A differential magnetoelastic-based sensor for in VIVO detection of a target in bodily fluid

Abstract

Disclosed herein is a device for providing in vivo detection of a target in a bodily fluid. The device may comprise a tubular structure and a differential magnetoelastic-based sensor associated with the tubular structure. The differential magnetoelastic-based sensor may comprise a sensing element comprising a surface, wherein the surface comprises a functional layer on at least a portion of the sensing element surface, and a reference element. Also disclosed are methods for detecting a target in a bodily fluid, system for providing in vivo detection of a target in a bodily fluid, differential magnetoelastic-based sensors having a curved cross-sectional shape, and methods for making a differential magnetoelastic-based sensors having a curved cross-sectional shape.

Description

2025-045 / 10738-1253-1-A DIFFERENTIAL MAGNETOELASTIC-BASED SENSOR FOR IN VIVO DETECTION OF A TARGET IN BODILY FLUIDCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 737,163, filed December 20, 2024, the entire contents of which are incorporated herein by reference.TECHNICAL FIELD

[0002] This disclosure relates to the field of sensors for in vivo detection of a target in bodily fluid. Specifically, this disclosure relates to differential magnetoelastic-based sensors for use with tubular structures.BACKGROUND

[0003] In clinical practices, intravenous (IV) catheters are widely used to deliver fluids, medications, blood products, or nutrition into the bloodstream and typically stay in the vein for as long as 72- 96 hours. These catheters typically include a polymer cannula wrapped around a metal needle; the latter is used for skin penetration and is retracted and discarded immediately after deploying the polymer cannula into the vein. Unlike other medical catheters used for the urinary tract, bladder, and circulatory system, IV catheters usually have a much smaller diameter. For example, the 18-gauge IV catheter frequently used for adults has a 1.3 mm outer diameter and 0.9 mm inner diameter, while higher gauges (i.e. smaller diameters) are commonly used for children.

[0004] In addition, there is significant interindividual variability in absorption, metabolism, and elimination of drugs as well as in the effect of drugs (i.e., pharmacodynamics). Accordingly, it is important to accurately measure real-time drug concentrations in the blood stream to optimize individual dosage regimens. Conventional methods for drug monitoring include liquid chromatography-tandem mass spectrometry (LC-MS) and enzyme-linked immunosorbent assays (ELISAs), and these methods can ensure high sensitivity and selectivity, but they are not suitable for real time monitoring for dosage adjustment nor would they be suitable for use in wearable drug delivery devices due their requirements on complicated equipment and extended processing times.2025-045 / 10738-1253-2-

[0005] Integrating sensors into medical catheters is a rapidly growing area of medical device development that has the potential to enable in situ analysis and quantification of health- related parameters for disease diagnosis and monitoring. Larger catheters have been integrated with sensors to measure temperature, pressure, flow, and other parameters. However, the smaller diameters and thin wall-thicknesses of IV catheters pose significant challenges to sensor integration. For example, the use of lead lines, batteries, or other electrical connections are impractical. Further, other sensors may not have a form suitable for use with the rounded nature of a tubular structure, such as a catheter.

[0006] A need exists for improved sensors for in vivo detection and monitoring.SUMMARY

[0007] Accordingly, provided herein is a magnetoelastic-based sensor and device that may be used for in vivo detection of a target in bodily fluid.

[0008] According to one or more embodiments, disclosed herein is a device for providing in vivo detection of a target in a bodily fluid. The device may comprise a tubular structure and a differential magnetoelastic-based sensor associated with the tubular structure. The differential magnetoelastic-based sensor may comprise a sensing element comprising a surface, wherein the surface comprises a functional layer on at least a portion of the sensing element surface, and a reference element.

[0009] According to one or more embodiments, also disclosed herein is a method for detecting a target in a bodily fluid. The method may comprise inserting the device as described herein into a body lumen of a patient. Once inserted, the differential magnetoelastic-based sensor may contact the bodily fluid. The method may further comprise interrogating the differential magnetoelastic-based sensor to determine the prevalence of the target captured by the functional layer, resulting in sensor output data. The method may further comprise using the sensor output data to determine the level of the target.

[0010] According to one or more embodiments, further disclosed herein is a system for providing in vivo detection of a target in a bodily fluid. The system may comprise the device as2025-045 / 10738-1253-3- described herein, a coil structured and arranged to induce electrical voltages and detect changes in magnetic flux from the differential electromagnetic-based sensor over time, resulting in sensor output data, and a unit for receiving and processing the sensor output data.

[0011] According to one or more embodiments, also disclosed herein is a differential magnetoelastic-based sensor. The sensor may comprise a sensing element comprising a surface, wherein the surface comprises a functional layer on at least a portion of the sensing element surface, the functional layer comprising one or more bio-recognizers are immobilized on at least a portion of the sensing element surface, or a hydrogel. The sensor may further comprise a reference element. The differential magnetoelastic-based sensor may have a curved cross- sectional shape.

[0012] According to one or more embodiments, further disclosed herein is a method for making a curved differential magnetoelastic-based sensor. The method may comprise forming a planar sensor from a magnetoelastic material. The method may further comprise curving the planar sensor in a mold to form a curved sensor. The method may further comprise annealing the curved sensor at elevated temperature. The method may further comprise applying a functional layer to a portion of a surface of the curved sensor to form a sensing element comprising the functional layer and a reference element that does not comprise the functional layer.

