase and quadrature sinusoidal reference signals generated in step 2215 to generate in-phase and quadrature products at all frequencies of interest. In step 2230, the in-phase and quadrature products obtained in step 2225 are accumulated under the control of the integration timing. In steps 2235-2250, similar processing is performed for the received measurement signal of the GMR sensor. In step 2250, the measurement result is solved in closed form by the in-phase and quadrature products of the reference resistor measurement signal and the GMR sensor measurement signal. Finally, in step 2255 , the test results obtained by solution are sent to the solution and I / O control unit 1750 of the signal processing control unit 1530 .

[0131] The order of steps 2220 - 2230 and 2235 - 2245 may be altered, ie, the accumulation of the reference resistor measurement signal may precede or follow the accumulation of the GMR sensor measurement signal.

[0132] As mentioned above Figure 8BAs described, the resistance of a GMR sensor changes under the influence of a magnetic field. The GMR sensor can be monitored in real time while superparamagnetic nanoparticles adhere to the GMR sensor through a calibration. Local changes in the magnetic field are translated into changes in the sensor resistance and observed as changes in voltage in a suitably configured measurement circuit.

[0133] However, by using conventional differential measurement circuits, such as a Wheatstone bridge or Anderson loop, it is not possible to directly distinguish between increased and decreased reluctance based on the voltage on the voltage probe. An example of a voltage measurement obtained on one possible measurement circuit topology is Fig.23 . From this graph, it can be seen that without phase sensitivity, it is difficult to derive the correct relationship between the sensor impedance (Zs) and the reference impedance (Zr). The only thing that can be seen from the increased voltage is that the components in the measurement circuit have changed relative to each other. As a result, when these conventional circuits are used for AC measurements, this problem must be solved in a suboptimal way.

[0134] A common suboptimal choice is to offset the measurement circuit from the equilibrium point so that the voltage signal on the voltage probe never crosses zero. This approach has a negative impact on the signal-to-noise ratio of the measurement circuit. In addition, even with an offset, the increased or decreased reluctance must be inferred through reasoning or other indirect knowledge.

[0135] Otherwise, if a balanced measurement circuit is used to achieve a good signal-to-noise level, large artifacts appear in the telemetry: the magnetic resistance appears to decrease to zero and then increase ( Fig.23 The V-shape shown in , which always looks positive), but in reality it may only be decreasing or increasing.

[0136] The present disclosure introduces phase sensitivity into the context of GMR-based detection to derive correct measurements. The signal processing techniques disclosed herein have the ability to make measurements on perfectly balanced GMR measurement circuits (e.g., balanced Wheatstone bridges) without the problems faced by the prior art. In addition, the techniques are general enough to be applied to any available circuit topology to achieve phase-sensitive measurement and calculation of the magnetoresistance in a GMR sensor. The versatility of the methods disclosed herein provides another competitive advantage because it enables direct comparison between different circuit topologies while continuing to deliver the same output signal to the end user.

[0137] Fig.24A A simple circuit topology for implementing this technique is shown. Fig. 24B -C shows several other possible circuit topologies. For example, the circuit topology based on Anderson loop and AC current source is shown in Fig. 24BThe circuit topology based on the Wheatstone bridge and AC voltage source is shown in Fig.24C The circuit topology includes a carrier source 2410 or 2415 , a first control circuit Ckt1 2420 , a second control circuit Ckt2 2430 , a voltage probe 2440 , at least one GMR sensor 2450 , at least one high-precision reference resistor 2460 , and a magnetic field generator 2470 .

[0138] like Fig.24A As shown, carrier source 2410 is configured to provide a buffer current source for applying an AC carrier signal with a frequency of ω1 (for different measurement circuit configurations, carrier source 2415 can operate to provide a buffer voltage source). Fig.24A In the embodiment of the present invention, the first control circuit Ckt1 2420 allows switching between the GMR sensor 2450 and a similarly arranged high precision reference resistor 2460 with known performance to apply the AC carrier signal from the carrier source 2410 to the GMR sensor 2450 or the high precision reference resistor 2460. By constructing the detection path and replicating the reference path in Ckt1, the present technology achieves balanced parasitic elements. In these structures, the parasitic elements appear at equivalent locations. Therefore, due to the common mode rejection of the differential voltage probe, the differential voltage on the voltage probe mainly comes from the difference between the GMR sensor and the reference resistor being measured. In other embodiments, in addition or as an alternative, the parasitic elements are explicitly modeled for decomposition from the measured signal to cancel the effects of the parasitic elements.

[0139] The second control circuit Ckt2 2430 and the magnetic field generator 2470 are used to apply a sinusoidal magnetic field with a frequency of ω2 to the GMR sensor 2450. The applied magnetic field will modulate the resistance of the GMR sensor but will not affect the high precision reference resistor 2460.

[0140] The differential voltage probe 2440 is connected to detect the impedance of the GMR sensor 2450 or the high precision reference resistor 2460. The voltage probe 2440 is designed to have a sufficiently high impedance so that the measurements of the GMR sensor and the reference resistor are not disturbed.

[0141] Since the applied sinusoidal magnetic field modulates the resistance of the GMR sensor, applying this sinusoidal magnetic field at frequency ω2 while applying a carrier signal at frequency ω1 will modulate the amplitude of the voltage associated with the GMR sensor 2450, generating sideband voltages. The first set of sideband voltages appear at frequencies ω1-ω2 and ω1+ω2.

[0142] However, the sideband voltage is not induced on the high precision reference resistor 2460 by applying a sinusoidal magnetic field. Therefore, when the high precision reference resistor 2460 is switched into the measurement circuit for observation, it is necessary to manually induce the sideband voltage on the reference resistor 2460. This can be done by mixing the sideband signal into the carrier with an amplitude equal to the carrier amplitude. In other words, the sideband signal can be induced by adding the carrier signal upstream of the buffer that buffers the voltage or current source. Specifically, the sideband signal can be added to the carrier signal with an amplitude equal to the carrier.

[0143] Fig.24A The measurement process for the topology shown is as follows: Via the first control circuit Ckt1 2420, the GMR sensor 2450 is switched into the measurement circuit while both the carrier signal and the sinusoidal magnetic field are applied. Using the voltage probe 2440, a time series of voltage is captured for a duration t1 selected based on noise requirements.

[0144] Similarly, the high precision reference resistor 2460 is switched into the measurement circuit. At this time, a carrier signal with a frequency of ω1 and a mixed signal with an amplitude equal to the carrier and frequencies of ω1-ω2 and ω1+ω2 are applied. Again, a voltage probe 2440 is used to capture the time series of the voltage for a duration t2 also selected based on the noise requirements.

[0145] Thus, each sample of the corresponding time series is multiplied by a sample from an in-phase sinusoidal time series of frequencies ω1, ω1-ω2, ω1+ω2 and a quadrature sinusoidal time series of frequencies ω1, ω1-ω2, ω1+ω2 offset by 90 degrees. By accumulating the in-phase and quadrature products at each frequency on an integrator for the GMR sensor 2450 and the high precision reference resistor 2460, six complex quantities are generated that are proportional to the voltage detected at the frequencies ω1, ω1-ω2, ω1+ω2 during the observation period of the GMR sensor 2450 and the high precision reference resistor 2460.

