Magnetic marker for imaging and surgical guidance

Abstract

To provide a magnetic marker that is improved and has a reduced MRI artefact.SOLUTION: An implantable marker for imaging and surgical guidance by susceptometry comprises one or more pieces of a ferromagnetic material having a total length to diameter ratio of at least about 500, and a total volume of less than about 1×10-11 m3. The one or more pieces of ferromagnetic material may have a high initial relative permeability (μr, i)>about 1000. Also disclosed is a detection system for locating an implantable marker comprising such an implantable marker; at least one drive coil arranged to excite the marker with an alternating magnetic field, and at least one sense coil arranged to detect a signal received from the excited marker; a magnetic field generator arranged to drive an alternating magnetic field through the at least drive coil; and at least one detector arranged to receive the signal from the sense coil and detect one or more harmonics of the drive frequency in the received signal.SELECTED DRAWING: Figure 9a

Description

[Technical Field]

[0001] The present disclosure relates generally to the field of magnetic markers for imaging and surgical guides, and more particularly to magnetosceptometry markers with reduced MRI artifacts. [Background technology]

[0002] Markers are used to guide surgeons to areas of interest during surgical procedures where the area of ​​interest cannot be physically seen or palpated, such as small tumors requiring resection. Ideally, such markers can be deployed through a thin-gauge needle, e.g., 18G to 12G, to reduce trauma to the patient. Typically, such markers are less than 10 mm in length to ensure unobtrusiveness and minimize trauma. Markers can be placed during biopsies or other surgical procedures of internal sites of interest, such as cancerous lesions. Markers are placed under imaging guidance, such as ultrasound or x-ray / mammography. During subsequent surgery, the markers are detected and located using a handheld probe that provides auditory, visual, or other feedback to the surgeon to guide the procedure. Typically, the marker is resected along with the surrounding tissue.

[0003] One such approach is to use markers containing radioactive isotopes, such as iodine-125, that can be detected using handheld gamma-ray detection probes. However, the use of radioactive materials is strictly regulated, making it difficult to organize a radioisotope program in any but the largest academic hospital centers.

[0004] A further approach is discussed in the applicant's previously published patent applications (e.g., U.S. Patent Nos. 5,629,997, ... and 5,629,997), which uses a magnetic field and a magnetic marker with high magnetic susceptibility. A handheld susceptometry probe generates an alternating magnetic field that excites the magnetically responsive marker and detects the responsive magnetic field. This approach has been found to be very effective for deeper sensing. However, this system has the disadvantage of producing artifacts in MRI settings that are large compared to the marker itself.

[0005] MRI is used to image invasive breast cancer lesions not visible on ultrasound or mammography, and MRI monitoring is increasingly being used to evaluate neoadjuvant therapy before surgical resection, allowing for tumor size tracking after neoadjuvant therapy and before surgery. MRI artifacts should not impair the medical professional's assessment of tumor size where markers are placed, as explained in more detail below.

[0006] Ferromagnetic materials are known to produce MRI distortions, which are widely documented in the scientific literature. For example, [1] explains that some ferromagnetic materials may be MRI-safe, but still produce significant artifacts. The artifacts are caused by the component of the magnetic field (B) produced by a ferromagnetic object that is in the same direction as the main magnetic field produced by the MRI machine. y ) is mainly produced by B y The effect of is to shift the local Larmor frequency of protons near the object, and if the shift is large enough, those protons will not show up in the correct slice reconstructed by the MRI machine.

[0007] Therefore, the present applicant has identified a need for small ferromagnetic markers for susceptometric detection that have acceptable response isotropy, long sensing distances, and exhibit minimal MRI artifacts. The MRI artifacts of such markers should not impair medical professionals' assessment of tumor size, as monitoring tumor size reduction provides a positive option in the management of cancer patients. In this regard, breast cancer stage is assessed using several criteria, including tumor size, whether the tumor has spread to lymph nodes, and whether the cancer has spread (metastasized) to other parts of the body. For early-stage cancer, in which breast-conserving surgery using lumpectomy may be considered, tumor size is preferably 2 cm or less. Non-Patent Document 2 indicates that smaller tumor size represents a favorable prognostic factor, and residual tumors >2 cm are associated with a high rate of local tumor recurrence after neoadjuvant chemotherapy. Non-Patent Document 3 indicates that tumors 2 cm or less in size are classified as T1, typically corresponding to cancer stage 1 or 2, in which breast-conserving surgery may be considered. Larger tumors are more likely to require more radical surgery, such as a mastectomy.

[0008] Therefore, it is desirable to be able to size tumors under MRI when they are greater than 2 cm in diameter, allowing for evaluation to observe whether the tumor has shrunk to a level that allows breast-conserving surgery. According to the present disclosure, a marker that provides an artifact of approximately 2 cm still allows for sufficient radiological diagnosis to determine whether a tumor is larger than 2 cm and requires further neoadjuvant treatment. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2011 / 067576 [Patent Document 2] International Publication No. 2014 / 032235 [Patent Document 3] International Publication No. 2014 / 140567 [Non-patent literature]

[0010] [Non-Patent Document 1] Hargreaves et al. (Metal Induced Artifacts in MRI, August 2017, DOI: 10.2214 / AJR.11.7364) [Non-patent document 2] Shashla (Neoadjuvant chemotherapy in breast cancers, September 2016, DOI: 10.1177 / 1745505716677139) [Non-patent document 3] Koh et al. (Introduction of a New Staging System of Breast Cancer for Radiologists: An Emphasis on the Prognostic Stage, January 2019, DOI: 10.3348 / kjr.2018.0231) Summary of the Invention [Problem to be solved by the invention]

[0011] It is an object of the present disclosure to provide an improved magnetic marker with reduced MRI artifacts that overcomes or at least mitigates the above-mentioned drawbacks. [Means for solving the problem]

[0012] According to a first aspect of the present disclosure, there is provided an implantable marker for imaging and surgical guides, the marker having a total length to diameter ratio of at least 50 and a thickness of at least 1×10 -10 m 3 The invention comprises one or more pieces of ferromagnetic material having a total volume of less than 1000 .mu.m.

[0013] In certain embodiments of the present disclosure, the ferromagnetic material can have a length to diameter ratio of at least about 500.

[0014] Preferably, the ferromagnetic material has a magnetic field of about 1×10 -11 m 3 Less than about 6 x 10 -12 m 3 may have a total volume of less than

[0015] Preferably, the piece or pieces of ferromagnetic material have a high relative initial permeability (μ r、i )>about 1000, preferably at least about 2000.

[0016] When the term "length" is used, unless expressly stated otherwise, one skilled in the art will understand that this refers to the length of the non-linear marker shape when the marker is extended linearly. For example, if the marker is a spiral, the length refers to the length of the marker when straightened and extended linearly. If the marker includes multiple pieces of ferromagnetic material, the length can include the combined lengths of the multiple pieces.

[0017] In some embodiments, one or more pieces of ferromagnetic material can have a circular cross-section with a readily measurable diameter. In some embodiments, one or more pieces of ferromagnetic material can have a non-circular cross-section; for example, one or more pieces of ferromagnetic material may comprise a strip having a generally rectangular cross-sectional shape. Thus, "diameter" herein also refers to the width (e.g., maximum width) of a non-circular piece of ferromagnetic material. Alternatively, the ratio of length to diameter may be equal to the ratio of length to the square root of the cross-sectional area of ​​the piece.

[0018] It has been found that a marker with a large length-to-diameter ratio and small volume, as defined herein, balances providing a good sensing response with small MRI artifacts. Increasing the length-to-diameter ratio of at least one piece of ferromagnetic material improves the sensing response of the marker. Reducing the volume of the ferromagnetic material reduces the MRI artifacts produced by the marker.

