Implantable markers for imaging and surgical guidance

Abstract

The present disclosure relates to implantable markers for imaging and surgical guidance. An implantable marker for imaging and surgical guidance by susceptibility measurement, comprising one or more pieces of ferromagnetic material having a total aspect ratio of at least about 500 and a total volume of less than about 1 x 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 sensing 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 one drive coil; and at least one detector arranged to receive a signal from the sensing coil and detect one or more harmonics of the drive frequency in the received signal.

Description

Field of the Invention

[0001] The present disclosure generally relates to the field of magnetic markers for imaging and surgical guidance, and more particularly to susceptibility measurement markers with reduced MRI artifacts. Background Art

[0002] Markers are used to guide a surgeon to an area of interest during a surgical procedure, where the area of interest is physically invisible or difficult to detect, e.g., a small tumor to be excised. Ideally, such markers would be deployable through a small gauge needle (e.g., 18G to 12G) to reduce trauma to the patient. Typically, the length of such markers is less than 10 mm, making them compact and minimizing trauma. Markers can be placed at the area of interest in the body during a biopsy or other surgical procedure, e.g., a cancerous lesion. The marker is placed under imaging guidance (e.g., ultrasound or X-ray / mammography). During a subsequent surgical procedure, the marker is detected and located with a hand-held probe that provides auditory, visual, or other feedback to the surgeon to guide the surgery. Typically, the marker is excised along with the surrounding tissue.

[0003] One such method is to use a marker containing a radioactive isotope (e.g., iodine-125), which can be detected using a hand-held gamma detection probe. However, the use of radioactive materials is strictly regulated, making it challenging to establish a radioactive seed program in all but the largest academic hospital centers.

[0004] Additional methods are discussed in the applicant's earlier published patent applications (e.g., WO 2011 / 067576, WO 2014 / 032235, and WO2014 / 140567), which use magnetic fields and magnetic markers with high susceptibility. A hand-held susceptibility measurement probe generates an alternating field that excites the magnetoresponsive marker and detects the response magnetic field. This method has been found to be highly effective for deeper sensing. However, a disadvantage of these systems is that the artifacts generated in an MRI environment are large compared to the marker itself.

[0005] MRI is used to image invasive breast cancer lesions that are not visible by ultrasound or mammography, and MRI monitoring is increasingly used to evaluate neoadjuvant therapy before surgical resection, allowing the size of the tumor to be tracked after neoadjuvant therapy and before surgery. MRI artifacts should not affect the healthcare provider's assessment of the size of the tumor at the location where the marker is placed, as further explained in detail below.

[0006] It is well known that ferromagnetic materials cause MRI distortion, and this has been widely described in the scientific literature. For example, Hargreaves et al. (Metal Induced Artifacts in MRI, August 2017, DOI: 10.2214 / AJR.11.7364) explain that some ferromagnetic materials may be safe for MRI but still produce significant artifacts. The artifacts are mainly caused by the magnetic field component (B y ) produced by the ferromagnetic object, which is in the same direction as the main magnetic field generated by the MRI machine. The effect of B y is to change the local Larmor frequency of the protons near the object, and if this change is large enough, these protons will not appear in the correct slice reconstructed by the MRI machine.

[0007] Accordingly, the applicant has determined the need for a small ferromagnetic marker for detection by susceptibility measurement, which has acceptable response isotropy, a long sensing distance, and shows small MRI artifacts. The MRI artifacts of such a marker should not impair the medical staff's assessment of the tumor size, as monitoring a decrease in tumor size provides a positive option in the management of cancer patients. In this regard, several criteria are commonly used to evaluate breast cancer stages, such as tumor size, whether the tumor has spread to the lymph nodes, and whether the cancer has spread to other parts of the body (metastasis). Early-stage cancers (for which breast-conserving surgery using lumpectomy can be envisaged) should preferably present a tumor size of 2 cm or less. Shashla (Neoadjuvant chemotherapy in breast cancers, September 2016, DOI: 10.1177 / 1745505716677139) shows that a smaller tumor size represents a good prognostic factor, and a residual tumor >2 cm is associated with a higher rate of local regional tumor recurrence after neoadjuvant chemotherapy. Koh et al. (Introduction of a New StagingSystem of Breast Cancer for Radiologists:An Emphasis onthe Prognostic Stage, January 2019, DOI: 10.3348 / kjr.2018.0231) show that tumors with a size below 2 cm are classified as T1 and correspond to cancer stage 1 or 2, which is usually the time when breast-conserving surgery can be envisaged. Larger tumors will be more likely to result in a more radical surgery, such as mastectomy.