[0146] Next, the GMR sensor accumulation is divided by t1 and the reference resistor accumulation is divided by t2. The complex voltage proportional term v associated with the GMR sensor 2450 is constructed by designating the in-phase accumulation as the real part and the quadrature accumulation as the imaginary part. s , we get v s (ω1),v s (ω1-ω2) and v s (ω1+ω2). Similarly, the complex voltage proportional term v associated with the high precision reference resistor 2460 is obtained. tx , that is, v tx (ω1),v tx (ω1-ω2) and v tx (ω1+ω2). Then, the six complex terms vs (ω1),v s (ω1-ω2), v s (ω1+ω2),v tx (ω1),v tx (ω1-ω2), v tx (ω1+ω2), the zero magnetic field resistance (R0) of the GMR sensor is solved analytically, and dR is solved by Taylor series expansion on the sidebands. From dR / R0, the magnetoresistance ratio MR is obtained, which is the resistance change of the GMR sensor under the application of a sinusoidal magnetic field divided by the sensor resistance under the application of a zero magnetic field.

[0147] In the above, both duration t1 and duration t2 are selected to meet the noise requirements. Noise introduced by system time variations due to finite t1 can be minimized by selecting t1 so that the cumulative time for signals with frequencies ω1, ω2, ω1-ω2, ω1+ω2 is not modulo 2π radians as a fraction of the total cumulative time. Random noise can be reduced by increasing t1. Duration t2 is selected in a manner similar to t1.

[0148] With the disclosed technique, there is no need to deviate from the equilibrium point, which allows for optimal gain stage management and improved signal-to-noise levels. Resistive and reactive components can be decomposed, and parasitic elements can be measured and removed. In addition, certain difficult artifacts can be cancelled, such as converter group delay, which appears in the form of large phase offsets without special treatment. In addition, the cancellation of transfer functions upstream and downstream of the GMR sensor under test provides a significant R&D advantage due to the high independence of component tolerances in hardware. Because the measurement is not perturbed by components outside Ckt1 and Ckt2, there are three unique benefits: (1) the designer has a lot of freedom to modify circuit components outside Ckt1 and Ckt2 without changing the output telemetry; (2) high-precision detection can be obtained even without tight tolerances for components outside Ckt1 and Ckt2; (3) high-precision detection does not require explicit modeling of components outside Ckt1.

[0149] Those skilled in the art will appreciate that Fig.24A -C are just a few limited examples of applicable circuit topologies. GMR-based analyte detection systems can be built around any of these and other available circuit topologies. Telemetry can be directly compared in any such circuits, given R0, dR, and MR. The performance of these circuits can be evaluated in terms of system specifications. These evaluations during system development may result in changes in circuit topology. By outputting the signal as magnetoresistance rather than voltage, the circuit topology can be changed without interrupting the end user's workflow.

[0150] An exemplary GMR-based analyte detection system is given below to describe the operation and structure of such a system in detail. This exemplary system introduces a reconfigurable on-chip Wheatstone bridge topology (in Fig.24C Phase-sensitive AC measurement of the amplitude-modulated magnetoresistive signal in FIG. Fig.24C The Wheatstone bridge shown includes a pair of GMR sensors in the GMR sensor chip 280 and a pair of reference resistors RTX1a-RTX2b disposed on the cartridge assembly 200 or the cartridge reader 310 or both. The GMR sensors GMR1a, GMR2b labeled black are functional for verification, while the GMR sensors GMR1b, GMR2a labeled white are blocked.

[0151] As mentioned previously, the GMR sensor itself is a resistive element whose resistance depends on the magnitude and direction of the total magnetic field. The total magnetic field includes the magnetic field applied from the magnetic field generator (which can be external to the GMR sensor chip, or integrated with the chip) and any perturbations from magnetic nanoparticles near the sensor.

[0152] Therefore, the basic principle of the system is to monitor the resistance and magnetoresistance of the GMR detection element before, during and after the application of functionalized magnetic nanoparticles. The components being tested can cause an increase or decrease in the number of magnetic nanoparticles adhering to the sensor surface. This increase or decrease can be observed relative to a reference element. The reference element can be a reference sensor or a reference resistor with a negative control. Such a reference element group can be used as a baseline for observing changes in an effective sensor.

[0153] By applying a sinusoidal voltage and observing the characteristics of the sensor compared to the reference element in the presence of this sinusoidal voltage or current, the exemplary system uses electrical subtraction to observe the resistance and magnetoresistance changes of the effective GMR sensor compared to the reference sensor (or reference resistor) with negative control after applying functional magnetic nanoparticles. In this example, since the applied signal is a voltage, the current flowing through the sensor and the reference element can be directly subtracted. Electrical subtraction in the presence of an applied sinusoidal voltage can be achieved by placing the effective GMR sensor and the reference element in a voltage divider and subtracting the voltage at the midpoint. In other examples, if the applied sine is a current, electrical subtraction can be achieved by subtracting the voltage drop on the effective GMR sensor and the reference element.

[0154] Between each observation of the effective sensor-reference element subtraction, the system observes the subtraction of the signal across a high precision reference resistor whose value is known to the code in the signal processor 1330. The signal processor 1330 uses the arithmetic division of each sensor-reference element observation with its previous (or next) reference resistor-reference resistor observation to cancel the transfer function of all circuits upstream of the sensor that provide the sinusoidal voltage or current signal, and to cancel the transfer function of all circuits downstream of the sensor that observe the signal. This provides a phase sensitive measurement that is immune to variations in the circuits whose transfer functions are cancelled. This immunity to variation is valid over unit time, from one unit to another, and from one system design modification to the next.

[0155] In a unit-by-unit calibration, the amplitude response of the circuit supplying the applied field is processed separately from the division-based transfer function cancellation of the signal processor 1330 to ensure that the strength of the applied magnetic field is as expected. In the case where the applied field is sinusoidal rather than DC, this produces an amplitude modulation of the applied sinusoidal current or voltage carrier. In the presence of such amplitude modulation, the magnetic resistance appears in the upper and lower sidebands. The phase response of the circuit supplying the applied field appears in the sidebands, where the lower sideband rotates the negative value of the phase of the applied field and the upper sideband rotates the positive value of the phase of the applied field. This rotation of the field is offset by the code of the signal processor system 1330 by rotating the sideband phase to its average value. Therefore, the transfer function of the circuit supplying the field is fully taken into account, making phase-sensitive and phase-accurate magnetic resistance measurements possible even when the applied field is AC. Importantly, the phase-sensitive and phase-accurate measurements allow the distinction between scenarios where the magnetic resistance is reduced and scenarios where the magnetic resistance is increased. Without phase-sensitive measurements, this would be difficult to distinguish.