[0019] The markers may be detectable by magnetic susceptometry probes such as those described in WO 2014 / 140566. The magnetic susceptometry probes may generate a magnetic field strength of about 0.1 mT to about 2.0 mT, preferably about 0.2 mT to about 1.2 mT, at the source, and a magnetic field strength of about 0.04 mT to about 0.4 mT within about 5 mm of the probe. Preferably, this allows for detection of the markers of the present disclosure at a range of up to about 50 mm, 60 mm, 70 mm, or 80 mm from the probe. The exact detection range for a particular marker will depend in part on its configuration, as described herein.

[0020] The length to diameter ratio of one or more pieces of ferromagnetic material may be at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500. In some embodiments, the length to diameter ratio of one or more pieces of ferromagnetic material may be at least about 650, at least about 700, at least about 750, at least about 1000, at least about 1500, at least about 2000, at least about 2500, at least about 3000, or more. In some embodiments, the length to diameter ratio of one or more pieces of ferromagnetic material may be about 2400.

[0021] The total volume of one or more pieces of ferromagnetic material is 5 × 10 -11 m 3 Less than 3 x 10 -11 m 3 Less than or equal to 1 x 10 -11 m 3 In some embodiments, the one or more pieces of ferromagnetic material may be less than 1×10 -12 m 3 The total volume can be as low as 1000 vol.

[0022] By way of example, the one or more pieces of ferromagnetic material may have a total length of 50 mm and a diameter of 15 μm. In such an example, the one or more pieces of ferromagnetic material may have a total length to diameter ratio of about 3333 and a volume of about 9×10 -12 m 3 It could be.

[0023] In another example, the one or more pieces of ferromagnetic material can have a total length of 36 mm and a diameter of 15 μm. In such an example, the one or more pieces of ferromagnetic material can have a total length to diameter ratio of about 2400, and the volume of the ferromagnetic material can be about 6.4×10 -12 m 3 It could be.

[0024] In preferred embodiments, the marker may comprise a wire or strip of ferromagnetic material having a length of at least 3 mm, 6 mm, 10 mm, 20 mm, 30 mm, 35 mm, 50 mm, or 100 mm. The wire may have a diameter of less than 100 μm, or 50 μm or less, 30 μm or less, 15 μm or less, or 10 μm or less. The marker may comprise a wire or strip of ferromagnetic material having a length of 3 mm or less, 6 mm or less, 10 mm or less, 20 mm or less, 30 mm or less, 35 mm or less, 40 mm or less, 50 mm or less, or 100 mm or less. Suitably, the wire or strip may be formed into one or more segments as described herein.

[0025] Markers according to the present disclosure may provide an MRI artifact of less than 3 cm in diameter, more preferably less than 2.5 cm, and especially less than 2 cm. The size of the MRI artifact may vary depending on the strength of the MRI magnetic field, and may be detected in a 1.5T or 3.0T MRI scanner, or any other suitable MRI scanner.

[0026] The ferromagnetic material may have a low saturation induction, for example, less than or equal to 1 T. Providing a ferromagnetic material with a low saturation induction can limit the size of MRI artifacts produced by the material when the marker is exposed to MRI field strengths greater than the field strength required to saturate the magnetization of the ferromagnetic material.

[0027] Ferromagnetic materials have, for example, r、i )>1000. Preferably, the ferromagnetic material has a high relative initial permeability of greater than 10,000. By providing a ferromagnetic material with a high relative initial permeability, the sensing performance of the marker may be improved.

[0028] Preferred materials having the properties required for the markers of the present disclosure are certain metals and amorphous metals. Preferably, the ferromagnetic material may be ductile so that it can be formed into a wire. The ferromagnetic material may be flexible so that at least one piece can be formed into a desired configuration; for example, to reduce or minimize the magnetic isotropy ratio of the marker, as described below. Preferably, cobalt- or nickel-based ferromagnetic alloys, particularly those sold under the trade names Yshield™ and Metglas 2714A™, can be used.

[0029] The ferromagnetic material is preferably in the form of a wire, e.g., a cylindrical wire having a circular cross section, a flat wire, or a strip, and the marker may include one or more pieces of material configured to provide maximum sensing performance, high isotropy of sensing performance, and reduced MRI artifacts. As used herein, the term "wire" includes strips as well as wires, unless the context dictates otherwise.

[0030] Preferred embodiments of markers according to the present disclosure may include one or more wires or strips according to the first aspect of the present disclosure provided as rods, coils, and / or rings, or combinations of the aforementioned rods, coils, and / or rings. The one or more wires or strips may be configured, individually or in combination, to extend in multiple different directions and / or define a serpentine path including twists, bends, or turns to reduce the magnetic anisotropy ratio of the marker. Embodiments of markers according to the present disclosure may include a helical coil having one, two, three, four, five, six, or more coils. When the ferromagnetic material is provided in the form of a multiple helix, e.g., a triple or quadruple helix, the individual helices preferably do not contact each other.

[0031] The or each helical coil may have a pitch-to-diameter ratio of 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, or more, hi some embodiments, the helical coil may have a pitch-to-diameter ratio of 1.33.

[0032] As used herein, "magnetic anisotropy ratio" is the ratio of the strongest to weakest magnetic signal generated by a marker at a given distance at different orientations of the marker relative to the probe. Because the calculated distance between the marker and the probe is relatively weakly dependent on the magnetic sensing response, the marker may suitably have an anisotropy ratio of less than 7 (i.e., 1-7), preferably less than 5, and more preferably less than 3.

[0033] A particularly preferred arrangement of the wire or wires is shown in Figure 7 of the accompanying drawings.

[0034] The ferromagnetic material configured into the required shape can be enclosed within a cylindrical housing. The cylindrical housing is preferably injectable to allow for placement of the marker. Therefore, the housing can preferably have a maximum diameter that allows it to be deployed through a narrow gauge needle, e.g., 18G to 12G. The marker may be packaged within other materials or may be coated to ensure that the marker is biocompatible and robust. The marker may be enclosed within a tube made of, for example, nitinol, titanium, stainless steel, or other biocompatible alloys, the material preferably being non-magnetic and having a relatively low conductivity. Low conductivity is achieved by using a material that is less than 10% of the marker's resistance to magnetic fields. 6 It may include conductivities below Siemens. Suitable coating materials include polymer coatings such as Invar, FEP, Parylene, PTFE, ETFE, PE, PET, PVC or silicone, or epoxy-based encapsulants.

[0035] The wire arrangement may extend in multiple directions and / or across multiple planes. For example, the wire arrangement may include two, three, four, or more linear wires, where the wires extend in different directions in the same or different planes. In another example, the wire arrangement may include two, three, four, or more curved or bent wires, where the curved or bent wires extend in a single plane, e.g., ring-shaped wires, L-shaped wires, or across a series of planes, e.g., helical wires. The wire arrangement may include at least one linear wire and at least one curved or bent wire. The linear wire and the curved or bent wire may extend in different planes, e.g., planes that are perpendicular to each other.

[0036] In one embodiment, the wire or strip arrangement within the housing is provided as offset parallel rods, substantially perpendicular rods, and / or rods arranged end-to-end, preferably spaced apart by at least one diameter of the rod. More preferably, two or more rods may intersect at an angle; for example, two rods may intersect at a substantially right angle. The marker may include a stacked arrangement of multiple such intersecting rods. The stacked intersecting arrangement may have intersections aligned or rotated relative to each other, for example, each intersection rotated by substantially 45 degrees relative to an adjacent stacked intersection. In some embodiments, each intersection may be arranged in a respective plane substantially perpendicular to an axis defined by the housing, such as the longitudinal axis of a cylindrical housing of the type described above. In some embodiments, each intersection may be arranged in a respective plane inclined relative to such an axis defined by the housing. The planes may preferably be spaced apart along the axis. Thus, the intersections may be arranged in two or more respective parallel planes perpendicular to or inclined relative to the housing axis.