[0008] Accordingly, it is desirable to be able to determine the size of a tumor under MRI when the tumor diameter exceeds 2 cm, so as to be able to evaluate whether the tumor has shrunk to a level allowing breast-conserving surgery. According to the present disclosure, a marker providing an artifact of approximately 2 cm will still allow sufficient radiological diagnosis to determine whether the tumor is larger than 2 cm and may require further neoadjuvant treatment.

[0009] An object of the present disclosure is to provide an improved magnetic marker with reduced MRI artifacts, which overcomes or at least mitigates the above-mentioned drawbacks. Summary of the Invention

[0010] According to a first aspect of the present disclosure, there is provided an implantable marker for imaging and surgical guidance, the marker comprising one or more pieces of ferromagnetic material having an overall aspect ratio of at least 50 and a total volume of less than 1×10 -10 m 3 .

[0011] In a particular aspect of the present disclosure, the ferromagnetic material may have an overall aspect ratio of at least about 500.

[0012] Suitably, the ferromagnetic material may have a total volume of less than about 1×10 -11 m 3 ; preferably less than about 6×10 -12 m 3 .

[0013] Suitably, the one or more pieces of ferromagnetic material may have a high initial relative permeability (μ r,i ) of > about 1000; preferably at least about 2000.

[0014] In the case of using the term "length", unless otherwise explicitly stated, those skilled in the art will understand that this means the length as if the non-linear marker shape extends linearly. For example, if the marker is a helix, the length means the length of the marker if it is straightened and extended linearly. In the case where the marker comprises multiple pieces of ferromagnetic material, the length may include the combined length of the multiple pieces of ferromagnetic material.

[0015] In some embodiments, the one or more pieces of ferromagnetic material may have a circular cross-section with an easily measurable diameter. In some embodiments, the one or more pieces of ferromagnetic material may have a non-circular cross-section; for example, the one or more pieces of ferromagnetic material may include a strip having a generally rectangular cross-sectional shape. Thus, for a non-circular piece of ferromagnetic material, the "diameter" herein also means the width (e.g., the maximum width). Alternatively, the aspect ratio may be equal to the ratio of the length of the piece to the square root of the cross-sectional area.

[0016] It has been found that markers having a high aspect ratio and small volume as defined herein balance the provision of a good sensing response with small MRI artifacts. Increasing the aspect ratio of at least one ferromagnetic material improves the sensing response of the marker. Reducing the volume of the ferromagnetic material reduces the MRI artifacts generated by the marker.

[0017] The marker can be detected by a susceptibility measurement probe (such as the probe described in WO 2014 / 140566A1). The susceptibility measurement probe can generate a magnetic field strength between about 0.1 mT and about 2.0 mT at the source; preferably, between about 0.2 mT and about 1.2 mT, and generate a field strength between about 0.04 mT and about 0.4 mT within about 5 mm of the probe. Appropriately, this can allow the detection of the markers of the present disclosure at a range up to about 50 mm, 60 mm, 70 mm, or 80 mm from the probe. The exact detection range of a particular marker depends to some extent on its construction, as described herein.

[0018] The total aspect ratio of the one or more ferromagnetic materials can 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 total aspect ratio of the one or more ferromagnetic materials can 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 total aspect ratio of the one or more ferromagnetic materials can be about 2400.

[0019] The total volume of the one or more ferromagnetic materials can be less than 5x10 -11 m 3 、3x10 -11 m 3 、or 1x10 -11 m 3 . In some embodiments, the total volume of the one or more ferromagnetic materials can be as low as 1x10 -12 m 3 .

[0020] For example, the one or more ferromagnetic materials can have a total length of 50 mm and a diameter of 15 μm. In such an example, the total aspect ratio of the one or more ferromagnetic materials can be approximately 3333, and the volume can be approximately 9x10 -12 m 3 .

[0021] In another example, the one or more ferromagnetic materials may have a total length of 36 mm and a diameter of 15 μm. In such an example, the aspect ratio of the total length to the diameter of the one or more ferromagnetic materials may be about 2,400, and the volume of the ferromagnetic material may be about 6.4x10 -12 m 3 .

[0022] In a preferred embodiment, the marker may include a ferromagnetic material wire or strip having a length of at least 3 mm, 6 mm, 10 mm, 20 mm, 30 mm, 35 mm, 50 mm or 100 mm. The diameter of the wire may be less than 100 μm, or less than or equal to 50 μm, 30 μm, 15 μm or 10 μm. The marker may include a ferromagnetic material wire or strip having a length not exceeding 3 mm, 6 mm, 10 mm, 20 mm, 30 mm, 35 mm, 40 mm, 50 mm or 100 mm. Suitably, the wire or strip may be formed into one or more pieces, as described herein.