[0013] Additional features and advantages of the articles described herein will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments described herein, including the detailed description which follows, the claims, as well as the appended drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] It is to be understood that both the foregoing general description and the following detailed description describe various embodiments and are intended to provide an overview or framework for understanding the nature and character of the claimed subject matter. The accompanying drawings are included to provide a further understanding of the various embodiments, and are incorporated into and constitute a part of this specification. The drawings illustrate the various embodiments described herein, and together with the description serve to explain the principles and operations of the claimed subject matter.2025-045 / 10738-1253-4-

[0015] FIG. 1 A schematically depicts a planar sensor prior to being curved;

[0016] FIG. IB schematically depicts a perspective view of the planar sensor of FIG. 1A after it has been curved, according to one or more embodiments disclosed herein;

[0017] FIG. 1C schematically depicts a side view the planar sensor of FIG. 1 A after it has been curved, according to one or more embodiments disclosed herein;

[0018] FIG. 2 schematically depicts a top view of a sensor, according to one or more embodiments disclosed herein;

[0019] FIG. 3 schematically depicts a top view of a sensor, according to one or more embodiments disclosed herein;

[0020] FIG. 4 schematically depicts a top view of a sensor, according to one or more embodiments disclosed herein;

[0021] FIGS. 5A-5E illustrate different embodiments of element shapes for use in a differential sensor configuration, according to one or more embodiments disclosed herein, where 5A is a rectangle; 5B is a triangle; 5C is a rhombus; 5D is a hexagon; 5E is circular;

[0022] FIGS. 6A-6C illustrate different embodiments of element arrangement modes for the sensor, according to one or more embodiments disclosed herein, where 6A is in serial; 6B is in parallel; 6C is in array;

[0023] FIGS. 7A-7D schematically depict a top view of sensors having different functional layer configurations, according to one or more embodiments disclosed herein;

[0024] FIGS. 8A-8B schematically depict a device inserted into a body lumen, with FIG. 8B being an enlargement of a portion of FIG. 8A, according to one or more embodiments disclosed herein;

[0025] FIGS. 9A-9D schematically depict a device, according to one or more embodiments disclosed herein;

[0026] FIG. 10A schematically depict a housing, according to one or more embodiments disclosed herein;2025-045 / 10738-1253-5-

[0027] FIG. 10B-10C schematically depict a device, with FIG. IOC being an enlargement of a portion of FIG. 10B, according to one or more embodiments disclosed herein;

[0028] FIG. 11 schematically depicts a housing of the device, according to one or more embodiments disclosed herein;

[0029] FIGS. 12A-12C schematically depicts a device, according to one or more embodiments disclosed herein;

[0030] FIG. 13A schematically depicts a housing, according to one or more embodiments disclosed herein;

[0031] FIGS. 13B-13C (b) schematically depict a device, with FIG. 13C being an enlarged portion from FIG. 13B, according to one or more embodiments disclosed herein;

[0032] FIGS. 14A-14D schematically depict a device, according to one or more embodiments disclosed herein;

[0033] FIGS. 15A-15C schematically depict a device, according to one or more embodiments disclosed herein;

[0034] FIG. 16 schematically depicts a single coil configuration of a device, according one or more embodiments disclosed herein;

[0035] FIGS. 17A-17C schematically depict a mold for forming curved sensors, according to one or more embodiments disclosed herein;

[0036] FIG. 18 is a graph showing amplitude improvement relative to the annealing temperature and time of the sensor, according to one or more embodiments disclosed herein;

[0037] FIG. 19 is a bar graph showing signal amplitude of a planar sensor, a curved but not annealed sensor, and a curved and annealed sensor, according to one or more embodiments disclosed herein; and

[0038] FIG. 20 is a graph showing the frequency shift as a function of mass loading before and after correction, according to one or more embodiments disclosed herein.2025-045 / 10738-1253-6-

[0039] Reference will now be made in greater detail to various embodiments of the present disclosure, some embodiments of which are illustrated in the accompanying drawings. Whenever possible, the same reference numerals will be used throughout the drawings to refer to the same or similar parts.DETAILED DESCRIPTION

[0040] Described herein is a differential magnetoelastic-based sensor 200 for detecting a target in a bodily fluid. In embodiments disclosed herein, the differential magnetoelastic-based sensor 200 may be curved and includes a sensing element 210 and a reference element 220. The present disclosure is also directed to devices 10 that include a tubular structure 100 that the differential magnetoelastic-based sensor 200 is associated with, methods of making the differential magnetoelastic-based sensor 200, methods for detecting a target in a bodily fluid using the devices 10 as described herein, and systems for providing in vivo detection of a target in a bodily fluid that include the devices 10 as described herein.

[0041] As discussed above, the rounded shape and small size of tubular structures, such as IV catheters, makes incorporation of a sensor with the tubular structure difficult. Further, for drug monitoring, conventional methods are not suitable for real time monitoring for dosage adjustment nor are they suitable for use in wearable drug delivery devices due their requirements on complicated equipment and extended processing times.

[0042] The present disclosure aims to solve this problem by forming a magnetoelasticbased sensor 200 for use in devices, systems, and methods as described herein.

[0043] Various non-limiting embodiments of the present disclosure will now be described to provide an overall understanding of the principles of the structure, function, and use of the apparatuses, systems, methods, and processes disclosed herein. One or more examples of these non-limiting embodiments are illustrated in the accompanying drawings. Those of ordinary skill in the art will understand that systems and methods specifically described herein and illustrated in the accompanying drawings are non-limiting embodiments. The features illustrated or described in connection with one non-limiting embodiment may be combined with the features of other nonlimiting embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure.2025-045 / 10738-1253-7-

[0044] Described herein is a device 10 for providing in vivo detection of a target in a bodily fluid. With reference to FIGS. 8A-15C, the device 10 may comprise a tubular structure 100 and a differential magnetoelastic-based sensor 200 associated with the tubular structure 100.

[0045] As used herein, the term “tubular structure” refers to a structure having a generally rounded cross-sectional shape, such as a circular or oval cross-sectional shape. A tubular structure may be hollow or solid.

[0046] In one or more embodiments, the tubular structure 100 may comprise any suitable tubular structure 100 that may be inserted into a body lumen. In one or more embodiments, the tubular structure 100 may be a catheter, such as an intravenous catheter, a urinary catheter, or a cardiac catheter, or an endoscope.

[0047] In one or more embodiments, the magnetoelastic-based sensor 200 may utilize a magnetoelastic (ME) transduction mechanism combined with a functional layer 230 to capture specific types of targets. Specifically, the sensor 200 may have a differential configuration in order to allow it to distinguish the effects of target bacteria from variations caused by the surrounding fluid medium. As used herein, a “differential magnetoelastic-based sensor” uses two or more linked magnetoelastic elements to measure physical changes (stress, strain, mass) by comparing their responses, cancelling out environmental noise (temp, fluid changes). In one or more embodiments of the present disclosure, the functional layer 230 may capture the target from a bodily fluid resulting in a change in mass for the sensing element 210.