[0037] Alternative configurations of rods may be provided, for example, as one or more groups of parallel rods distributed throughout the housing. The rods of each group may extend in respective planes that are inclined or substantially perpendicular to an axis defined by the housing, e.g., the longitudinal axis of a cylindrical housing. Thus, the groups of parallel rods may be arranged in a series of respective planes spaced apart along the longitudinal axis of the housing. As previously mentioned, the planes may be spaced apart along the axis. The rods of each group may be aligned with and / or rotated relative to the rods of at least one other group.

[0038] In some embodiments, each group of parallel rods can be rotated approximately 15 to 90 degrees relative to the other groups; for example, four groups of parallel rods can be arranged so that each group is rotated approximately 45 degrees, approximately 60 degrees, and approximately 90 degrees relative to each of the other groups. In another configuration, the tilted rods can form a twist ladder configuration in which each rod extends in a respective plane substantially perpendicular to an axis defined by the housing, particularly the longitudinal axis, and the planes are spaced apart along the axis and rotated approximately 10 to 45 degrees relative to one or more adjacent rods; for example, an arrangement can include eight linear rods, each of which is rotated approximately 11.25 degrees relative to each of the adjacent rods.

[0039] Optionally, one or more longitudinal rods may be provided through the housing, e.g., through its center, or separate from the cylindrical casing, forming a shape (e.g., a three- or four-sided tetrahedron, an isolated circle connected to perpendicular rods, a "Jack" shape, or a snake) that provides the same rod orientation as described in GB 2582123, the contents of which are incorporated herein by reference; e.g., as shown in Figures 11-19. In some embodiments, one or more transverse rods may be provided through the housing, extending in one or more planes substantially perpendicular to the axis of the housing, e.g., the longitudinal axis of a cylindrical housing.

[0040] In a more preferred embodiment, the marker according to the first aspect of the present disclosure is provided in a spiral shape or comprises a plurality of spaced apart rings, optionally comprising one or more straight longitudinal rods extending through the spirals or rings.

[0041] In preferred embodiments, the marker is provided as a single helix combined with one longitudinal wire aligned parallel to the longitudinal axis of the helix, or as multiple helices, e.g., double, triple, or quadruple helices. Preferably, the pitch of the or each helical coil may be about 1.0 to 1.5 times the diameter of the coil.

[0042] According to another aspect of the present disclosure, there is provided a detection system for locating an implantable marker, the system comprising: an implantable marker according to the first aspect of the present disclosure, at least one drive coil arranged to excite the marker with an alternating magnetic field, and at least one sense coil arranged to detect signals received from the excited marker; a magnetic field generator arranged to drive the alternating magnetic field through at least the drive coil; and at least one detector arranged to receive signals from the sense coil and detect one or more harmonics of the drive frequency in the received signals.

[0043] The following is a detailed description, by way of example only, of embodiments of the present disclosure, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0044] [Figure 1a] Graph showing the effective permeability (μapp) of ferromagnetic materials as a function of geometry and material [Figure 1b] Diagram showing the shapes of cylinders with different length / diameter ratios [Figure 2] A graph of magnetic flux density (B) versus magnetic field strength (H) for a ferromagnetic material, illustrating the definitions of saturation induction (BS) and relative initial permeability (μr, i). [Figure 3a] Graph of maximum wire length for a given maximum MRI artifact size and sensing performance at a distance of 40 mm versus both rod length and rod diameter for ferromagnetic materials with a saturation induction BS of 1 T. [Figure 3b] Graph of maximum wire length for a given maximum MRI artifact size and sensing performance at a distance of 30 mm or 40 mm versus both rod length and rod diameter for ferromagnetic materials with a saturation induction BS of 0.5 T or 1.0 T. [Figure 4] Graph of saturation induction (BS) versus relative initial permeability (μr, i) for various ceramics, metals, and amorphous metals [Figure 5a]Graph showing the magnetic dipole moment of one of two parallel spaced rods with diameters of 50 μm and 100 μm, 5 mm long and with a magnetic permeability of 2300, when subjected to a weak magnetic field (in this case, about 7 μT) [Figure 5b] Graph showing the dipole moment of one of two perpendicularly spaced rods with diameters of 50 μm and 100 μm, each 5 mm long and with a magnetic permeability of 2300, when subjected to a weak magnetic field (in this case, about 7 μT). [Figure 5c] Graph showing the dipole moment of one of two axially offset, parallel-spaced rods with diameters of 50 μm and 100 μm, each 5 mm long and with a magnetic permeability of 2300, when subjected to a weak magnetic field (in this case, approximately 7 μT). [Figure 6] FIG. 11 details the sensing response for different embodiments of markers according to the present disclosure, showing their geometry, dimensions covered, and impact on MRI artifacts. [Figure 7] FIG. 1 shows the maximum sensing distance of different embodiments of markers according to the present disclosure, with good sensitivity and low MRI artifacts. [Figure 8a] 1 is a schematic perspective view of a marker according to one embodiment of the present disclosure; [Figure 8b] 8b is a schematic side view of the marker of FIG. 8a, with the optional marker housing shown in dotted lines. [Figure 9a] FIG. 1 is a schematic perspective view of a marker according to another embodiment of the present disclosure; [Figure 9b] Schematic side view of the marker in Figure 9a [Figure 10a] Graph of sensing distance (mm) vs. pitch (mm) for 1.3mm diameter markers [Figure 10b] Graph of sensing distance (mm) vs. pitch (mm) for 1.15mm diameter markers [Figure 10c] Graph of sensing distance (mm) vs. pitch (mm) for 1.0 mm diameter markers [Figure 11] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 12] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 13] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 14] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 15] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 16] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 17] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 18] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 19] 1A-1C illustrate various additional possible marker configurations according to the present disclosure. [Figure 20] FIG. 1 illustrates a detection system for locating markers according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0045] Definition: Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art.

[0046] Magnetic flux density (B) is a vector quantity that measures the strength and direction of the magnetic field around a magnet or electric current.

[0047] Magnetic field strength, also known as magnetic field (H), is a vector field that describes the magnetic effect of an external magnetic field on moving charges, currents, and magnetic materials.

[0048] Coercivity is the magnetic field (W) required to completely demagnetize a ferromagnetic material.

[0049] Hard magnetic materials have high coercivity. They are also called permanent magnets.

[0050] Soft magnetic materials have low coercivity. They are easily magnetized and demagnetized.

[0051] Magnetization, also known as magnetic polarization (M), is a vector field that represents the density of permanent or induced magnetic dipole moments in a magnetic material.

[0052] Saturation of induction is the state reached when the magnetization M of the material cannot be further increased by increasing the applied external magnetic field H. In this state, the total magnetic flux density produced is the saturation induction (B S ), and the magnetization is called saturation magnetization (M S )

[0053] The initial magnetic susceptibility (χ) is a measure of how much an infinite material can be magnetized in a small applied magnetic field. It is defined as χ = M / H for small H, or equivalently, is less than or equal to:

number

[0054] Apparent initial magnetic susceptibility (χ app ), also known as the effective magnetic susceptibility, is the initial magnetic susceptibility of a material of a particular geometry in a small applied magnetic field, i.e., χ after taking into account the demagnetization factor (see below).