[0023] The marker according to the present disclosure may provide an MRI artifact having a diameter of less than 3 cm, more preferably less than 2.5 cm, especially less than 2 cm. The size of the MRI artifact may vary depending on the intensity of the MRI field, and the size of the MRI artifact may be detected in a 1.5T, or 3.0T MRI scanner, or any other suitable MRI scanner.

[0024] The ferromagnetic material may have a low saturation induction intensity, for example, less than or equal to 1 T. Providing a ferromagnetic material having a low saturation induction intensity may limit the size of the MRI artifact generated by the material when the marker is subjected to an MRI magnetic field intensity greater than the field strength required to saturate the magnetization of the ferromagnetic material.

[0025] The ferromagnetic material may have a high initial relative permeability, for example, (μ r,i )>1000. Suitably, the ferromagnetic material may have a high initial relative permeability greater than 10,000. Providing a ferromagnetic material having a high initial relative permeability may improve the sensing performance of the marker.

[0026] Preferred materials having the properties required for the marker according to the present disclosure are certain metals and amorphous metals. Suitably, the ferromagnetic material may be malleable such that it can be formed into a wire. The ferromagnetic material may be flexible such that the at least one piece can be formed into a desired configuration; for example, reducing or minimizing the magnetic anisotropy ratio of the marker, as described below. Preferably, cobalt-based or nickel-based ferromagnetic alloys may be used, especially those sold under the trade names Yshield TM and Metglas 2714A TM .

[0027] The ferromagnetic material is preferably in the form of a wire, such as a cylindrical wire with 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, isotropic high sensing performance, and reduced MRI artifacts. As used herein, the term "wire" includes strips as well as wires, unless the context indicates otherwise.

[0028] Preferred embodiments of the marker 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 loops, or combinations of the foregoing rods, coils, and / or loops. The one or more wires or strips may be configured to individually or in combination define one or more meandering paths that extend in several different directions and / or include twists, bends, or turns in order to reduce the magnetic anisotropy ratio of the marker. Embodiments of the marker according to the present disclosure may include a helical coil having 1, 2, 3, 4, 5, 6, or more coils. When the ferromagnetic material is provided in the form of a multi-helix (e.g., a triple helix or a quadruple helix), the individual helices preferably do not contact each other.

[0029] The helical coil or individual helical coils may have a pitch-to-diameter ratio of 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, or greater. In some embodiments, the helical coil may have a pitch-to-diameter ratio of 1.33.

[0030] As used herein, the "magnetic anisotropy ratio" is the ratio of the strongest magnetic signal to the weakest magnetic signal produced by the marker at a constant distance with the marker in different orientations relative to the probe. Since the calculated distance between the marker and the probe depends relatively weakly on the magnetic sensing response, the marker may suitably have an anisotropy ratio of less than 7 (i.e., between 1 and 7), preferably less than 5, and more preferably less than 3.

[0031] A particularly preferred arrangement of one or more wires is shown in the Figure 7 drawing.

[0032] The ferromagnetic material configured in the desired shape may be encapsulated in a cylindrical housing. The cylindrical housing is preferably injectable to allow placement of the marker. Accordingly, suitably, the housing may have a maximum diameter such that it can be deployed through a small gauge needle (e.g., 18G to 12G). The marker may be packaged within other materials, or a coating may be applied to the marker to ensure that the marker is biocompatible and robust. The marker may be loaded into a tube made of, for example, nitinol, titanium, stainless steel, or other biocompatible alloys, which material is preferably non-magnetic and has a relatively low electrical conductivity. The low electrical conductivity may include less than 10 6The conductivity of Siemens. Suitable coating materials include polymer coatings such as Invar, FEP, parylene, PTFE, ETFE, PE, PET, PVC, or silicone or epoxy-based sealants.

[0033] The arrangement of the wires can extend in multiple directions and / or across multiple planes. For example, the arrangement of the wires can include two, three, four, or more straight wires that extend in different directions in the same or different planes. In another example, the arrangement of the wires can include two, three, four, or more curved or bent wires that extend within a single plane, such as loop wires, L-shaped wires, or across a series of planes, such as helical wires. The arrangement of the wires can include at least one straight wire and at least one curved or bent wire. The straight wire and the curved or bent wire can extend in different planes (e.g., mutually orthogonal planes).