[0156] The high precision reference resistor 2460 can be placed on either the cartridge reader 310 or the cartridge assembly 200. In either location, their logical function and connections are the same, but there is a cost vs. performance tradeoff regarding their placement. Placing the high precision reference resistor 2460 near the GMR sensor on the cartridge assembly 200 can theoretically improve performance by further canceling out common mode artifacts. This can also make it possible to match the reference resistor and the GMR sensor it is paired with on a cartridge by cartridge basis. However, if the cartridge assembly 200 is very cost sensitive and the cartridge assembly 200 is a larger mass-produced product than the signal preparation unit 1540 of the cartridge reader 310, it may be more cost-effective to place the high precision reference resistor 2460 on the cartridge reader 310.

[0157] Similarly, the multiplexer can be arranged on the card box assembly 200, the card box reader 310, or on both. The arrangement of the multiplexer should be selected to optimize system cost and performance, while limiting the design to a controllable number of connections between the card box assembly 200 and the card box reader 310, but supporting the desired number of addressable sensors in the system. In the case where the multiplexer is placed on both the card box assembly 200 and the card box reader 310 and both are used together to address the GMR sensors, many signals can travel from the card box assembly 200 to the multiplexer on the reader. The second layer of multiplexers on the card box assembly allows for bank switching. With bank switching, the number of sensors that can be addressed is greatly increased.

[0158] The observation of the GMR sensor and the reference resistor is performed by measuring the current flowing through them or the voltage across them with an analog-to-digital converter 1910 at discrete times. The digital-to-analog converter 1910, which generates the applied sinusoidal voltage or current and generates the applied field, is clocked by the same source as the analog-to-digital converter 1980. The signal processor 1330 implements a phase-locked amplifier in the code that measures the correlation between the signal observed on the analog-to-digital converter 1980 and the in-phase and quadrature (rotated 90 degrees) sinusoids at all frequencies of interest generated internally. For each sample at each frequency of interest, the signal from the analog-to-digital converter 1980 is multiplied by the internal in-phase and quadrature sinusoids, producing in-phase products and quadrature products. These products are accumulated over the duration of each observation.

[0159] In a time-invariant system with infinite observation time, the ratio of in-phase and quadrature accumulations will be fixed for given circuit and sensor conditions. The signal processor 1330 automatically selects the generator frequency and observation time so that all signals of interest are at the same phase angle at the beginning and end of each observation. This allows the system to simulate the operation of a time-invariant system, even for very short observation durations. The signal processor 1330 also starts sensor observations at a consistent generator phase angle from one observation to the next. This eliminates variations that may be introduced due to differences in phase response and group delay of the circuits generating the applied sinusoidal current or voltage and the circuits generating the applied field.

[0160] GMR sensor measurements are performed as follows. By sending appropriate commands to the multiplexer 1950 (which may be located on the card box assembly 200 or the card box reader 310 or both), the signal processor 1330 configures the circuit for observing the reference resistor structure. The digital-to-analog converter 1910 is used to generate the applied sinusoidal voltage or current and the applied field. A minimum waiting time is observed to allow the transient state of the multiplexer switching to stabilize. After this minimum waiting time, the signal processor 1330 begins to accumulate the in-phase and quadrature products derived from the reference resistor signal observed on the digital-to-analog converter 1980. After all internal (and external) sine wave generators 2110 have passed an integer number of cycles, the integrator 2130 is frozen and captured. The number of past cycles can be different at multiple observation frequencies, but must all be integers. After the first capture of the integrator 2130, the signal generation from the digital-to-analog generator 1910 continues, and at the same time, the signal processor 1330 commands the multiplexer 1950 to configure the circuit for GMR sensor observation. A minimum waiting time is observed to allow transients from multiplexer switching to settle. After this minimum waiting time, the signal processor 1330 waits for all signal generators to reach a predetermined phase angle. After reaching the predetermined phase angle, the signal processor 1330 begins to accumulate the in-phase and quadrature products derived from the sensor signals observed at the analog-to-digital converter 1980. After an integer number of cycles of all internal (and external) sine wave generators 2110 have passed, the integrator 2130 is frozen and captured again. The signal processor 1330 divides the captured sensor accumulation by the captured reference accumulation, and, since the reference resistance value is previously known, uses the quotient to calculate the phase-accurate sensor resistance and reluctance that are not affected by the frequency, amplitude or phase of the applied sinusoidal current or voltage, nor by the amplitude or phase response of the circuit that feeds it. The sensor resistance and reluctance are also not affected by the frequency or phase angle of the applied field, nor by the phase response of the circuit that feeds it. Therefore, all of these elements can be freely modified (for example, to achieve the best signal-to-noise ratio) without interfering with the resistance and reluctance telemetry.

[0161] As mentioned above, the GMR sensor is modeled as a resistor that changes proportionally to the total magnetic field. This resistance value can be expressed as:

[0162] R=Rn(1+kH),

[0163] Where Rn is the nominal resistance of the GMR sensor with zero magnetic field applied to it, H is the total magnetic field, k is the GMR sensor characteristic that relates resistance changes to the total magnetic field, and R is the total resistance including resistance changes induced by the magnetic field.

[0164] The dimensionless quantity magnetoresistance (MR) is defined as a measure of the change in resistance of a GMR sensor. It is expressed as the total resistance in the presence of a magnetic field divided by the nominal resistance at zero magnetic field. Therefore:

[0165] MR=Rn(1+kH) / Rn=1+kH

[0166] For those GMR sensors that are functionalized for characterization, magnetic nanoparticles adhere to the sensor surface, thus changing the total magnetic field, which in turn changes the magnetoresistance. The change in MR, delta(MR), is the ultimate observable quantity, as this is a quantity directly related to the concentration of magnetic nanoparticles in the vicinity of the functionalized sensor, and can therefore be used to infer their presence as well as measure their concentration.

[0167] like Fig.24C As shown, for a full-bridge topology, a voltage divider sensor pair is provided, wherein each pair of sensors includes a sensor functionalized for verification and a blocking sensor. When a voltage is applied to any one of these voltage dividers, and assuming that the performance of the functionalized sensor and the blocking sensor is otherwise identical, a voltage that varies only due to the delta (MR) caused by the attachment of magnetic nanoparticles to the functionalized sensor can be observed at the midpoint of each voltage divider. Since other aspects of sensor performance may be unstable over time, arranging otherwise identical sensors in a voltage divider pair also provides for canceling artifacts introduced by these time-varying (e.g., thermal) changes.

[0168] Depend on Fig.24C It can be seen that the voltage divider sensor pair can have one of two arrangements. Functionalized Sensor ( Fig.24C The black GMR1a, GMR2b in the middle (in FIG. 24) can be connected to a voltage source or ground, and the blocking sensor (white GMR1b, GMR2a in FIG. 24) is next to it. Although at least one multiplexer is shown in the topology, in practice, a freely configurable switch group can be used to enable multiple nodes to be connected simultaneously. By using a freely configurable multi-channel switch with drains (e.g., drains A, B), the midpoint of any voltage divider can be connected to the inverting input or the non-inverting input of the instrumentation amplifier.