[0055] The magnetic permeability μ is a measure of the resistance of a material to the formation of a magnetic field, μ=B / H.

[0056] Relative permeability (μ r ) is the ratio of magnetic permeability to the permeability of free space (μ0), and μ r =μ / μ0.

[0057] Ferromagnetic materials have a variable relative permeability (μ r ) Many ferromagnetic materials have a maximum relative permeability that can exceed 100,000.

[0058] Paramagnetic materials have a constant relative permeability (μr )

[0059] Diamagnetic materials have a constant relative permeability (μ r Diamagnetism creates a repulsive effect by generating a small magnetic field that opposes an externally applied magnetic field.

[0060] Specific initial relative permeability (μ r、i ) is μ for small H r is the value of μ r It is related to the initial magnetic susceptibility by =1+χ.

[0061] Apparent relative permeability (μ app ) is the relative permeability of a material of a particular shape, i.e., μ after taking into account the demagnetization factor r is.

[0062] A demagnetizing field, also known as a stray field, is a magnetic field (H) generated by magnetization (M), which causes shape anisotropy in ferromagnetic materials with a single magnetic domain and magnetic domains in larger ferromagnetic materials.

[0063] The demagnetization factor is a number that represents the strength of the magnetic field generated by an object of a specific geometric shape compared to an object of infinite range. It must be used to determine the demagnetization field. A magnetic object of any shape will have a total magnetic field that varies with position within the object, making it extremely difficult to calculate. This makes it very difficult to determine the magnetic properties of a material, such as how the magnetization of a material varies with its shape and magnetic field.

[0064] Magnetic anisotropy describes the change in magnetic properties depending on the orientation of a material in response to an externally applied magnetic field.

[0065] The magnetic moment, also known as the magnetic dipole moment, is a vector quantity that describes the magnetic strength and orientation of a magnet or other object, such as a current loop, that generates a magnetic field, H.

[0066] MRI metal artifacts are distortions in MR images characterized by areas of signal void (black) or bright fringing near metal objects. They occur at the interface between tissue and metals with different magnetic susceptibilities, causing the local magnetic field to distort the external magnetic field. This distortion alters precession frequencies within the tissue, leading to spatial mismapping of information.

[0067] The present disclosure relates to improved magnetic markers that provide MRI artifacts that are small enough (preferably less than 2 cm) to enable surgical guidance and effective wireless diagnosis. A high length-to-diameter ratio (as defined above) of greater than 50, preferably at least about 500, more preferably at least 650, at least 750, or at least 1000, and a ratio of about 1×10 -10 m 3 It has surprisingly been found that markers that provide satisfactory sensing performance balanced with small MRI artifacts can be created using thin wires of ferromagnetic material as defined herein, having a low volume of less than 100 μm. The markers of the present disclosure can be further improved by selecting ferromagnetic materials with low saturation induction, which can further limit MRI artifact size. The markers of the present disclosure can be further improved by selecting ferromagnetic materials with high initial permeability, which can improve sensing performance. Various shapes of such markers have also been developed that improve the isotropy of magnetic susceptibility.

[0068] "Artifacts" can be produced on MRI images when objects alter the magnetic field within the MRI machine. Ferromagnetic material markers therefore produce significant artifacts, making them less attractive for use as long-term markers for patients undergoing treatment, such as neoadjuvant therapy, prior to surgical resection. The artifacts are primarily due to the component of the magnetic field (B) produced by ferromagnetic objects that is in the same direction as the main magnetic field produced by the MRI machine (referred to herein as the y-axis). y ) is generated by B yThe effect of |B is to shift the local Larmor frequency of protons near the object, and if the shift is large enough, those protons will not appear in the correct slice reconstructed by the MRI machine. y |≧B crit The point where B crit is the magnitude of the y-component of the magnetic flux density B at which a voxel is mapped onto another slice, and its value depends on the MRI scan parameters.

[0069] At large distances compared to the object, the magnetic field generated by a ferromagnetic object can be described by a dipole model. Along the axis of magnetization, in this model, the magnetic flux density is

number

number

number

[0070] If we consider the edges of the MRI artifacts, then B marker、MRI =B critwhere y represents the distance from the center of the artifact to its edge. At that point, using the above formula,

number

number

number

[0071] In summary, the saturation induction (B S ) and the volume of magnetic material (F) determine the size of the MRI artifact as follows:

number

[0072] This constraint on the maximum volume of magnetic material that can be used makes it difficult to create markers from magnetic materials that have effective sensing distances, good isotropy, and low artifacts. The markers of the present disclosure address this problem.

[0073] To apply this knowledge to ferromagnetic materials that retain good magnitude of magnetic fields during sensing, magnetic susceptibility versus shape has also been studied.

[0074] As mentioned above, the magnitude of the magnetic flux density B from a ferromagnetic object along its magnetization axis is given by the following equation:

number

number

[0075] This last equation states that the strength of the sensing response depends on (a) the volume of the magnetic material (V), (b) the strength of the applied magnetic field (H), and (c) the apparent magnetic susceptibility of the magnetic material (χ app ) This last quantity is much larger for long, thin magnetic materials, as shown in Figure 1 of the accompanying drawings. The equation also shows that the strength of the sensing response decreases with distance from the marker (inversely proportional to the cube of the distance).

[0076] Certain shapes of markers containing ferromagnetic materials have proven unsuitable for the intended purpose. For example, spheres have low magnetic susceptibility for any given diameter, so they cannot produce the expected artifact size for the required sensing distance. For MRI artifacts with diameters of 10 mm or less under a 1.5 T MRI magnetic field, the sphere diameter cannot exceed 0.18 mm, which is too small to handle during manufacturing and to be seen by surgeons after tumor removal. On the other hand, for sensing distances greater than 40 mm, the sphere must exceed 1.1 mm, which produces artifacts far larger than what is considered acceptable.

[0077] Example 1: Physical properties of markers according to the present disclosure. As mentioned above, during sensing, the marker is exposed to a small oscillating field. Its magnetic response is determined by the magnetic permeability μ r or magnetic susceptibility χ (μ r= 1 + χ). If the initial magnetic susceptibility or specific relative magnetic permeability is known, the magnetic response of the marker can be predicted. It is known that the apparent initial magnetic susceptibility depends on the material, geometry, and frequency of the applied magnetic field.

[0078] It has been deduced that by increasing the aspect ratio (L / D, where L is the length of the cylinder of material and D is its diameter) of a magnetic material, its sensing performance in the direction of its central axis can be dramatically increased. This is shown in Figure 1: as the ratio L / D increases, the apparent magnetic permeability μ app also increases, increasing the distance at which the object can be sensed. This phenomenon is due to the demagnetization effect and can be understood intuitively as follows: if the object is substantially perpendicular to the applied magnetic field, the microscopic magnetic dipole fields generated within the object act to largely cancel each other out. Conversely, if the object is substantially parallel to the applied magnetic field (as in the case of an elongated rod aligned with the magnetic field), the microscopic dipoles generated within the object interact constructively, thereby generating a stronger magnetic field and allowing the marker to be more easily detected.

[0079] Under an AC magnetic field, a further phenomenon occurs: eddy currents are then induced in the material, generating an additional magnetic field that partially shields the material from the external magnetic field, thus reducing sensing performance. Eddy currents can make a significant difference when the object exposed to the magnetic field has a large area perpendicular to the magnetic field. In contrast, in very thin rods (φ approximately 50 μm), eddy currents practically do not significantly affect the sensing performance of magnetic wires. In the case of significantly thicker rods (φ approximately 500 μm), eddy currents become significant when L / D > 1. Therefore, to reduce or eliminate the effect of eddy currents on the sensing performance of magnetic wires, it is preferable to thin the wire.