[0034] In one embodiment, the arrangement of the wires or strips within the housing is provided as offset parallel rods, substantially perpendicular rods, and / or end-to-end placed rods, preferably spaced from each other by at least one diameter length of the rod. More preferably, two or more rods can cross each other at an angle; for example, two rods can cross each other substantially at right angles. The markers can include a stacked arrangement of multiple such crossed rods. The stacked crossed body arrangement can have the crossed bodies in line or rotated relative to each other, for example, each crossed body is rotated approximately 45 degrees relative to an adjacent stacked crossed body. In some embodiments, each crossed body can be disposed in a respective plane that is substantially orthogonal to the axis defined by the housing; for example, the longitudinal axis of a cylindrical housing of the above type. In some embodiments, each crossed body can be disposed in a respective plane that is inclined relative to such an axis defined by the housing. These planes can be appropriately spaced along the axis. Thus, the crossed bodies can be disposed in two or more respective parallel planes that are orthogonal to the housing axis or inclined relative to the housing axis.

[0035] An alternative configuration of the rods can be provided, for example, a set or more sets of parallel rods disposed throughout the housing. The rods in each set can extend in a respective plane that can be inclined or substantially orthogonal to the axis defined by the housing; for example, the longitudinal axis of a cylindrical housing. Thus, multiple sets of parallel rods can be arranged in a series of respective planes spaced along the longitudinal axis of the housing. As described above, the planes can be spaced along the axis. The rods in each set can be aligned with and / or rotated relative to the rods in at least another set.

[0036] In some embodiments, the groups of parallel rods can be rotated relative to each other group by about 15 - 90°; for example, four groups of parallel rods can be arranged such that each group is rotated by about 45°, about 60°, and about 90° relative to each corresponding group in the other groups. In another configuration, the inclined rods can form a twisted ladder-like structure, where each rod extends in a respective plane that is substantially orthogonal to the axis defined by the housing (in particular, the longitudinal axis), these planes are spaced apart along the axis, and are rotated by an angle of about 10 - 45° relative to one or more adjacent rods; for example, the arrangement can include 8 straight rods, and each straight rod is rotated by approximately 11.25° relative to each of one or more adjacent rods.

[0037] Optionally, one or more longitudinal rods can be provided to pass through the housing, for example, through the center of the housing or independently of the cylindrical outer shell, forming a shape (such as a triangular or quadrilateral tetrahedron, a solitary circle connected to a vertical rod, a "Jack" shape, or a snake shape) that provides the same rod orientation as described in GB 2582123 A, the content of which is incorporated herein by reference; for example, as Figures 11a to 19 shown. In some embodiments, one or more transverse rods can be provided to pass through the housing and extend in one or more planes that are substantially orthogonal to the axis of the housing (such as the longitudinal axis of a cylindrical housing).

[0038] In a more preferred embodiment, the marker according to the first aspect of the present disclosure is provided in a helical shape or includes a plurality of spaced-apart rings, optionally including one or more straight longitudinal rods extending through the helix or the rings.

[0039] In a preferred embodiment, the marker is provided as a single helix combined with a longitudinal wire arranged parallel to the longitudinal axis of the helix, or provided as a multi-helix, such as a double helix, a triple helix, or a quadruple helix. Preferably, the pitch of the helical coil or each helical coil can be about 1.0 - 1.5 times the coil diameter.

[0040] According to another aspect of the present disclosure, there is provided a detection system for positioning 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 sensing coil arranged to detect a signal received from the excited marker; a magnetic field generator arranged to drive an alternating magnetic field through at least one drive coil; and at least one detector arranged to receive a signal from the sensing coil and detect one or more harmonics of the drive frequency in the received signal. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Embodiments of the present disclosure will be described in detail below by way of example only with reference to the accompanying drawings:

[0042] In the drawings:

[0043] Figure 1a is a graph illustrating the relationship between the effective permeability (μ app ) of a ferromagnetic material and its shape and material;

[0044] Figure 1b illustrates the shapes of cylinders with different length / diameter ratios.

[0045] Figure 2 is a graph showing the relationship between the magnetic flux density (B) and the magnetic field strength (h) of a ferromagnetic material, as well as an illustration of the definitions of the saturation induction strength (B s ) and the initial relative permeability (μ r,i ).

[0046] Figure 3a is a graph showing the relationship between the maximum wire length and both the rod length and the rod diameter for a ferromagnetic material with a saturation induction strength B s of 1 T, given the maximum MRI artifact size and the induction performance at a distance of 40 mm;

[0047] Figure 3b is a graph showing the relationship between the maximum wire length and both the rod length and the rod diameter for a ferromagnetic material with a saturation induction strength B s of 0.5 T or 1.0 T, given the maximum MRI artifact size and the sensing performance at a distance of 30 mm or 40 mm.