[0048] In one or more embodiments, with reference to FIGS. IB and 1C, the differential magnetoelastic-based sensor 200 may have a curved cross-sectional shape. As used herein, the term “curved’ refers to a non-planar shape, such as a circular or oval cross-sectional shape, although polygonal cross-sectional shapes may also be included within the scope of the term curved and be employed for the cross-sectional shape of the differential magnetoelastic-based sensor 200. The exact nature of the curvature may depend upon the cross-sectional shape of the tubular structure 100. For example, in one or more embodiments, the tubular structure 100 may have a curved cross-sectional shape, and the curved cross-sectional shape of the differential magnetoelastic-based sensor 200 may be conformal to the curved cross-sectional shape of the tubular structure 100 wherein the cross-sectional shape of the differential magnetoelastic-based sensor 200 matches, mirrors, or reflects the cross-sectional shape of the tubular structure 100, as2025-045 / 10738-1253-8- shown in FIGS. 9, 12, 14, and 15. In one or more embodiments, the radius of the curvature may be from 0.1 mm to 10 mm, from 0.2 mm to 5 mm, from 0.3 mm to 2 mm, from 0.4 mm to 1 mm, from 0.5 mm to 0.6 mm, or about 0.55 mm.

[0049] In one or more alternative embodiments, the differential magnetoelastic-based sensor 200 may be planar and not curved.

[0050] As shown in the FIGS. 1A-7D, the differential magnetoelastic-based sensor 200 may have at least two elements (210, 220). In one or more embodiments, with reference to FIGS. 5A-5E, the elements (210, 220) may have any suitable geometric shape, such as, for example, triangular, circular, oval, square, rhombus, rectangular, other polygonal shapes having more than four sides, or combinations thereof. In one or more embodiments, a triangular geometry may be used for each element (210, 220) of the sensor 200 design as it may enhance the mass sensitivity and facilitate early detection of the target. In one or more embodiments, the elements (210, 220) may be arranged in any suitable configuration, such as, as shown in FIGS. 6A-6C, in serial (FIG. 6A), in parallel (FIG. 6B), or in an array (FIG. 6C, with four elements illustrated). In one or more embodiments, the elements (210, 220) of the differential magnetoelastic-based sensor 200 may be connected via anchors, and the anchors may be used to connect the differential magnetoelasticbased sensor 200 to the tubular structure 100 and / or housing 300 (discussed below). Although the sensing element 210 and reference element 220 are generally referred to as being distinct elements, in one or more embodiments, the sensing element 210 may be defined as a portion of two or more elements, and the reference element 220 may be referred to as a portion of two or more elements, wherein a portion of the sensing element 210 and the reference element 220 are on the same element, as depicted in, for example, FIG. 7B.

[0051] In one or more embodiments, referring to FIGS. 2-4, the sensing element 210 and the reference element 220 may each independently have a length from 0.05 mm to 10 mm, from 0.05 mm to 5 mm, from 0.05 mm to 3 mm, from 0.05 mm to 2.5 mm, from 0.05 mm to 1.5 mm, from 0.05 mm to 1 mm, from 0.05 mm to 0.5 mm, from 0.05 mm to 0.25 mm, from 0.1 mm to 10 mm, from 0.1 mm to 5 mm, from 0.1 mm to 3 mm, from 0.1 mm to 2.5 mm, from 0.1 mm to 1.5 mm, from 0.1 mm to 1 mm, from 0.1 mm to 0.5 mm, from 0.1 mm to 0.25 mm, from 0.05 mm to 10 mm, from 0.05 mm to 5 mm, from 0.05 mm to 3 mm, from 0.05 mm to 2.5 mm, from 0.5 mm2025-045 / 10738-1253-9- to 1.5 mm, from 0.5 mm to 1 mm, from 1 mm to 10 mm, from 1 mm to 5 mm, from 1 mm to 3 mm, from 1 mm to 2.5 mm, from 1 mm to 1.5 mm, from 1.5 mm to 10 mm, from 1.5 mm to 5 mm, from 1.5 mm to 3 mm, or from 1.5 mm to 2.5 mm, or about 1.8 mm, or about 2 mm.

[0052] In one or more embodiments, referring to FIGS. 2-4, the sensing element 210 and the reference element 220 may each independently have a width from 0.01 mm to 3 mm, from 0.01 mm to 1 mm, from 0.01 mm to 0.4 mm, from 0.01 mm to 0.1 mm, from 0.1 mm to 3 mm, from 0.1 mm to 1 mm, from 0.1 mm to 0.4 mm, from 0.2 mm to 3 mm, from 0.2 mm to 1 mm, or from 0.2 mm to 0.4 mm, or about 0.3 mm.

[0053] In one or more embodiments, referring to FIGS. 2-4, the sensing element 210 and the reference element 220 may each independently have a thickness from 0.005 mm to 0.1 mm, from 0.005 mm to 0.05 mm, from 0.005 mm to 0.04 mm, from 0.005 mm to 0.03 mm, from 0.01 mm to 0.1 mm, from 0.01 mm to 0.05 mm, from 0.01 mm to 0.04 mm, from 0.01 mm to 0.03 mm, from 0.02 mm to 0.1 mm, from 0.02 mm to 0.05 mm, from 0.02 mm to 0.04 mm, or from 0.02 mm to 0.03 mm.

[0054] In one or more embodiments, referring to FIGS. 2-3, a separation gap (g) between the sensing element 210 and the reference element 220 may be from 0.01 mm to 1 mm, from 0.1 mm to 0.5 mm, or from 0.2 mm to 0.4 mm, or about 0.3 mm.

[0055] In one or more embodiments, referring to FIGS. 2-3, the sensing element 210 and the reference element 220 may have a length difference (AL) of from 0.01 mm to 3 mm, from 0.1 mm to 1 mm, or from 0.2 mm to 0.3 mm, or about 0.2 mm.