[0080] For cylinders, the aspect ratio is the most important factor.

[0081] As is clear from Figure 1, for rods with aspect ratios L / D<10, the relative initial permeability (μ r、i) makes little difference as long as it is >1,000. However, for rods with larger aspect ratios, a higher initial relative permeability is beneficial: for example, for rods with L / D = 400, μ r、i When increasing μ from 1,000 to 50,000, app increases by about seven times.

[0082] The magnitude of the magnetic field induced in ferromagnetic materials under MRI determines the size of the MRI artifact. During MRI, the marker is exposed to a large, constant magnetic field, and the magnetization is B S =μ0M S ("saturation induction"). For most ferromagnetic materials, B S The range of magnetic fields is approximately 0.25 to 1.5 T. Therefore, the MRI magnetic field (1.5 to 3.0 T) is strong enough to saturate these materials, so the magnetization of ferromagnetic markers in MRI is simply M S B S =B S / μ0. Therefore, to minimize the artifact size, B S Therefore, materials with low

[0083] This is shown in Figure 2 of the accompanying drawings.

[0084] This results in a limited range of properties that must be met by the marker to provide a satisfactory sensing response and reduced MRI artifacts: a minimum volume of magnetic material is used, the aspect ratio is high, the marker preferably has a high apparent initial magnetic susceptibility, and the material should have a low saturation induction, preferably less than about 1.0 T.

[0085] It has surprisingly been found that long, thin wires of ferromagnetic material can provide the required property of apparent magnetic susceptibility of 1,000 or more. Figure 3a shows simulations confirming the feasibility of straight wires detectable in a useful range while exhibiting small MRI artifacts. The dotted lines indicate, for each wire diameter, the minimum length required to be sensed at 40 mm, assuming the wire material has a magnetic susceptibility χ = 72,000. The dash-dot lines indicate, for each wire diameter, the minimum length required for the wire material to achieve a saturation induction B of 1 T. S Figure 1 shows the maximum allowable length for a wire such that its MRI artifact has a diameter of less than 10 mm, assuming a wire with a diameter of 40 mm or greater. The shaded area in the upper left corner of the graph corresponds to wire dimensions that are simultaneously detectable at 40 mm or greater, while still producing an MRI artifact with a diameter of 10 mm or less. This figure shows that the wire length must be much greater than the wire diameter to simultaneously satisfy both of these conditions.

[0086] Figure 3b shows the same simulated data as Figure 3a, but over a narrower range of wire diameters and for more sensing distance and saturation induction. The dotted and dashed-dotted lines have the same meaning as in Figure 3a. The dashed and solid lines correspond to additional values ​​of sensing distance and saturation induction as indicated in the legend. This figure shows that a wider range of wire dimensions can be used if a lower sensing distance is acceptable (30 mm instead of 40 mm) or if the material has a lower saturation induction (0.5 T instead of 1 T).

[0087] A low saturation magnetization provides a small ferromagnetic dipole in an MRI scanner, and a high initial permeability means that a small volume of material provides a large sensing response on a probe, such as a magnetic susceptometry probe as described in WO 2014 / 140566, the contents of which are incorporated herein by reference. TIFF2025129273000012.tif121170

[0088] The sensing response and MRI artifacts of ferromagnetic materials under magnetic susceptometry probe fields depend on different variables. For small oscillating magnetic fields, such as those produced by Sentimag®, commercially available from Endomagnetics Ltd., UK, sensing performance depends almost exclusively on the aspect ratio and volume, as well as the specific initial permeability (μ r、i ) (initial slope of the B-μH curve) is recognized to be weak. In contrast, the magnitude of the magnetic field produced by a marker in an MRI machine, and therefore the MRI artifact size, depends on the saturation-induced B S and depends on the volume of material. This means that χ = ​​72,000 and B S This means that it is possible to produce the required small MRI artifacts using very thin pieces of low saturation induction ferromagnetic material that can still be sensed at a satisfactory distance, as shown in Table 1 below for materials with Θ = 0.5T: [Table 1]

[0089] It has been found that markers having a large aspect ratio, preferably having a length to diameter ratio of at least 50, more preferably at least 60, particularly at least 100, more particularly at least about 500, and having a low total volume, for example markers having a length of at least 3 mm, preferably at least 6 mm, and a diameter of less than 100 μm, preferably 50 μm or less, particularly 30 μm or less, with low saturation induction ferromagnetic material pieces that are adequately sensed while producing low MRI artifacts.

[0090] This is illustrated in Figures 3a and 3b of the accompanying drawings, which show the MRI performance depending on the length and diameter of the rod. S For , anything below the curve gives acceptable artifacts.

[0091] Example 2: Investigation of preferred materials for magnetic markers according to the present disclosure. The marker described in Example 1 was further investigated to determine the required high specific initial permeability μ r、i >1000, can be formed into very thin strips or wires, allowing for large aspect ratios but small volumes, low saturation induction B S and ideally a low B below 1T. S This allows for the selection of a preferred magnetic material having the above properties.

[0092] It has been found that preferred materials having the required properties are certain metals, amorphous metals and ceramic ferrites, preferably the following: cobalt-based amorphous metals, such as those sold under the trade names Yshield MCE61™, Metglas 2705M™ and Metglas 2714A™; manganese-zinc ceramic ferrites, such as those sold under the trade names Fair-Rites 31™, 76™ and 78™; nickel-iron-based soft ferromagnetic alloys, such as those sold under the trade names Mu-metal, Permalloy 80, Permalloy C, Permalloy and Supermalloy; nickel-zinc ceramic ferrites, such as those sold under the trade names Fair-Rites 15™, 20™ and 43™; and more preferably cobalt-based amorphous metals, such as Yshield™ and Metglas 2714A™.

[0093] Ceramics have low saturation induction, but are less easily formed into wires or flat wires and are therefore less suitable for markers according to the present disclosure.

[0094] Figure 4 is a plot of saturation induction versus relative initial permeability for a variety of different materials. Materials that may make suitable markers fall in the upper left region of the graph, exhibiting low saturation induction and high relative initial permeability.

[0095] Example 3: Investigation of optimized design of magnetic markers according to the present disclosure. The elongated wire markers discussed in connection with Examples 1 and 2 have the required specific initial permeability μ r、i >1000, preferably >10,000, with a large aspect ratio but a small volume and low saturation induction B S However, this type of marker has a high anisotropy ratio and exhibits a strong sensing response only in its axial direction.

[0096] From a practical perspective, high anisotropy is undesirable during surgery when detecting markers using the magnetic probe described in WO 2014 / 013235: the magnetic signal at a certain distance varies depending on the orientation of the marker relative to the probe, appearing closer when the marker approaches from one orientation and farther away when it recedes from another. Minimizing the anisotropy of implanted markers improves the surgeon's ability to more intuitively locate the marker and enhances their ability to safely resect tissue surrounding the lesion. An anisotropy ratio of 1 is ideal, providing a uniform response from any direction. However, in practice, this is difficult to achieve within the geometric constraints of delivery through a small needle. An anisotropy ratio of less than 7 (i.e., 1-7), preferably less than 5, and more preferably less than 3, is desirable. Because the magnetic sensing response is strongly dependent on distance (under certain conditions, it is approximately inversely proportional to the sixth power of the distance), the calculated distance is relatively weakly dependent on the magnetic sensing response. Therefore, an anisotropy ratio of less than 2 is practically close to ideal, 5 is practically indistinguishable from isotropy, and 7 provides sufficient uniformity.