[0169] For example, by connecting one or more voltage dividers of one arrangement to drain A and one or more voltage dividers of another arrangement to drain B, meaningful delta(MR) measurements can be made. Alternatively, the midpoints of similarly arranged voltage dividers can be connected to drain A or B, and a high-precision reference resistor divider pair ( Fig.24C The midpoint of the reference resistors (referred to as RTX1a, RTX1b, RTX2a, and RTX2b) can be connected to the other drain. A third configuration is to connect the midpoints of two high precision reference resistor divider pairs, one to each drain. This third configuration provides a means of measuring circuit characteristics external to the bridge circuit.

[0170] For example, Fig.24CMeasurements of the topology shown can be performed as follows: Before the introduction of the magnetic nanoparticles, all sensor dividers can be measured individually in a bridge configured such that the sensor divider midpoint is connected to one drain and the high-precision resistor divider midpoint is connected to the other. The resistance balance and the magnetoresistance balance can be confirmed for each sensor divider separately. For out-of-spec dividers, the individual dividers can be isolated, rather than isolating the entire bridge as is necessary in a setup with a static configuration of the bridge.

[0171] For the characterization measurement itself, in some embodiments, the midpoints of any number of voltage divider pairs can be connected to the drain simultaneously, as long as the functionalized sensors of the voltage divider pairs are functionalized for the same target and the midpoints of similarly arranged voltage dividers are connected to the same drain and the midpoint of another arranged voltage divider is connected to the other drain. In other embodiments, since the differential voltage probe does not need to be offset from 0 volts, more than one voltage divider sensor pair in configuration 1 (or 2) can be connected to one input of the voltage probe and the midpoints of more than one voltage divider sensor pair also in configuration 1 (or 2) can be connected to the other input. The advantage is twofold: first, by connecting many voltage dividers, the effective sensor area can be increased, and second, the voltage appearing on the differential probe is zero until the functionalized sensor changes relative to the non-functionalized sensor. In other words, the voltage is generated only due to this difference, which means optimal gain stage management and improved SNR.

[0172] Connecting many voltage dividers simultaneously is beneficial because it reduces noise and coefficient of variation: for voltage dividers connected simultaneously, their sensors then act as one unit and combine the volume of the free layer, and the magnetoresistive sensor noise decreases as the square root of the volume of the free layer. The reduced coefficient of variation is due to the fact that the random distribution of the magnetic nanoparticles will allow for better measurements using a larger sensing area (it is known from the literature that magnetoresistive sensors detect nanoparticles differently based on their position relative to the free layer).

[0173] In one example, further optimization is performed to ensure that the same number of voltage divider pairs are connected to drain A and drain B. Connecting an equal number of voltage dividers presents balanced impedances to the non-inverting and inverting inputs of the instrumentation amplifier, thereby maximizing the common mode rejection ratio of the instrumentation amplifier. However, the process and algorithm described in this example are also valid for other examples where an unmatched number of voltage dividers are connected to the two drains.

[0174] For observation of sensor magnetoresistance, an AC voltage is connected to the configured bridge and, at the same time, an AC magnetic field is applied. The applied AC magnetic field modulates the sensor resistance via the magnetoresistance effect. In the case of magnetic nanoparticles attached to the sensor functionalized for the assay, the sensor voltage divider becomes unbalanced in a predictable manner related to delta(MR). This in turn presents an amplitude modulated voltage on the instrumentation amplifier with upper and lower sideband components related to delta(MR).

[0175] The analog-to-digital converter 1980 is connected to the output of the instrumentation amplifier 1970. The output of the analog-to-digital converter 1980 is collected by the signal processing unit 1550. Internally to the signal processing unit 1550, in-phase and quadrature (rotated 90 degrees) sinusoidal signals are generated at the frequency of the carrier voltage applied to the bridge and the frequency of the sideband voltages generated due to the carrier amplitude modulation. The correlation between the internal in-phase and quadrature signals and the signal observed at the analog-to-digital converter 1980 is measured by evaluating the integrated average of the product of the internally generated signals and the sampled signals observed at the output of the analog-to-digital converter 1980 over the course of an integer number of cycles at all three frequencies. The in-phase and quadrature correlations at each frequency are equivalent to the complex voltages observed at each frequency, which are normalized by multiplying by the transfer function of the logic and circuitry external to the bridge.

[0176] Immediately before or after each sensor bridge observation, an observation of the high precision reference resistor bridge is performed. In order to produce a non-zero voltage on the reference resistor bridge, one or more reference resistors 1955 must be mismatched with the others. In the algorithm presented here, one resistor can be mismatched with the others, and the other three can have equal values.

[0177] Since the reference resistor bridge is field insensitive, no amplitude modulated sideband voltages appear on it. Instead, the voltages at the carrier and two sideband frequencies are generated, added and applied together directly to the reference resistor bridge. For sensor bridge observation, the complex voltages at the three frequencies are measured by multiplying the internally generated in-phase and quadrature sinusoids. The average correlation is also integrated here over a period of time over which an integer number of cycles have elapsed at all three frequencies. The complex voltages observed on the reference resistor bridge at the three frequencies of interest are normalized by multiplying by the same transfer function as appears in the sensor voltages.

[0178] In order to solve delta(MR) from the six voltages, three observed voltages on the sensor bridge and three voltages observed at the same frequency on the reference resistor bridge, the model of magnetoresistance R=Rn(1+kH) is decomposed into a first-order Taylor approximation, where the constant term describes the relationship between the sensor bridge voltages observed at the carrier frequency, and the second term, proportional to H, describes the relationship between the sensor bridge voltages observed on the two sidebands and all of Rn, k, and H.

[0179] Dividing by the voltage observed across the reference resistor bridge yields a direct, phase-sensitive solution for the components of delta(MR) that appear in the upper and lower sidebands:

[0180] delta(MR,lower)=

[0181] (4*(RTX'-RTX)*(RTX+RTX')*v s (lower)*v tx (carrier)*v tx (carrier)) / ((RTX'-RTX)*(RTX'-RTX)*v s (carrier)*v s (carrier)*v tx (lower)-4*(RTX+RTX')*(RTX+RTX')*v tx (lower)*v tx (carrier)*v tx (carrier)

[0182] delta(MR,upper)=

[0183] (4*(RTX'-RTX)*(RTX+RTX')*v s (upper)*v tx (carrier)*v tx (carrier)) / ((RTX'-RTX)*(RTX'-RTX)*v s (carrier)*v s (carrier)*v tx (upper)-4*(RTX+RTX')*(RTX+RTX')*v tx (upper)*v tx (carrier)*v tx (carrier)

[0184] In the above formula, the variables are defined as:

[0185] delta(MR, lower): complex quantity, the delta(MR) component observed from the lower sideband voltage

[0186] delta(MR, upper): complex quantity, the delta(MR) component observed from the upper sideband voltage

[0187] RTX: Values ​​of the three matched resistors in the reference resistor bridge

[0188] RTX': The value of the fourth, non-matched resistor in the reference resistor bridge

[0189] v s (carrier): complex voltage at the carrier frequency observed on the sensor bridge

[0190] v s (lower): complex voltage at the lower sideband frequency observed on the sensor bridge

[0191] v s (upper): complex voltage at the upper sideband frequency observed on the sensor bridge