[0056] In one or more embodiments, with reference to FIGS. 7A-7D, the sensing element 210 of the differential magnetoelastic-based sensor 200 may comprise a surface, and a functional layer 230 may be present on at least a portion of the sensing element 210 surface. In one or more embodiments, the functional layer 230 may comprise one or more bio-recognizers 231 immobilized on at least a portion of the sensing element 210 surface. As used herein, the term “bio-recognizers” refers to a biological composition that can be immobilized on the sensing element 210 surface and can identify and are capable of binding to one or more analytes, such as pathogens like bacteria and virus, biomarkers, proteins, nucleic acids, pH, temperature, or chemicals. In one or more embodiments, the bio-recognizers 231 may comprise or be selected from the group consisting of antibodies, aptamers, nucleic acids, and proteins. In one or more2025-045 / 10738-1253-10- embodiments, as shown in FIGS. 7A-7D, multiple bio-recognizers 231 may be applied over the entire surface of the sensing element 210 where each binds to a different target (7A), a single biorecognizer 231 may be applied over a portion of the surface of the sensing element 210 and a second bio-recognizer 231 may be applied over a portion of the surface of a different sensing element 210 (7B), or a single bio-recognizer 231 may be applied over the entire surface of the sensing element 210 (7C). In one or more embodiments, as shown in FIG. 7D, the functional layer 230 may comprise a functional polymer 232, such as a hydrogel, that targets specific drugs, chemicals, or biomarkers. In one or more embodiments, the target may comprise a drug used for anesthesia, such as benzodiazepines, midazolam, or an opioid analgesic, such as fentanyl, morphine, or hydromorphone. In one or more embodiments, the device 10 may allow for therapeutic drug monitoring (TDM) of the concentration of a specific drug and may provide information regarding dosage adjustment to maintain a constant drug concentration in a patient’s bloodstream. In one or more embodiments, the device 10 and / or system disclosed herein may be able to automate such monitoring and drug delivery by connecting the device 10 with a drug delivery device that provides real time adjustment of drug dosage to the patient.

[0057] In one or more embodiments, referring to FIGS. 8A-15C the device 10 may further comprise a housing 300 that may comprise the differential magnetoelastic-based sensor 200. The housing is not limited and may comprise any suitable biocompatible material produced by any suitable method, such as 3D printing, injection molding, or other precision manufacturing techniques. For example, in some embodiments, the housing 300 may comprise TOP AS® 8007 COC polymer or other biocompatible polymers. The housing 300 may be and allow for fluid communication between the bodily fluid and the differential magnetoelastic-based sensor 200 within the housing 300. In one or more embodiments, the housing 300 may prevent undesirable materials from the bodily fluid, such as blood cells, from entering the housing. In one or more embodiments, referring to FIGS. 8A-8B and 11, for example, the housing 300 may comprise one or more micro fluidic channels 310 are structured and arranged to be in fluid communication with the body lumen and the differential magnetoelastic-based sensor 200, wherein the bodily fluid may flow through the microfluidic channel 310 to contact the differential magnetoelastic-based sensor 200. The combined effect of blood pressure and capillary force may allow for the bodily fluid (e.g., blood serum) to enter the microfluidic channel 310 and reach the differential magnetoelastic-based sensor 200 in a chamber of the housing 300. In one or more embodiments, the housing 300 may comprise one or more microfluidic features 320. The microfluidic features2025-045 / 10738-1253-11-320 may be structured and arranged to perform functions similar to those available in “lab-on-a- chip” devices, such as fdtration, pre-concentration, separation, amplification, and analysis of a bodily fluid passing through the microfluidic features 320. In one or more embodiments, the housing 300 may comprise a housing base 301 and a housing cover 302 wherein one or more chambers and / or microfluidic channels 310 are formed when joined.

[0058] In one or more embodiments, the housing 300 may have a curved cross-sectional shape that conforms to the cross-sectional shape of the tubular structure 100 and the differential magnetoelastic-based sensor 200 such that the housing may be joined to the tubular structure 100 without interfering with its function. In one or more embodiments, the housing 300 may be positioned on an outer wall of the tubular structure 100 along the longitudinal direction of the tubular structure 100, and the differential magnetoelastic-based sensor 200 may likewise extend along the longitudinal direction of the tubular structure 100 from within the housing 300. In one or more alternative embodiments, the housing 300 may be integral with the tubular structure 100.

[0059] In one or more alternative embodiments, referring to FIGS. 14A-14D, the housing 300 may be in the form of, or a part of, an expansion tube 800 for insertion into a tubular structure 100, such as a catheter. The expansion tube 800 may be made from any suitable material, including, for example, hard plastics and metal materials. The expansion tube 800 may have an inner diameter slightly larger than the outer diameter of the needle 700 and an outer diameter slightly larger than the inner diameter of the tubular structure 100 (e.g., IV catheter) such that the expansion tube 800 slightly expands the tubular structure 100 after deployment without interfering with the needle 700 movements. The expansion tube 800 may comprise micro fluidic channels 310 that are in fluid communication with the bodily fluid outside of the tubular structure 100 via apertures in the tubular structure 100 that align with the microfluidic channels 310 for both fluid inlet and outlet. The expansion tube 800 may avoid excessive deformations of the tubular structure 100 wall and may maintain a continuous outer surface of the tubular structure 100 that may allow for improved safety and stability.

[0060] In one or more embodiments, referring to FIGS. 15A-15C, the device 10 may comprise two or more of the differential magnetoelastic-based sensors 200. For example, the differential magnetoelastic-based sensors 200 may be stacked over each other, as shown in FIG. 15 A. Alternatively, the differential magnetoelastic-based sensors 200 may be in series or in an array. Such configurations may be useful when multiple targets are of interest.2025-045 / 10738-1253-12-

[0061] In one or more embodiments, referring to FIGS. 9A-9D, 12A-12C, and 15A-15C, the device 10 may further comprise a needle 700. The tubular structure 100 may be wrapped around the needle 700, and the needle 700 may be used for skin penetration upon insertion of the device 10 into a body lumen, and the needle 700 may then be retracted and discarded immediately after deploying the tubular structure 100 of the device 10 into the body lumen.