[0097] Two methods have been identified to increase axial sensing and magnetic susceptibility isotropy. It is also desirable to provide a marker that does not need to be unpacked at the injection site, because a deployable concept must have a consistent unpacking mechanism that allows for accurate placement and complete unpacking to provide the necessary sensitivity and isotropy. Therefore, having a marker that does not need to be unpacked at the injection site would also provide a significant improvement over the prior art. To achieve this, the marker may comprise multiple small ferromagnetic rods, using the wire of Example 1, encapsulated within a single cylinder with all axes covered. However, this type of marker still faces several challenges regarding detection sensitivity (short rods are expected to have low axial sensitivity and destructive interaction effects), MRI artifacts (the complexity of the magnetic dipole is the greatest complication to estimate), safety and regulations, as well as the manufacturing process and consistency for encapsulating the rods.

[0098] Therefore, further configurations were investigated for optimized markers according to the present disclosure. It has been found that for a given artifact size, there is a limit to the maximum volume of magnetic material suitable for use in the marker. Low saturation induction B S Using materials with a .gtoreq. ...

[0099] Since it is the wire diameter that is most strongly dependent on the diameter of the artifact, important variables that can be modified to improve the design of the marker have been identified: total wire volume and wire length, so that the latter does not vary too much. If the design consists of a wire diameter D, the allowable length L of the wire is:

number

[0100] It was initially thought that an arrangement comprising multiple rods of thin wires arranged in different orientations would enhance the anisotropy of the marker. Unexpectedly, it was found that adjacent rods can have positive or negative interactions with respect to the total dipole moment, as shown in Figures 5a, 5b and 5c of the accompanying drawings.

[0101] Figure 5a shows that parallel rods spaced 0.5 mm apart reduce the dipole moment by 5% for a 50 μm diameter rod and by 10% for a 100 μm diameter rod. Conversely, as seen in Figure 5b, when two identical rods are placed perpendicularly with their ends separated by a rod diameter, the total dipole moment increases by 5%. Furthermore, as seen in Figure 5c, the perpendicular rods show a smaller reduction in their dipole moment when offset axially.

[0102] Based on these findings, marker configurations with closely spaced parallel rods were excluded from the present disclosure. However, a satisfactory marker forming an embodiment of the present disclosure was one in which the placement of these parallel rods could be offset, as shown in Figure 5c. A further embodiment is one in which the perpendicular rods can be placed end-to-end.

[0103] The preferred spacing of the rods is at least one diameter apart.

[0104] The rod, once provided in the required configuration, can be enclosed in a cylindrical housing as known in the art. For example, the marker can be packaged in other materials to ensure biocompatibility, be rigid, or have a coating to prevent reaction with body tissue. The marker can be enclosed in a tube made of, for example, nitinol, titanium, stainless steel, or other biocompatible alloys, preferably non-magnetic and with relatively low electrical conductivity. Suitable coating materials include polymer coatings such as FEP, Parylene, PTFE, ETFE, PE, PET, PVC, or silicone, or epoxy-based encapsulants.

[0105] Given the difficulty in assessing the magnetic dipole moments of complex structures, methodologies have been developed to establish how different geometries behave and interact. The findings are summarized in Figure 6.

[0106] It was concluded that larger aspect ratio designs, either longer rods or larger rings, produced designs with significantly better sensing performance than MRI artifacts. In this regard, 5 mm long rods were found to be approximately 8 times better per unit volume than 1 mm long ones, and rings were found to be superior per unit volume to two perpendicular rods. Ring- or coil-based designs were also found to be superior to two perpendicular rods for generating sensing responses in two directions.

[0107] In this regard, with reference to Figure 6 of the accompanying drawings, the quantity m Z / V indicates how much sensory response the marker generates per unit volume. A 5 mm straight rod produces a stronger response per unit volume than a ring, but (m Z(V is 54 for the rod and 42 for the ring) The rod produces a magnetic response only along its axis, whereas the ring produces it in the two dimensions covered by its plane. Therefore, the correct figure of merit for the ring is 2 x 42 = 84, i.e., about 50% better than the rod.

[0108] Figure 7 of the accompanying drawings shows a multiple marker configuration according to an embodiment of the present disclosure that has been found to produce the required low MRI artifact with good sensing response in multiple directions. Figure 7 provides sensing distance at 200 mA for an artifact diameter of 10 mm. Material parameters are as follows: μ r =72,000, B S =0.55T, and the wire diameter is 30 μm, with a maximum total length of 21 mm.

[0109] This figure also highlights the preferred embodiments of the present disclosure: helical shapes, rings, and offset parallel or perpendicular rod arrays, which provide the best performance per volume of material used.

[0110] Example 4: Further investigation into helical coil markers according to embodiments of the present disclosure. Given the ease of manufacturing of the helical shape, optimization of this shape was further investigated as a preferred marker according to the present disclosure.

[0111] Two different types of helix designs were demonstrated to produce acceptable sensing responses, both in terms of minimum sensing distance and isotropy. These are (i) a single helix combined with one longitudinal wire aligned parallel to the axis (Figures 8a and 8b), and (ii) a multiple helix consisting of double or triple helices (Figures 9a and 9b), as shown in Figures 8a-9b, respectively. In Figures 8a and 8b, the longitudinal wire is aligned parallel and coaxially with the axis. In another arrangement, the longitudinal wire is positioned to the side of the helix rather than coaxially with the axis.

[0112] A marker with a single helix design derives most of its lateral response from its helical coil and its axial response from its axial rod, while a marker with a triple helix design uses a larger pitch to derive both lateral and axial response from its helical coil (larger pitch means the coil is more axially oriented). In the context of triple helices and other multiple helices, the term "pitch" as used herein means the pitch of the individual coils of each component of the multiple helix, unless the clear context indicates otherwise.

[0113] As shown in Table 2 below, sensing distances were predicted using a combination of standard physical simulation software (COMSOL), custom computer models, and experiments for one or more axial rods and two diameters used. [Table 2]

[0114] According to the present disclosure, it is desirable to minimize the amount of material used to minimize MRI artifacts, and by combining this with the results of the simulation, it can be concluded that it is desirable to use a smaller diameter and one long rod rather than two short rods.

[0115] For the single helix design (FIGS. 8a and 8b) with the longitudinal wire aligned parallel to the core axis, it was determined that the thinnest possible wire (see Example 1 above) with the longest possible length should be used. As shown in FIG. 6, the coil diameter should be maximized to provide a stronger lateral sensing response for the same volume of material. FIG. 8b shows an optional housing or tube 80 (shown in dotted lines) positioned around the helical coil. The marker may be encapsulated within a tube made, for example, of nitinol, titanium, stainless steel, or other biocompatible alloys; the material is preferably nonmagnetic and has relatively low electrical conductivity. Suitable coating materials include polymer coatings such as FEP, Parylene, PTFE, ETFE, PE, PET, PVC, or silicone, or epoxy-based encapsulants.

[0116] The graph of pitch versus lateral sensing distance surprisingly does not show a sharp peak near the optimum; instead, the pitch must be balanced with increased axial sensing to reach the sweet spot. Figures 10a-c show that the pitch that maximizes lateral sensing performance is approximately equal to the helix diameter—this is the optimal pitch for a single helix design, where the helix coil needs to generate only the lateral sensing response, with the axial component coming from the axial wire. The pitch that produces isotropic sensing performance is approximately equal to 1.6 times the helix diameter, but this pitch is useful for a multiple helix design that excludes the axial wire, where both axial and lateral sensing responses need to be generated by the helix coil. Figures 10a-c show the pitch (mm) versus sensing distance (mm) for a 1 mm diameter marker, a 1.15 mm diameter marker, and a 1.3 mm diameter marker, respectively.