[0192] v tx (carrier): The complex voltage at the carrier frequency observed across the reference resistor bridge

[0193] v tx (lower): complex voltage at the lower sideband frequency observed across the reference resistor bridge

[0194] v tx (upper): complex voltage at the upper sideband frequency observed across the reference resistor bridge

[0195] By dividing the reference resistor voltage, the transfer function of the circuitry external to the sensor bridge is largely cancelled. The only remaining step to obtain a phase-sensitive and phase-accurate measurement of delta(MR) is to cancel the phase angle of the applied AC magnetic field, at which delta(MR, lower) and delta(MR, upper) rotate, one in the positive direction and one in the negative direction. It is known that MR is purely resistive, so the components of delta(MR) that appear at multiple frequencies should all be the same and should be strictly real numbers. Therefore, the rotation of delta(MR) with the phase shift of the applied magnetic field can be cancelled by calculating the average of the apparent phase angles of delta(MR, lower) and delta(MR, upper). This will be approximately 0 for positive delta(MR) and approximately 180 degrees for negative delta(MR). That is, delta(MR) appears on the real axis. The apparent deviation of delta(MR) from the real axis can be minimized by a balanced arrangement of parasitic elements on each side of the bridge. With this balanced arrangement (eg, by using a multi-channel switch for both sides of the bridge configuration), the apparent deviation of delta(MR) from the real axis can be minimized, often to the system's noise floor.

[0196] The magnitude of delta(MR) can be simply calculated as the sum of the magnitudes of delta(MR, lower) and delta(MR, upper). Thus, taking the real component of this calculated delta(MR) realizes the concept of phase-sensitive and phase-accurate (i.e., real) magnetoresistance as a dimensionless quantity that can be positive or negative and can freely cross zero without perturbation. This delta(MR) is also immune to a large number of possible variations in the external circuitry and non-MR variations in the sensor itself.

[0197] In GMR detection systems according to the prior art, the voltage magnitude dependent on the GMR is used directly without calculating the phase. This works to a certain extent, but has disadvantages compared to the design described above. In contrast, the present disclosure has the following advantages:

[0198] Continuous run-time calibration of circuits with transfer function cancellation;

[0199] In these circuits, immunity to time-dependent changes in, for example, temperature;

[0200] With regard to these circuits, there was excellent consistency from unit to unit in the operation of the system, without any special additional effects on our part;

[0201] The ability to freely optimize for performance without perturbing output telemetry, which enables R&D to be streamlined;

[0202] Phase sensitivity means that the ability to distinguish between situations where the magnetic resistance is rising and situations where the magnetic resistance is falling is always retained.

[0203] According to an embodiment herein, a signal processing system is provided for GMR-based detection of a target analyte in a test sample. The system includes: a measurement circuit configuration unit configured to construct a GMR sensor measurement circuit by connecting at least one GMR sensor, and to construct a reference resistor measurement circuit by connecting at least one reference resistor; a magnetic field excitation unit configured to apply an AC magnetic field with a frequency of ω2 to the at least one GMR sensor; a carrier signal application unit configured to apply a carrier signal with a frequency of ω1 to the GMR sensor measurement circuit, and to apply carrier signals with frequencies of ω1, ω1+ω2, and ω1-ω2 to the reference resistor measurement circuit; a measurement signal pickup unit coupled to the measurement circuit, configured to collect a reference resistor measurement signal from the reference resistor measurement circuit, and to collect a GMR sensor measurement signal from the GMR sensor measurement circuit; and a phase-sensitive resolution unit coupled to the measurement signal pickup unit, configured to analytically resolve a resistance change of the at least one GMR sensor based on both the reference resistor measurement signal from the reference resistor measurement circuit and the GMR sensor measurement signal from the GMR sensor measurement circuit.

[0204] In some embodiments, the phase sensitive solver includes: a reference signal generator configured to generate in-phase and quadrature sinusoidal reference signals at all frequencies of interest; a multiplier configured to multiply the measurement signal by the reference signal to generate in-phase products and quadrature products for the reference resistor measurement signal and the GMR sensor measurement signal at all frequencies of interest; an integrator configured to accumulate the in-phase products and quadrature products for the reference resistor measurement signal and the GMR sensor measurement signal at all frequencies of interest; and a closed-form solver configured to solve for the resistance change of the GMR sensor by integrating the in-phase products and quadrature products of the reference resistor measurement signal and the GMR sensor measurement signal at all frequencies of interest. In some embodiments, the frequencies of interest are ω1, ω1+ω2, and ω1-ω2.

[0205] In some embodiments, the phase sensitive solution unit is further configured to solve the magnetoresistance change of the at least one GMR sensor. In some embodiments, the signal processing system includes a detection result judgment unit configured to judge whether the target analyte is present in the tested sample based on the magnetoresistance change of the at least one GMR sensor obtained by solution. In some embodiments, the signal processing system further includes a detection result judgment unit configured to judge the concentration of the target analyte in the tested sample based on the magnetoresistance change of the at least one GMR sensor obtained by solution.

[0206] In certain embodiments, the carrier signal applying unit is a carrier current source configured to apply a carrier current to the measuring circuit, wherein the reference resistor measuring circuit is constituted by a reference resistor connected in series between the carrier current source and ground, wherein the GMR sensor measuring circuit is constituted by a GMR sensor connected in series between the carrier current source and ground, or by a parallel combination of more than one GMR sensors connected in series between the carrier current source and ground, and wherein the GMR sensor is functionalized for a target analyte.

[0207] In some embodiments, the carrier signal applying unit is a carrier voltage source configured to apply a carrier voltage to the measurement circuit, wherein the GMR sensor measurement circuit is a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm, wherein the first bridge arm includes a voltage divider or a parallel combination of more than one first voltage divider, wherein the first voltage divider consists of a GMR sensor functionalized for a target analyte and a reference element, wherein the second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider, wherein the second voltage divider consists of a GMR sensor functionalized for a target analyte and a reference element, wherein the functionalized GMR sensor in the first voltage divider is connected to the carrier voltage source and the reference element in the first voltage divider is connected to ground, and wherein the functionalized GMR sensor in the second voltage divider is connected to ground and the reference element in the second voltage divider is connected to the carrier voltage source.

[0208] In some embodiments, the carrier signal applying unit is a carrier voltage source, which is configured to apply a carrier voltage to the measurement circuit, wherein the GMR sensor measurement circuit is a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm, wherein the first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage divider, wherein the first voltage divider consists of a GMR sensor functionalized for the target analyte and a reference element, wherein the second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider, wherein the second voltage divider consists of a GMR sensor functionalized for the target analyte and a reference element, wherein the functionalized GMR sensor in the first voltage divider is connected to the carrier voltage source, and the reference element in the first voltage divider is connected to ground, and wherein the functionalized GMR sensor in the second voltage divider is connected to the carrier voltage source, and the reference element in the second voltage divider is connected to ground.

[0209] In certain embodiments, the reference resistor measurement circuit is a Wheatstone full-bridge circuit composed of four reference resistors, wherein three of the four reference resistors have matched resistance values, and wherein the fourth reference resistor has an unmatched resistance value.