[0062] In one or more embodiments, referring to FIG. 16, the device 10 may further comprise a coil 400 structured and arranged to induce electrical voltages and detect changes in magnetic flux from the differential electromagnetic-based sensor 200 over time. The working principle of the differential magnetoelastic-based sensor 200 is illustrated in FIG. 16. When the differential magnetoelastic-based sensor 200 is excited by a time-varying magnetic field generated from a transmit coil 400, it produces a longitudinal vibration. This generates a magnetic flux with a resonance frequency, which can vary with changes in the boundary conditions of the sensor such as the mass and fluid medium in contact with the sensor. This flux can be detected wirelessly with a receive coil 400 to measure the resonance frequency. For example, FIG. 16 shows a single coil 400 used for both excitation and readout using signal reflection. The single coil 400 configuration involves a transmit / receive coil 400. The differential magnetoelastic-based sensor 200 is located inside the coil 400. The surface of the differential magnetoelastic-based sensor 200 comprises the functional layer 230 that captures the target over time. The transmit / receive coil 400 produces an AC field line, and the differential magnetoelastic-based sensor 200 produces a sensor field line. Various coil 400 configurations with different wire gauge, number of turns, diameter, number of coils, and coil orientation, can be used to enhance the sensor interrogation quality and performance. For example, a single coil 400 can be used for both excitation and readout using signal reflection, as shown in FIG. 16. Alternatively, different orientations of coil 400 placement relative to the sensor (such as horizontal or vertical) can be implemented.

[0063] In one or more alternative embodiments, a two-coil configuration with a separate transmit coil and a receive coil may be used (not shown). The differential magnetoelastic-based sensor 200 may be positioned between, or, alternative, above the coils. The surface of the differential magnetoelastic-based sensor 200 comprises the functional layer 230 that captures the target over time. The transmit coil produces an AC field line. The differential magnetoelasticbased sensor 200 produces a sensor field line.2025-045 / 10738-1253-13-

[0064] When a small mass, Am, is applied to the differential magnetoelastic-based sensor 200 of an initial mass M, the resonance frequency shift, Af, can be derived from equations given in as:Am J E4 / = Equationl 4LM Jp(l - v2) where L is the length of the sensor; E, p, and v are Young's modulus, density, and Poisson's ratio for the magnetoelastic material that comprises the differential magnetoelastic-based sensor 200, respectively. When the properties of the fluid medium change, the corresponding Af is given as:Equation2where fo is the resonance frequency in air, p and d are the density and thickness of the differential magnetoelastic-based sensor 200, and pmand q are the density and viscosity of the medium, respectively.

[0065] Magnetoelastic-based sensors have shown high performance as wireless immunosensors for in vitro applications in liquid media. Changes in the medium properties and conditions such as temperature, density, viscosity, and pH, can cause significant changes in the resonance frequency of the magnetoelastic-based sensors; therefore, these parameters are usually controlled carefully to maintain the sensor performance for immunoassay under in vitro conditions. However, for the targeted in vivo application, the properties of the surrounding bodily fluid, particularly the viscosity and density, can change at any time. To eliminate the effect of the surrounding medium, the differential magnetoelastic-based sensor 200 comprising or consisting of two elements (210, 220) may be utilized: one element (210) with, and the other element (220) without a functionalized layer 230. The element without functionalization is used as a reference (reference element 220). When targets are present in the medium and become bound to the functionalized layer 230, mass loading is applied only to the sensing element 210 and any common mode changes such as those of the medium properties are eliminated by subtracting the outputs of the sensing element 210 and reference element 220.

[0066] Mass sensitivity is defined as the frequency shift caused by a unit amount of mass loading. Higher mass sensitivity is desirable to provide a larger frequency shift for a given amount2025-045 / 10738-1253-14- of mass loading, which is particularly important for the detection of targets having low concentrations or relatively small masses. It has been shown previously that the geometry of a magnetoelastic-based sensor can affect its magnetic domain distribution; geometries with sharp corners may result in small magnetic domains, leading to stronger vibration and higher sensitivity. In one embodiment of the present invention, triangular geometry may be used for the sensor design instead of the traditional rectangular geometry that has been commonly used for magnetoelasticbased immunosensors.

[0067] Also disclosed herein is a method for detecting a target in a bodily fluid. Referring to FIGS. 8A-8B, the method may comprise inserting the device 10 described herein into a body lumen of a patient, wherein the differential magnetoelastic-based sensor 200 contacts the bodily fluid, interrogating the differential magnetoelastic-based sensor 200 to determine the prevalence of the target captured by the functional layer, resulting in sensor output data, and using the sensor output data to determine the level of the target. In one or more embodiments, the differential magnetoelastic-based sensor 200 may be interrogated by a coil 400 in a location adjacent to the inserted differential magnetoelastic-based sensor 200 and external to the patient’s body. In one or more embodiments, the coil 400 may be located in a patch, and the coil patch 401 may be applied to the skin of the patient adjacent to the insertion point of the device 10. In one or more embodiments, the coil patch 401 may be connected to a small wearable unit to wirelessly excite and interrogate the sensor. The portable readout unit 500, or wearable unit, may have built-in alarms and user interface for patient interaction. For example, in one or more embodiments, the alarm may be triggered if a concentration of the target in the bodily fluid exceeds, or in some cases falls below, a threshold amount. In one or more other embodiments, the alarm may be triggered if the certain conditions of the bodily fluid fall above or below certain threshold amounts, such as low or high temperature or pH. It may also connect with a smartphone 600 through a Bluetooth Low Energy (BLE) link, or other low power wireless communication methods, for remote monitoring and control. The sensor data can be uploaded by the smartphone 600 through a cellular link to the cloud to enable remote access and telediagnosis with hospitals and doctors.