[0117] Other design options were further investigated, including multiple helices to avoid the need for an axial rod. Table 3 below shows that for the same total length of wire, the total number of turns per helix increases between a single helix with a rod and a double or triple helix without a rod. [Table 3]

[0118] To maintain the same marker length and diameter, the double and triple helices had a higher pitch, which was expected to improve axial detection, but surprisingly, it was found to have only a small effect on lateral detection, and even more surprisingly, to have increased lateral detection, as shown below in Table 4. Another major unexpected finding was the non-destructive effect on sensitivity of intertwining the helices closely together without touching.

[0119] In conclusion, it was found that for a given amount of material and marker length, a single helix exhibits a short pitch and may require combination with a ferromagnetic rod. Alternatively, a double or triple helix incorporated into a marker with the same amount of material for the same length would require the helix to be stretched so that the pitch increases, which serves to move the coil more axially but surprisingly does not reduce transverse detection.

[0120] If stronger sensing performance is required in a more compact geometry, a higher order helix can be used to provide more coils per unit length, however, if too many coils are packed together (spacing less than one coil diameter), destructive interactions begin.

[0121] Marker size in all cases in Table 4 was 1.15 mm diameter and 8.0 mm length. [Table 4]

[0122] As can be seen from Table 4 above, decreasing the pitch and increasing the number of turns improves lateral sensing performance but decreases axial sensing performance. It also increases the overall length of wire used and increases the size of MRI artifacts. Increasing the pitch and decreasing the number of turns decreases lateral sensing performance but improves axial sensing performance. It also reduces the overall length of wire used and decreases the size of MRI artifacts. For each type of multi-helix marker, there is an optimal pitch that produces isotropic sensing performance (e.g., for triple helix, a pitch of approximately 2.0 mm for a 1.15 mm diameter marker using 15 μm Co-Fe amorphous metal wire).

[0123] Example 5: Investigation of alternative ferromagnetic materials for markers according to the present disclosure. All of the markers disclosed above use the thin wire described in connection with Example 1 above to produce markers of optimized design. However, the high specific initial permeability μ required r、i >1000, preferably >10,000, resulting in a low saturation induction B S The preferred magnetic material having the formula (I) can also be formed into a strip, which is a flat wire having an oval cross section to provide a marker according to the present disclosure.

[0124] For example, Table 5 below lists a number of microcrystalline cellulose esters that meet the requirements for markers according to the present disclosure and that may be provided in rolled sheet form before being cut into wires or strips. r、i ≧15,000. [Table 5] ( ** ) A measure of the amount of material available for a given artifact size. The more material there is, the stronger the signal response should be.

[0125] Marker designs can be created from these thin sheets using known manufacturing techniques such as etching or laser cutting. These manufacturing techniques are intended to create wires that may or may not result in a flat shape. In the case of flat wires, the diameters described in other sections of this application essentially correspond to the average radial length of the wire.

[0126] From the above description, it is readily apparent that the implantable marker according to the present disclosure provides a small ferromagnetic marker that has good isotropy of magnetic susceptibility, sensing distance, and exhibits low MRI artifacts.

[0127] Example 6: Use of markers according to the present disclosure in monitoring and treating breast cancer. The markers according to the present disclosure are particularly suitable for monitoring and treating breast cancer, allowing tracking of tumor size during preliminary neoadjuvant therapy with the aim of reducing tumor size to less than 2 cm in length or at least to a size sufficiently small compared to the total size (BCS).

[0128] Patients with breast cancer tumors larger than 2 cm but smaller than 5 cm that have not spread further than nearby lymph nodes (often classified as "stage 2" breast cancer) can undergo BCS, which generally requires neoadjuvant therapy to shrink the tumor to approximately 2 cm or less. In parallel, healthcare professionals also need to assess the exact nature of the tumor, typically performing a biopsy to sample some of the tumor tissue.

[0129] Markers according to the present disclosure can be placed in the cavity formed by tissue sampling to identify tumor location using a magnetic susceptometry probe, such as the probe described in WO 2014 / 140566. This allows tumor location to be identified during future assessment of tumor progression and / or for tumor resection. A susceptometry detection system for locating a marker is shown in FIG. 20 , in which a marker 20 according to the present disclosure is shown with a magnetic susceptibility probe 22, which includes a drive coil 24 arranged to excite the marker with an alternating magnetic field and a detector 24 arranged to receive signals from a sensing coil. A magnetic field generator 28 is arranged to drive an alternating magnetic field through the drive coil 24, and the detector 24 is arranged to detect one or more harmonics of the drive frequency in the received signal.

[0130] The markers of the present disclosure also allow for tracking of tumor response to adjuvant therapy, for example, by periodic examination under MRI, by keeping the size of the artifacts produced by the marker under the MRI field to a minimum, ideally 2 cm or less in length. In this regard, the markers are too large for BCS (essentially about 2 cm, but possibly larger), but do not interfere with assessment of tumor size.

[0131] Therefore, the markers disclosed herein are particularly suited to protocols typically pursued by medical professionals when tracking breast cancer progression under MRI, as their low induction saturation and small mass per volume can significantly reduce the size of MRI artifacts. Once the tumor has shrunk to a size that allows for BCS, the markers allow medical professionals to identify the tumor's location. The markers can be detected by a magnetic susceptometry probe positioned at least 3 cm and up to 5 cm away, allowing for the location of tumors several centimeters below the skin's surface. This allows medical professionals to determine the best route to access and remove the tumor by excision before dissecting the tissue.

[0132] 11a and 11b, and 19, the marker 6 comprises a length of magnetic marker material bent to describe three or four sides 6a, 6b, 6c of a tetrahedron. By doing so, the harmonic signal response of the marker is more uniform from any given sensing direction. In further embodiments, the radius of the bend 6d can be configured, for example, by being larger, to allow the marker to be more easily packed into the outer tube prior to deployment.

[0133] In Figure 12, the marker comprises a length of magnetic marker material bent into a portion of a circle 6e, with one end 6f bent radially towards the centre and then bent substantially 90° out of the plane of the circle 6e to form a portion 6g along or parallel to the axis of the circle.

[0134] In Figure 13, marker 6 comprises a length of magnetic marker material arranged along three orthogonal axes x, y, and z, forming the shape of a "jack" (also known as a jackstone or knucklebone).

[0135] 14a and 14b, the marker comprises a length of magnetic marker material having a straight central portion 6h and two further portions 6i, 6j at each end bent perpendicularly to each other and from the central portion. In further embodiments, the radius of the bent portion 6k may be larger to allow the marker to be more easily inserted into the outer tube.

[0136] In Figure 15, the marker 6 comprises a length of magnetic marker material formed into a circular standing wave shape, i.e., a uniform wave shape, and then bent into a circle to join the ends and form a circle in plan view.

[0137] In Figure 16, the marker includes an oval or elliptical length of magnetic marker material 6n with wire ends 6o that are joined or adjacent but not joined to one another. The two sections of the ellipse or ellipse at the ends of its major axis are bent at approximately 90° in the plane of the ellipse. The bent sections occupy approximately one-quarter to one-third of the area of ​​the ellipse or ellipse.

[0138] In Figure 17, the marker includes three lengths of magnetic marker material 6t, 6u, 6v arranged orthogonally to one another to form the vertices of a substantially orthogonal tripod or cuboid. The three lengths are joined at a joint 6w, which allows the lengths to become parallel to one another prior to deployment and then redeploy to form the orthogonal tripod.