[0210] In some embodiments, the carrier signal applying unit is a carrier current source configured to apply a carrier current to the measurement circuit, wherein the reference resistor measurement circuit is an Anderson loop including a reference resistor voltage divider consisting of two reference resistors, wherein the GMR sensor measurement circuit is an Anderson loop including one GMR sensor voltage divider or a parallel combination of more than one GMR sensor voltage dividers, and wherein the GMR sensor voltage divider consists of a GMR sensor functionalized for a target analyte and a reference element.

[0211] In certain embodiments, the reference element is a GMR sensor that is not functionalized for the analyte to be detected.

[0212] In some embodiments, the reference element is a reference resistor.

[0213] In some embodiments, the measurement circuit configuration unit includes at least one multiplexer.

[0214] In some embodiments, the measurement circuit configuration unit includes a freely configurable switch group.

[0215] In some embodiments, the buffer is coupled between the carrier signal applying unit and the measuring circuit so that the carrier signal applying unit presents a low impedance output relative to the measuring circuit.

[0216] In some embodiments, the measurement signal pickup unit includes a differential amplifier and an A / D converter, wherein the differential amplifier is coupled to the measurement circuit and is configured to differentially amplify the measurement signal from the measurement circuit, and wherein the A / D converter is coupled to the differential amplifier and is configured to convert the amplified measurement signal from an analog signal to a digital signal.

[0217] In certain embodiments, a buffer is coupled between the measurement circuit and the differential amplifier such that the measurement circuit presents a high impedance output relative to the differential amplifier.

[0218] According to certain embodiments, a signal processing method is used for GMR-based target analyte detection in a tested sample, the method comprising: obtaining a GMR sensor measurement signal, which includes: constructing a GMR sensor measurement circuit by connecting at least one GMR sensor, applying a carrier signal with a frequency of ω1 to the GMR sensor measurement circuit, applying an AC magnetic field with a frequency of ω2 to the at least one GMR sensor, and collecting the GMR sensor measurement signal from the GMR sensor measurement circuit; and, collecting a reference resistor measurement signal, which includes: constructing a reference resistor measurement circuit by connecting at least one reference resistor, applying carrier signals with frequencies of ω1, ω1+ω2, ω1-ω2 to the reference resistor measurement circuit, and collecting the reference resistor measurement signal from the reference resistor measurement circuit; and, based on both the reference resistor measurement signal from the reference resistor measurement circuit and the GMR sensor measurement signal from the GMR sensor measurement circuit, analytically resolving the resistance change of the at least one GMR sensor.

[0219] In certain embodiments, the method includes obtaining a reference resistor measurement signal prior to obtaining the GMR sensor measurement signal.

[0220] In some embodiments, analytically resolving the resistance change of the at least one GMR sensor includes: generating in-phase and quadrature sinusoidal reference signals at all frequencies of interest; multiplying the measurement signal by the reference signal to generate in-phase products and quadrature products for the reference resistor measurement signal and the GMR sensor measurement signal, respectively, at all frequencies of interest; accumulating the in-phase products and quadrature products for the reference resistor measurement signal and the GMR sensor measurement signal, respectively, at all frequencies of interest; and resolving the resistance change of the GMR sensor by integrating the in-phase products and quadrature products of the reference resistor measurement signal and the GMR sensor measurement signal, respectively, at all frequencies of interest. In some embodiments, the frequencies of interest are ω1, ω1+ω2, and ω1-ω2.

[0221] In some embodiments, analytically resolving the resistance change of the at least one GMR sensor further comprises resolving the magnetoresistance change of the at least one GMR sensor. In some embodiments, the method comprises: determining whether a target analyte is present in the tested sample based on the resolved magnetoresistance change of the at least one GMR sensor.

[0222] In certain embodiments, the method includes: determining the concentration of a target analyte in the tested sample based on the resolved magnetoresistance change of the at least one GMR sensor.

[0223] In certain embodiments, applying a carrier signal to a measurement circuit includes applying a carrier current to the measurement circuit using a carrier current source, wherein constructing a reference resistor measurement circuit includes connecting a reference resistor in series between the carrier current source and ground, wherein constructing a GMR sensor measurement circuit includes connecting a GMR sensor in series between the carrier current source and ground, or connecting a parallel combination of more than one GMR sensors in series between the carrier current source and ground, and wherein the GMR sensor is functionalized for a target analyte.

[0224] In some embodiments, applying a carrier signal to a measurement circuit includes applying a carrier voltage to the measurement circuit using a carrier voltage source, wherein constructing the GMR sensor measurement circuit includes constructing a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm, wherein the first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers, wherein the first voltage divider consists of a GMR sensor functionalized for a target analyte and a reference element, wherein the second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage dividers, wherein the second voltage divider consists of a GMR sensor functionalized for a target analyte and a reference element, wherein the functionalized GMR sensor in the first voltage divider is connected to the carrier voltage source and the reference element in the first voltage divider is connected to ground, and wherein the functionalized GMR sensor in the second voltage divider is connected to ground and the reference element in the second voltage divider is connected to the carrier voltage source.

[0225] In some embodiments, applying a carrier signal to a measurement circuit includes applying a carrier voltage to the measurement circuit using a carrier voltage source, wherein constructing the GMR sensor measurement circuit includes constructing a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm, wherein the first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers, wherein the first voltage divider is composed of a GMR sensor functionalized for a target analyte and a reference element, wherein the second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage dividers, wherein the second voltage divider is composed of a GMR sensor functionalized for a target analyte and a reference element, wherein the functionalized GMR sensor in the first voltage divider is connected to the carrier voltage source and the reference element in the first voltage divider is connected to ground, and wherein the functionalized GMR sensor in the second voltage divider is connected to the carrier voltage source and the reference element in the second voltage divider is connected to ground.

[0226] In certain embodiments, constructing the reference resistor measurement circuit includes constructing a Wheatstone full-bridge circuit comprised of four reference resistors, wherein three of the four reference resistors have matched resistance values, and wherein a fourth reference resistor has an unmatched resistance value.

[0227] In certain embodiments, applying a carrier signal to a measurement circuit includes applying a carrier voltage to the measurement circuit using a carrier voltage source, wherein constructing a reference resistor measurement circuit includes constructing an Anderson loop including a reference resistor voltage divider formed by two reference resistors, wherein constructing a GMR sensor measurement circuit includes constructing an Anderson loop including one GMR sensor voltage divider or a parallel combination of more than one GMR sensor voltage dividers, and wherein the GMR sensor voltage divider is formed by a GMR sensor functionalized for a target analyte and a reference element.

[0228] In certain embodiments, the reference element in the method is a GMR sensor that is not functionalized for the analyte to be detected.

[0229] In certain embodiments, the reference element in the method is a reference resistor.

[0230] In some embodiments, constructing the measurement circuit includes configuring at least one multiplexer.

[0231] In some embodiments, constructing the measurement circuit includes configuring a freely configurable switch group.

[0232] In some embodiments, collecting the measurement signal on the measurement circuit includes: differentially amplifying the measurement signal from the measurement circuit, and converting the amplified measurement signal from an analog signal to a digital signal.