[0068] Further disclosed herein is a system for providing in vivo detection of a target in a bodily fluid. The system may comprise the device 10 as described herein, a coil structured and arranged to induce electrical voltages and detect changes in magnetic flux from the differential electromagnetic-based sensor 200 over time, resulting in sensor output data, and a unit for receiving and processing the sensor output data.2025-045 / 10738-1253-15-

[0069] Further disclosed herein is a differential magnetoelastic-based sensor 200. The differential magnetoelastic-based sensor 200 may be any as described herein with respect to the device 10. For example, in one or more embodiments, the differential magnetoelastic-based sensor 200 may comprise a sensing element 210 comprising a surface, wherein the surface comprises a functional layer 230 on at least a portion of the sensing element surface, the functional layer 230 comprising one or more bio-recognizers 231 are immobilized on at least a portion of the sensing element 210 surface, or a polymer 232 used as a functional layer 230 (e.g., a hydrogel), and a reference element 220, wherein the differential magnetoelastic-based sensor 200 has a curved cross-sectional shape.

[0070] Also disclosed herein is a method for making a curved differential magnetoelasticbased sensor 200.

[0071] In one or more embodiments, referring now to FIGS. 17A-17C, the method may comprise providing a planar sensor from a magnetoelastic material. The planar sensor may be commercially purchased or may be formed from the magnetoelastic material. The method of forming is not limited. For example, in one or more embodiments, the planar sensor may be cut from a sheet of magnetoelastic metal alloy using a suitable technique, such as a high-precision micro-electro discharge machine. Non-limiting examples of suitable magnetoelastic materials include those sold under the Metglas® name from Metglas Inc., such as ribbons of Metglas® 2826 MB (Fe45Ni45Mo?B3) alloy.

[0072] In one or more embodiments, the method may further comprise curving the planar sensor in a mold to form a curved sensor. The curing may comprise any suitable technique. In one or more embodiments, the curing may comprise placing the planar sensor into a mold having the desired curvature, applying a pressure rod over the planar sensor to compress the sensor into the mold, wherein the pressure mold mirrors the curvature of the mold. The method may optionally further comprise placing a cover plate over the mold, wherein the cover plate contacts the pressure rod to apply pressure to the pressure road that is translated to the sensor to form the curved sensor. Alternatively, other methods of applying force onto the pressure rod may be used. In one or more embodiments, heat and / or vacuum may be applied when applying pressure to curve the planar sensor.2025-045 / 10738-1253-16-

[0073] In one or more embodiments, the method may further comprise annealing the curved sensor at elevated temperature. It has been surprisingly found that annealing the curved sensor after it has been formed helps to improve the performance of the curved sensor. Without intending to be bound by theory, it is believed that curving the sensor creates stress points in the sensor that disrupt its performance. Annealing at a temperature and for a certain time period may result in release of these stress points and better sensor performance. For example, the annealing may comprise heating at a temperature of from 220 °C to 260 °C, or 230 °C to 250 °C, or 235 °C to 245 °C, or about 240 °C, and the time period may be from 1.5 hours to 4.5 hours, or from 2 hours to 4 hours, or from 2.5 hours to 3.5 hours, or about 3 hours. The heating may be done under vacuum.

[0074] In one or more embodiments, the method may further comprise applying a functional layer 230 to a portion of a surface of the curved sensor 200 to form a sensing element 210 comprising the functional layer 230 and a reference element 220 that does not comprise the functional layer.

[0075] In one or more embodiments, the differential magnetoelastic-based sensor 200 made by the method may be any of the differential magnetoelastic-based sensors 200 described herein.

[0076] The terms “free” and “substantially free,” when used to describe the concentration and / or absence of a particular constituent component means that the constituent component is not intentionally added.

[0077] Ranges can be expressed herein as from “less than or equal to” one particular value, and / or to “less than or equal to” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “less than or equal to,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. Any ranges used herein include all ranges and subranges and any values there between unless explicitly stated otherwise.

[0078] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes2025-045 / 10738-1253-17- from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0079] Directional terms as used herein - for example up, down, right, left, front, back, top, bottom - are made only with reference to the figures as drawn and are not intended to imply absolute orientation.

[0080] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order, nor that with any apparatus specific orientations be required. Accordingly, where a method claim does not actually recite an order to be followed by its steps, or that any apparatus claim does not actually recite an order or orientation to individual components, or it is not otherwise specifically stated in the claims or description that the steps are to be limited to a specific order, or that a specific order or orientation to components of an apparatus is not recited, it is in no way intended that an order or orientation be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps, operational flow, order of components, or orientation of components; plain meaning derived from grammatical organization or punctuation, and; the number or type of embodiments described in the specification.

[0081] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a” component includes aspects having two or more such components, unless the context clearly indicates otherwise.

[0082] Reference throughout the specification to “various embodiments,” “some embodiments,” “one embodiment,” “some example embodiments,” “one example embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with any embodiment is included in at least one embodiment. Thus, appearances of the phrases “in various embodiments,” “in some embodiments,” “in one embodiment,” “some example embodiments,” “one example embodiment,” or “in an embodiment” in places throughout2025-045 / 10738-1253-18- the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner in one or more embodiments.

[0083] In various embodiments disclosed herein, a single component can be replaced by multiple components and multiple components can be replaced by a single component to perform a given function or functions. Except where such substitution would not be operative, such substitution is within the intended scope of the embodiments.

[0084] The examples discussed herein are examples only and are provided to assist in the explanation of the apparatuses, devices, systems and methods described herein. None of the features or components shown in the drawings or discussed below should be taken as mandatory for any specific implementation of any of the apparatuses, devices, systems or methods unless specifically designated as mandatory. For ease of reading and clarity, certain components, modules, or methods may be described solely in connection with a specific figure. Any failure to specifically describe a combination or sub-combination of components should not be understood as an indication that any combination or sub-combination is not possible. Also, for any methods described, regardless of whether the method is described in conjunction with a flow diagram, it should be understood that unless otherwise specified or required by context, any explicit or implicit ordering of steps performed in the execution of a method does not imply that those steps must be performed in the order presented but instead may be performed in a different order or in parallel.