[0139] In Figures 18a and 18b, the marker includes three lengths of magnetic marker material 6x, 6y, 6z arranged to form a tripod with non-orthogonal angles between the legs of the tripod. The three lengths are joined at a joint 6w, which allows the lengths to become parallel to each other before deployment and then redeploy to form the tripod.

[0140] In one embodiment, the magnetic marker may include a wire made of a ferromagnetic material in the form of a helical coil having the following properties: [Table 6]

[0141] Preferably, the angle between the legs is chosen so that the harmonic magnetic response is as uniform as possible from any direction. A tripod is uniform with three legs equally spaced apart.

[0142] Although the markers of the present disclosure have been described and illustrated with reference to particular embodiments, it will be understood by those skilled in the art that the markers are compatible with many different variations not specifically illustrated herein.

[0143] Where the foregoing description refers to integers or elements having known, obvious, or foreseeable equivalents, such equivalents are incorporated herein as if individually set forth. Reference should be made to the claims to determine the true scope of the present disclosure, and the claims should be construed to encompass any such equivalents. The reader will also understand that any integers or features of the present disclosure described as preferred, advantageous, convenient, or the like are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that such optional integers or features may be advantageous in some embodiments of the present disclosure, but undesirable and therefore absent in other embodiments. Other embodiments 1. An implantable marker for imaging and surgical guides, comprising: a length-to-diameter ratio of at least about 500 and a -11 m 3 one or more pieces of ferromagnetic material having a total volume of less than The one or more pieces of ferromagnetic material have a high relative initial permeability (μ r、i )> about 1000 An implantable marker. 2. An implantable marker for imaging and surgical guides, comprising: a length-to-diameter ratio of at least about 650, preferably at least about 750 or at least about 1000, and a -11 m 3 comprising one or more pieces of ferromagnetic material having a total volume of less than An implantable marker. 3. A marker as described in embodiment 1 or 2, characterized in that the total length to diameter ratio of one or more pieces of ferromagnetic material is at least about 2000. 4. The total volume of the one or more pieces of ferromagnetic material is about 6×10 -12 m 3 The marker according to any one of embodiments 1 to 3, wherein the marker has a molecular weight of less than 10 ... 5. A marker described in any one of embodiments 1 to 4, characterized in that one or more pieces of ferromagnetic material have a low saturation induction of about 1 T or less. 6. A marker according to any one of embodiments 1 to 5, characterized in that the one or more pieces of ferromagnetic material are wires or strips. 7. A marker described in any one of embodiments 1 to 6, characterized in that the marker comprises a wire or strip of ferromagnetic material having a length of at least about 10 mm. 8. A marker described in any one of embodiments 1 to 7, characterized in that the marker comprises a wire or strip of ferromagnetic material having a length of at least about 20 mm. 9. A marker according to any one of embodiments 1 to 8, characterized in that the marker comprises a wire of ferromagnetic material having a diameter of less than about 100 μm. 10. A marker according to any one of embodiments 1 to 9, characterized in that the marker comprises a wire of ferromagnetic material having a diameter of about 30 μm or less. 11. A marker according to any one of embodiments 1 to 10, characterized in that the marker produces an MRI artifact of less than about 2.5 cm in a magnetic field of about 1.5 T or greater. 12. The marker according to any one of the preceding claims, characterized in that the ferromagnetic material is selected from cobalt-based amorphous metals (e.g., Yshield MCE61™, Metglas 2705M™, and Metglas 2714A™); manganese-zinc ceramic ferrites (e.g., Fair-Rites 31™, 76™, and 78™); nickel-iron-based soft ferromagnetic alloys (e.g., Mu-metal, Permalloy 80, Permalloy C, Permalloy, and Supermalloy); and nickel-zinc ferrites (e.g., Fair-Rites 15™, 20™, and 43™); and more preferably, cobalt-based amorphous metals (e.g., Yshield™ and Metglas 2714A™). 13. A marker described in any of embodiments 1 to 12, characterized in that the ferromagnetic material comprises one or more wires or strips configured in the form of one or more rods, spiral coils and / or rings. 14. A marker described in any one of embodiments 1 to 13, characterized in that the one or more pieces of ferromagnetic material, individually or in combination, are configured to extend in multiple different directions and / or define a serpentine path that includes twists, bends, or turns. 15. A marker described in any of embodiments 1 to 14, characterized in that the one or more pieces of ferromagnetic material comprise one or more wires or strips extending in different directions in the same or different planes, and are arranged such that the marker has a signal anisotropy ratio of less than about 7, preferably less than about 5. 16. A marker described in any of embodiments 1 to 15, characterized in that the one or more pieces of ferromagnetic material include one or more wires or strips of ferromagnetic material arranged as offset parallel rods, rods that are substantially perpendicular to one another, and / or rods arranged end to end without touching one another. 17. A marker described in any one of embodiments 1 to 16, characterized in that the one or more pieces of ferromagnetic material include multiple pairs of rods crossed at substantially right angles to each other, and the marker includes a stacked arrangement of multiple crossed pairs of rods. 18. A marker as described in embodiment 17, characterized in that the pairs of crossed rods are aligned or rotated relative to each other, each pair preferably being rotated substantially by about 45 degrees relative to an adjacent pair. 19. A marker described in any one of embodiments 1 to 18, characterized in that the one or more pieces of ferromagnetic material include one or more groups of parallel rods, the parallel rods being in different groups extending in the same or different directions within the housing; or forming a twisted ladder configuration. 20. A marker described in any of embodiments 16 to 19, characterized in that the one or more pieces of ferromagnetic material further comprise one or more longitudinal or transverse rods extending through the housing. 21. A marker described in any one of embodiments 1 to 20, characterized in that the one or more pieces of ferromagnetic material include one or more helical coils. 22. A marker described in any one of embodiments 1 to 21, characterized in that the one or more pieces of ferromagnetic material comprise a plurality of spaced apart rings. 23. A marker as described in embodiment 21 or 22, characterized in that the one or more pieces of ferromagnetic material comprise a helical coil or one or more straight rods extending through a plurality of spaced apart rings. 24. A marker described in any of embodiments 1 to 23, characterized in that the one or more pieces of ferromagnetic material include a single helical coil combined with a straight wire aligned parallel to the helical coil axis. 25. A marker described in any of embodiments 1 to 24, characterized in that the one or more pieces of ferromagnetic material comprise multiple helical coils, for example forming double or triple helices. 26. A marker described in any one of embodiments 21 or 23 to 25, characterized in that the pitch of each helical coil is approximately 1.0 to 1.5 of the diameter of the coil. 27. A marker described in any one of embodiments 1 to 26, characterized in that the marker further comprises an outer housing, the ferromagnetic material being enclosed within the housing; and the outer housing is configured and dimensioned for injection, for example, via an 18G to 12G gauge needle. 28. A detection system for locating an implanted marker, comprising: An implantable marker according to any one of embodiments 1 to 27; at least one drive coil arranged to excite the marker with an alternating magnetic field, and at least one sense coil arranged to detect signals received from the excited marker; a magnetic field generator arranged to drive an alternating magnetic field through the at least one drive coil; and at least one detector positioned to receive a signal from the sensing coil and to detect one or more harmonics of the drive frequency in the received signal; A detection system comprising:

Claims

[Claim 1] 1. An implantable marker for imaging and surgical guides, comprising: Length-to-diameter ratio of at least about 500 and about 1×10 －１１ m ３ one or more pieces of ferromagnetic material having a total volume of less than The one or more pieces of ferromagnetic material have a high relative initial permeability (μ ｒ、ｉ ) > about 1000 An implantable marker.

Images