[0233] Although the principles of the present disclosure have been illustrated in the exemplary embodiments given above, it will be apparent to those skilled in the art that various modifications may be made to the structure, arrangement, proportions, elements, materials and components used to implement the present disclosure.

[0234] Therefore, it will be seen that the features of the present disclosure have been fully and effectively realized. However, it will be appreciated that the preferred specific embodiments above are given for the purpose of illustrating the functional and structural principles of the present disclosure, and modifications may be made without departing from these principles. Therefore, the present disclosure includes all modifications that fall within the spirit and scope of the appended claims.

Claims

1. A signal processing system based on GMR detection for a target analyte in a test sample, comprising: A measurement circuit configuration unit configured to construct a GMR sensor measurement circuit by connecting at least one GMR sensor, and to construct a reference resistor measurement circuit by connecting at least one reference resistor; a magnetic field excitation unit configured to apply an AC magnetic field with a frequency of ω2 to the at least one GMR sensor; A carrier signal applying unit configured to apply a carrier signal having a frequency of ω1 to the GMR sensor measuring circuit, and to apply carrier signals having frequencies of ω1, ω1+ω2, and ω1-ω2 to the reference resistor measuring circuit; a measurement signal pickup unit coupled to the GMR sensor measurement circuit and the reference resistor measurement circuit and configured to collect a reference resistor measurement signal from the reference resistor measurement circuit and to collect a GMR sensor measurement signal from the GMR sensor measurement circuit; as well as a phase sensitive resolving unit, coupled to the measurement signal pick-off unit, configured to analytically resolve a resistance change of the at least one GMR sensor based on both a reference resistor measurement signal from the reference resistor measurement circuit and a GMR sensor measurement signal from the GMR sensor measurement circuit, The phase sensitive solution unit includes: a reference signal generator configured to generate in-phase and quadrature sinusoidal reference signals at all frequencies of interest; a multiplier configured to multiply the measurement signal by the reference signal to generate in-phase products and quadrature products for each of the reference resistor measurement signal and the GMR sensor measurement signal at all frequencies of interest; an integrator configured to accumulate in-phase products and quadrature products for each of the reference resistor measurement signal and the GMR sensor measurement signal over all frequencies of interest; as well as A closed-form solver is configured to resolve the resistance change of the GMR sensor from the accumulation of the in-phase product and the quadrature product of the reference resistor measurement signal and the GMR sensor measurement signal, respectively, over all frequencies of interest.

2. The signal processing system according to claim 1, wherein: The frequencies of interest are ω1, ω1+ω2, and ω1-ω2.

3. The signal processing system according to claim 1, wherein: The phase sensitive resolving unit is further configured to resolve a magnetoresistance change of the at least one GMR sensor.

4. The signal processing system according to claim 3, wherein: The signal processing system comprises a detection result judgment unit, which is configured to judge whether a target analyte exists in the tested sample based on the calculated change in magnetic resistance of the at least one GMR sensor.

5. The signal processing system according to claim 3, wherein: The signal processing system further comprises a detection result determination unit, which is configured to determine the concentration of the target analyte in the tested sample based on the calculated change in magnetic resistance of the at least one GMR sensor.

6. The signal processing system according to claim 1, wherein: The carrier signal applying unit is a carrier current source configured to apply a carrier current to the GMR sensor measuring circuit and the reference resistor measuring circuit, The reference resistor measurement circuit is composed of a reference resistor connected in series between a carrier current source and ground. The GMR sensor measurement circuit is composed of a GMR sensor connected in series between a carrier current source and ground, or a parallel combination of more than one GMR sensor connected in series between a carrier current source and ground, and Therein, the GMR sensor is functionalized with respect to the target analyte.

7. The signal processing system according to claim 1, wherein: The carrier signal applying unit is a carrier voltage source configured to apply a carrier voltage to the GMR sensor measuring circuit and the reference resistor measuring circuit, The GMR sensor measurement circuit is a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm. The first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers. The first voltage divider is composed of a first GMR sensor functionalized for the target analyte and a first reference element, The second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider. wherein the second voltage divider is composed of a second GMR sensor functionalized for the target analyte and a second reference element, wherein the first GMR sensor in the first voltage divider is connected to a carrier voltage source, and the first reference element in the first voltage divider is connected to ground, and The second GMR sensor in the second voltage divider is connected to ground, and the second reference element in the second voltage divider is connected to a carrier voltage source.

8. The signal processing system according to claim 1, wherein: The carrier signal applying unit is a carrier voltage source configured to apply a carrier voltage to the GMR sensor measurement circuit and the reference resistor measurement circuit. The GMR sensor measurement circuit is a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm. The first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers. The first voltage divider is composed of a first GMR sensor functionalized for the target analyte and a first reference element, The second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider. wherein the second voltage divider is composed of a second GMR sensor functionalized for the target analyte and a second reference element, wherein the functionalized first GMR sensor in the first voltage divider is connected to a carrier voltage source, and the first reference element in the first voltage divider is connected to ground, and Therein, the functionalized second GMR sensor in the second voltage divider is connected to the carrier voltage source, and the second reference element in the second voltage divider is connected to ground.

9. A signal processing system according to claim 7 or 8, wherein: The reference resistor measurement circuit is a Wheatstone full-bridge circuit consisting of four reference resistors. where three of the four reference resistors have matching resistance values, and Among them, the fourth reference resistor has a non-matching resistance value.

10. The signal processing system according to claim 1, wherein: The carrier signal applying unit is a carrier current source configured to apply a carrier current to the GMR sensor measurement circuit and the reference resistor measurement circuit. The reference resistor measurement circuit is an Anderson loop including a reference resistor voltage divider composed of two reference resistors. Wherein, the GMR sensor measurement circuit is an Anderson loop including a GMR sensor voltage divider or a parallel combination of more than one GMR sensor voltage dividers, and The GMR sensor voltage divider is composed of a GMR sensor functionalized for a target analyte and a reference element.

11. A signal processing system according to claim 7, 8 or 10, wherein: The reference element is a GMR sensor that is not functionalized for the analyte to be detected.

12. A signal processing system according to claim 7, 8 or 10, wherein: The reference element is a reference resistor.

13. The signal processing system according to claim 1, wherein: The measurement circuit configuration unit includes at least one multiplexer.

14. The signal processing system according to claim 1, wherein: The measurement circuit configuration unit contains freely configurable switch groups.

15. The signal processing system according to claim 1 further comprising a buffer, wherein: The buffer is coupled between the carrier signal applying unit and the GMR sensor measuring circuit and the reference resistor measuring circuit so that the carrier signal applying unit presents a low impedance output relative to the GMR sensor measuring circuit and the reference resistor measuring circuit.

16. The signal processing system according to claim 1, wherein: The measurement signal pickup unit contains a differential amplifier and an A / D converter. wherein the differential amplifier is coupled to the GMR sensor measurement circuit and the reference resistor measurement circuit and is configured to differentially amplify measurement signals from the GMR sensor measurement circuit and the reference resistor measurement circuit, and The A / D converter is coupled to the differential amplifier and is configured to convert the amplified measurement signal from an analog signal to a digital signal.