[0085] Having shown and described various versions in the present disclosure, further adaptations of the methods and systems described herein may be accomplished by appropriate modifications by one of ordinary skill in the art without departing from the scope of the present disclosure. Several of such potential modifications have been mentioned, and others will be apparent to those skilled in the art. For instance, the examples, versions, geometries, materials, dimensions, ratios, steps, and the like discussed above are illustrative and are not required. Accordingly, the scope of the present disclosure should be considered in terms of the following claims and is understood not to be limited to the details of structure and operation shown and described in the specification and drawings.2025-045 / 10738-1253-19-EXAMPLES

[0086] The various embodiments of systems and processes of the present disclosure will be further clarified by the following examples. The examples are illustrative in nature, and should not be understood to limit the subject matter of the present disclosure.

[0087] Fabrication of a Differential Magnetoelastic-Based Sensor: Sensors were fabricated from Metglas® 2826MB (Fe45Ni45Mo?B3) alloy ribbons into the planar pattern shown in FIG. 1 A using an in-house high-precision micro-electro-discharge machine (Smaltec® EM203 pEDM). The planar sensors were then curved and annealed in a metal mold as shown in FIGS. 17A-C at elevated temperature in a vacuum oven to obtain the desired curvature as shown in FIGS. IB and 1C as well as to relieve stress that can degrade sensor performance. The radius of the curved sensor was 0.55 mm, and the length difference (AL) was 0.2 mm, and the separation gap between the elements was 0.3 mm. The annealing conditions were evaluated and optimized for improved stress relief while minimizing degradation of material magnetization at higher temperatures. The housing, including a cover and a base, were 3D-printed from Tough Resin by Boston Micro Fabrication Inc. (FIG. 10A). The curved ME sensor was assembled in the chamber of the housing with the anchors. The assembled device was then integrated with the cannula of an 18-gauge IV catheter having an outer diameter of 1.3 mm and an inner diameter of 0.9 mm, as shown in FIG. 10B.

[0088] Experimental Results: All experiments discussed below were conducted using a coil of 50 turns and 10 mm diameter made from a 30 AWG magnet wire. A network analyzer (Keysight® E5061B) was connected to the coil to measure the resonance frequencies of the sensor.

[0089] To demonstrate the microfluidic function of the housing, the housing parts were assembled and immersed in emulated blood flow (z. e. red color water) through a tube mimicking the blood vessel, and the colored water was observed fdling up the microfluidic features in the housing, confirming flow under combined effect of vessel pressure and capillary force.

[0090] Experiments were performed to find the optimal annealing conditions and verify the effectiveness of the annealing process in restoring sensor performance after curving. As shown in FIG. 18, annealing at 240 °C for 3 hours was determined to be optimal with maximum signal amplitude improvement. FIG. 19 shows the comparison of signal amplitude of sensors at different stages of preparation. After curving the sensors, the signal amplitude degraded significantly2025-045 / 10738-1253-20- compared to their planar counterparts without curving because of the stress introduced by curving. This stress was effectively released by annealing and the signal amplitude was fully restored with 120% improvement from after curving.

[0091] Preliminary differential sensing was experimentally validated. Mass loading was applied by coating multiple ink layers on the sensing element of the differential sensors. The curved differential sensors were tested in three different media (DI water, 10% and 20% w / w glycerol solutions) to emulate varying medium properties (z.e. density and viscosity). As shown in FIG. 20, before correction, under the impact of fluid properties, different frequency shifts were generated with the same amount of mass loading in different media. After correcting the results by subtracting reference element outputs, frequency shift related only to mass loading was recovered. The medium effect was effectively eliminated, demonstrating the effectiveness of the differential mechanism for the ME sensor. Mass sensitivity was found as 5.35 Hz / ng.

[0092] It is noted that any two quantitative values assigned to a property may constitute a range of that property, and all combinations of ranges formed from all stated quantitative values of a given property are contemplated in this disclosure.

[0093] It is noted that one or more of the following claims utilize the term "where" as a transitional phrase. For the purposes of defining the present technology, it is noted that this term is introduced in the claims as an open-ended transitional phrase that is used to introduce a recitation of a series of characteristics of the structure and should be interpreted in like manner as the more commonly used open-ended preamble term "comprising."

[0094] Having described the subject matter of the present disclosure in detail and by reference to specific aspects, it is noted that the various details of such aspects should not be taken to imply that these details are essential components of the aspects. Rather, the claims appended hereto should be taken as the sole representation of the breadth of the present disclosure and the corresponding scope of the various aspects described in this disclosure. Further, it will be apparent that modifications and variations are possible without departing from the scope of the appended claims.

Claims

2025-045 / 10738-1253-21-CLAIMS1. A device for providing in vivo detection of a target in a bodily fluid, the device comprising: a tubular structure; and a differential magnetoelastic-based sensor associated with the tubular structure, the differential magnetoelastic-based sensor comprising: a sensing element comprising a surface, wherein the surface comprises a functional layer on at least a portion of the sensing element surface; and a reference element.

2. The device of claim 1, wherein the differential magnetoelastic-based sensor has a curved cross-sectional shape.

3. The device of claim 2, wherein the curved cross-sectional shape of the differential magnetoelastic-based sensor is a circular cross-sectional shape.

4. The device of claim 2, wherein the tubular structure has a curved cross-sectional shape, and the curved cross-sectional shape of the differential magnetoelastic-based sensor conforms to the curved cross-sectional shape of the tubular structure.

5. The device of claim 1, wherein the reference element and the sensing element each have a length from about 0.05 mm to about 10 mm.

6. The device of claim 1, wherein the reference element and the sensing element each have a width from about 0.01 mm to about 3 mm.

7. The device of claim 1, wherein the reference element and the sensing element each have a thickness from about 0.005 mm to about 0.1 mm.

8. The device of claim 1, wherein the reference element and the sensing element have a length difference (AL) from about 0.01 mm to about 1 mm and a separation gap (g) from about 0.01 mm to about 3 mm.

9. The device of claim 1, wherein the reference element and sensing element have a length difference (AL) of about 0.2 mm and a separation gap (g) of about 0.3 mm.2025-045 / 10738-1253-22-10. The device of claim 1, wherein the reference element and sensing element have shapes selected from the group consisting of triangular, circular, oval, square, rectangular, other polygonal shapes having more than four sides.

11. The device of claim 1, wherein the reference element and sensing element are both a triangular shape.

12. The device of claim 1, wherein the functional layer comprises one or more biorecognizers are immobilized on at least a portion of the sensing element surface.

13. The device of claim 12, wherein the bio-recognizers are selected from the group consisting of antibodies, aptamers, nucleic acids, and proteins.

14. The device of claim 12, wherein the bio-recognizers are capable of binding to one or more analytes, the analytes selected from the group consisting of pathogens, bacteria, virus, biomarkers, proteins, nucleic acids, and chemicals.

15. The device of claim 14, wherein the chemical is a drug used for anesthesia.

16. The device of claim 15, wherein the drug used for anesthesia comprises benzodiazepines, midazolam, or an opioid analgesic.

17. The device of claim 16, wherein the opioid analgesic comprises fentanyl, morphine, or hydromorphone.

18. The device of claim 12, wherein the bio-recognizers of the differential magnetoelasticbased sensor are structured and arranged to detect changes in temperature or pH.

19. The device of claim 1, wherein the functional layer comprises a hydrogel.

20. The device of claim 1, further comprising a housing comprising the differential magnetoelastic-based sensor.

21. The device of claim 20, wherein the housing comprises one or more micro fluidic channels are structured and arranged to be in fluid communication with the body lumen and the differential magnetoelastic-based sensor, wherein the bodily fluid may flow through the one or more microfluidic channels to contact the differential magnetoelastic-based sensor.2025-045 / 10738-1253-23-22. The device of claim 20, further comprising one or more microfluidic features structured and arranged for fdtration, pre-concentration, separation, amplification, and analysis of a bodily fluid passing through the microfluidic features.

23. The device of claim 20, wherein the differential magnetoelastic-based sensor has a curved cross-sectional shape, and the housing has a curved cross-sectional shape that conforms to the curved cross-sectional shape of the differential magnetoelastic-based sensor.

24. The device of claim 20, wherein the housing is integral to the tubular structure.

25. The device of claim 20, wherein the housing is positioned on an outer wall of the tubular structure along the longitudinal direction of the tubular structure.

26. The device of claim 1, wherein the tubular structure is an intravenous catheter, a urinary catheter, a cardiac catheter, or an endoscope.

27. The device of claim 1, wherein the tubular structure is an intravenous catheter.

28. The device of claim 1, further comprising a coil structured and arranged to induce electrical voltages and detect changes in magnetic flux from the differential electromagneticbased sensor over time.

29. A method for detecting a target in a bodily fluid, the method comprising: inserting the device of claim 1 into a body lumen of a patient, wherein the differential magnetoelastic-based sensor contacts the bodily fluid; interrogating the differential magnetoelastic-based sensor to determine the prevalence of the target captured by the functional layer, resulting in sensor output data; and using the sensor output data to determine the level of the target.

30. The method of claim 29, wherein the differential magnetoelastic-based sensor is interrogated by a coil in a location adjacent to the inserted differential magnetoelastic-based sensor and external to the patient’s body.

31. The method of claim 30, wherein the coil is located in a coil patch.

32. The method of claim 30, wherein the coil patch is connected to a unit that is wearable by the patient.2025-045 / 10738-1253-24-33. The method of claim 32, wherein the unit comprises a user interface and an alarm if a concentration of the target in the bodily fluid exceeds a threshold amount.

34. The method of claim 29, wherein the body lumen is a vein.

35. A system for providing in vivo detection of a target in a bodily fluid, the system comprising: the device of claim 1 ; a coil structured and arranged to induce electrical voltages and detect changes in magnetic flux from the differential electromagnetic-based sensor over time, resulting in sensor output data; and a unit for receiving and processing the sensor output data.

36. A differential magnetoelastic-based sensor comprising: a sensing element comprising a surface, wherein the surface comprises a functional layer on at least a portion of the sensing element surface, the functional layer comprising one or more bio-recognizers are immobilized on at least a portion of the sensing element surface, or a hydrogel; and a reference element; wherein the differential magnetoelastic-based sensor has a curved cross-sectional shape.

37. The differential magnetoelastic-based sensor of claim 36, wherein the one or more biorecognizers are selected from the group consisting of antibodies, aptamers, nucleic acids, and proteins.

38. The differential magnetoelastic-based sensor of claim 36, wherein the bio-recognizers are capable of binding to one or more analytes, the analytes selected from the group consisting of pathogens, bacteria, virus, biomarkers, proteins, nucleic acids, and chemicals.

39. The differential magnetoelastic-based sensor of claim 38, wherein the chemical is a drug used for anesthesia.

40. The differential magnetoelastic-based sensor of claim 39, wherein the drug used for anesthesia comprises benzodiazepines, midazolam, or an opioid analgesic.2025-045 / 10738-1253-25-41. The differential magnetoelastic-based sensor of claim 40, wherein the opioid analgesic comprises fentanyl, morphine, or hydromorphone.

42. A method for making a curved differential magnetoelastic-based sensor comprising: forming a planar sensor from a magnetoelastic material; curving the planar sensor in a mold to form a curved sensor; annealing the curved sensor at elevated temperature; and applying a functional layer to a portion of a surface of the curved sensor to form a sensing element comprising the functional layer and a reference element that does not comprise the functional layer.

43. The method of claim 42, wherein the curving comprises: placing the planar sensor into a mold having the desired curvature; applying a pressure rod over the planar sensor to compress the sensor into the mold, wherein the pressure mold mirrors the curvature of the mold; placing a cover plate over the mold, wherein the cover plate contacts the pressure rod to apply pressure to the pressure road that is translated to the sensor to form the curved sensor; and optionally heating and / or applying vacuum when applying pressure.

44. The method of claim 42, wherein the annealing comprises heating at a temperature of 220 °C to 260 °C for a time period of 1.5 hours to 4.5 hours under vacuum.

45. The method of claim 42, wherein the annealing comprises heating at a temperature of 230 °C to 250 °C for a time period of 2.5 hours to 3.5 hours under vacuum.

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