17. The signal processing system according to claim 1, wherein: The buffer is coupled between the GMR sensor measurement circuit and the reference resistor measurement circuit and the differential amplifier so that the GMR sensor measurement circuit and the reference resistor measurement circuit present a high impedance output relative to the differential amplifier.

18. A signal processing method for GMR-based detection of a target analyte in a test sample, the method comprising: Obtaining a GMR sensor measurement signal includes: A GMR sensor measurement circuit is constructed by connecting at least one GMR sensor. Apply a carrier signal with a frequency of ω1 to the GMR sensor measurement circuit, applying an AC magnetic field having a frequency of ω2 to the at least one GMR sensor, and collecting a GMR sensor measurement signal from a GMR sensor measurement circuit; Obtaining a reference resistor measurement signal includes: A reference resistor measurement circuit is constructed by connecting at least one reference resistor. applying carrier signals with frequencies ω1, ω1+ω2, ω1-ω2 to the reference resistor measurement circuit, and collecting a reference resistor measurement signal from a reference resistor measurement circuit; and analytically resolving a change in resistance of the at least one GMR sensor based on both a reference resistor measurement signal from the reference resistor measurement circuit and a GMR sensor measurement signal from the GMR sensor measurement circuit, Wherein, analytically calculating the resistance change of the at least one GMR sensor comprises: Generate in-phase and quadrature sinusoidal reference signals at all frequencies of interest; multiplying the measurement signal by the reference signal to generate in-phase products and quadrature products for each of the reference resistor measurement signal and the GMR sensor measurement signal at all frequencies of interest; accumulating in-phase products and quadrature products over all frequencies of interest for each of the reference resistor measurement signal and the GMR sensor measurement signal; and The resistance change of the GMR sensor is resolved from the accumulation of the in-phase and quadrature products of the reference resistor measurement signal and the GMR sensor measurement signal, respectively, over all frequencies of interest.

19. The signal processing method according to claim 18, wherein: The reference resistor measurement signal is obtained before the GMR sensor measurement signal is obtained.

20. The signal processing method according to claim 18, wherein: The frequencies of interest are ω1, ω1+ω2, and ω1-ω2.

21. The signal processing method according to claim 18, wherein: Analytically resolving a change in resistance of the at least one GMR sensor also includes resolving a change in magnetoresistance of the at least one GMR sensor.

22. The signal processing method according to claim 21, further comprising: The determination of whether the target analyte exists in the tested sample is made based on the calculated change in the magnetic resistance of the at least one GMR sensor.

23. The signal processing method according to claim 21, further comprising: The concentration of the target analyte in the tested sample is determined based on the calculated change in the magnetic resistance of the at least one GMR sensor.

24. The signal processing method according to claim 18, wherein: Applying an AC carrier signal to the GMR sensor measurement circuit and the reference resistor measurement circuit includes applying a carrier current to the GMR sensor measurement circuit and the reference resistor measurement circuit using a carrier current source, The construction of the reference resistor measurement circuit includes connecting the reference resistor in series between the carrier current source and the ground. Wherein, constructing the GMR sensor measurement circuit includes connecting the GMR sensor in series between the carrier current source and the ground, or connecting a parallel combination of more than one GMR sensor in series between the carrier current source and the ground, and Therein, the GMR sensor is functionalized with respect to the target analyte.

25. The signal processing method according to claim 18, wherein: Applying a carrier signal to the GMR sensor measurement circuit and the reference resistor measurement circuit includes applying a carrier voltage to the GMR sensor measurement circuit and the reference resistor measurement circuit using a carrier voltage source, Wherein, constructing the GMR sensor measurement circuit includes constructing a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm. The first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers. The first voltage divider is composed of a first GMR sensor functionalized for the target analyte and a first reference element, The second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider. wherein the second voltage divider is composed of a second GMR sensor functionalized for the target analyte and a second reference element, wherein the functionalized first GMR sensor in the first voltage divider is connected to a carrier voltage source, and the first reference element in the first voltage divider is connected to ground, and Therein, the functionalized second GMR sensor in the second voltage divider is connected to ground, and the second reference element in the second voltage divider is connected to a carrier voltage source.

26. The signal processing method according to claim 18, wherein: Applying the carrier signal to the GMR sensor measurement circuit and the reference resistor measurement circuit includes applying a carrier voltage to the GMR sensor measurement circuit and the reference resistor measurement circuit using a carrier voltage source, Wherein, constructing the GMR sensor measurement circuit includes constructing a Wheatstone full-bridge circuit consisting of a first bridge arm and a second bridge arm. The first bridge arm includes a first voltage divider or a parallel combination of more than one first voltage dividers. The first voltage divider is composed of a first GMR sensor functionalized for the target analyte and a first reference element, The second bridge arm includes a second voltage divider or a parallel combination of more than one second voltage divider. wherein the second voltage divider is composed of a second GMR sensor functionalized for the target analyte and a second reference element, wherein the functionalized first GMR sensor in the first voltage divider is connected to a carrier voltage source, and the first reference element in the first voltage divider is connected to ground, and Therein, the functionalized second GMR sensor in the second voltage divider is connected to the carrier voltage source, and the second reference element in the second voltage divider is connected to ground.

27. The signal processing method according to claim 25 or 26, wherein: Building the reference resistor measurement circuit involves building a Wheatstone full-bridge circuit consisting of four reference resistors. where three of the four reference resistors have matching resistance values, and Among them, the fourth reference resistor has a non-matching resistance value.

28. The signal processing method according to claim 18, wherein: Applying the carrier signal to the GMR sensor measurement circuit and the reference resistor measurement circuit includes applying a carrier voltage to the GMR sensor measurement circuit and the reference resistor measurement circuit using a carrier voltage source, Wherein, constructing a reference resistor measurement circuit includes constructing an Anderson loop including a reference resistor voltage divider composed of two reference resistors, Wherein, constructing the GMR sensor measurement circuit includes constructing an Anderson loop including a GMR sensor voltage divider or a parallel combination of more than one GMR sensor voltage divider, and The GMR sensor voltage divider is composed of a GMR sensor functionalized for a target analyte and a reference element.

29. The signal processing method according to claim 25, 26 or 28, wherein: The reference element is a GMR sensor that is not functionalized for the analyte to be detected.

30. The signal processing method according to claim 25, 26 or 28, wherein: The reference element is a reference resistor.

31. The signal processing method according to claim 18, wherein: Constructing the GMR sensor measurement circuit and the reference resistor measurement circuit includes configuring at least one multiplexer.

32. The signal processing method according to claim 18, wherein: Building a GMR sensor measurement circuit and a reference resistor measurement circuit involves configuring groups of freely configurable switches.

33. The signal processing method according to claim 18, wherein: Collecting measurement signals at the GMR sensor measurement circuit and the reference resistor measurement circuit includes: differentially amplifying the measurement signals of the GMR sensor measurement circuit and the reference resistor measurement circuit, and The amplified measurement signal is converted from an analog signal to a digital signal.

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