[0048] Figure 4 is a graph showing the relationship between the saturation induction strength (B S ) and the initial relative permeability (μ r,i ) of various ceramics, metals, and amorphous metals;

[0049] Figure 5a is a graph illustrating the magnetic dipole moment of one of two parallel and spaced-apart rods when exposed to a weak magnetic field (in this case, approximately 7 μT), where the two rods have diameters of 50 μm and 100 μm, a length of 5 mm, and a relative permeability of 2300;

[0050] Figure 5b is a graph illustrating the dipole moment of one of two perpendicularly spaced-apart rods when exposed to a weak magnetic field (in this case, approximately 7 μT), where the two rods have diameters of 50 μm and 100 μm, a length of 5 mm, and a relative permeability of 2300;

[0051] Figure 5c is a graph illustrating the dipole moment of one of two axially offset and parallel-spaced rods when exposed to a weak magnetic field (in this case, approximately 7 μT), where the two rods have a diameter of 50 μm, a length of 5 mm, and a permeability of 2300;

[0052] Figure 6 The sensing responses of different embodiments of the markers according to the present disclosure are described in detail, illustrating their geometries, the covered dimensions, and their impact on MRI artifacts;

[0053] Figure 7 The maximum sensing distances of different embodiments of the markers according to the present disclosure are shown, which have good sensitivity and low MRI artifacts;

[0054] Figure 8a is a schematic perspective view of a marker according to an embodiment of the present disclosure;

[0055] Figure 8b is Figure 8a a schematic side view of the marker, in which an optional marker housing is shown in dashed lines;

[0056] Figure 9a is a schematic perspective view of a marker according to another embodiment of the present disclosure;

[0057] Figure 9b is Figure 9a a schematic side view of the marker;

[0058] Figures 10a to 10c are graphs showing the relationship between the sensing distance (mm) and the pitch (mm) of a 1.3 mm diameter marker, a 1.15 mm diameter marker, and a 1.0 mm diameter marker, respectively; and

[0059] Figures 11a to 19 show further various possible marker configurations according to the present disclosure.

[0060] Figure 20 shows a detection system for positioning a marker according to the present disclosure.

[0061] Definition:

[0062] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art.

[0063] The magnetic flux density (B) is a vector that measures the strength and direction of the magnetic field around a magnet or an electric current.

[0064] The magnetic field strength, also known as the magnetizing field (H), is a vector field that describes the magnetic influence of an external magnetic field on moving charges, electric currents, and magnetic materials.

[0065] The coercivity is the magnetizing field (H) required to completely demagnetize a ferromagnetic material.

[0066] Hard magnetic materials have high coercivity. They are also called permanent magnets.

[0067] Soft magnetic materials have low coercivity. They are easily magnetized and demagnetized.

[0068] Magnetization intensity, also known as magnetic polarization (M), is a vector field representing the density of permanent or induced magnetic dipoles in a magnetic material.

[0069] Inductive saturation is the state reached when an increase in the applied external magnetic field H can no longer further increase the magnetization intensity M of the material. In this state, the total magnetic flux density generated is called the saturation induction intensity (B s ), and the magnetization intensity is the saturation magnetization intensity (M s ).

[0070] The initial magnetic susceptibility (χ) is a measure of the degree of magnetization of a material with an infinite range in a small applied magnetic field. For a small H, it is defined as χ = M / H, or equivalently

[0071] The apparent initial magnetic susceptibility (χ app ), also known as the effective magnetic susceptibility, is the initial magnetic susceptibility of a material with a specific geometry in a small applied magnetic field. That is, χ after considering the demagnetization factor (see below).

[0072] The magnetic permeability (μ) is a measure of the ability of a material to resist the formation of a magnetic field, where μ = B / H.

[0073] The relative magnetic permeability (μ r ) is the ratio of the magnetic permeability to the magnetic permeability of free space (μ 0 ), i.e., μ r = μ / μ 0 .

[0074] Ferromagnetic materials have a variable relative magnetic permeability (μ r ), which increases in relation to the magnetic field and reaches a maximum value. The maximum relative magnetic permeability of many ferromagnetic materials can exceed 100,000.

[0075] Paramagnetic materials have a constant relative magnetic permeability (μ r ) slightly greater than 1.

[0076] Diamagnetic materials have a constant relative magnetic permeability (μ r ) slightly less than 1. Diamagnetism causes a repulsive effect by generating a small magnetic field opposite to the externally applied field.

[0077] The initial relative magnetic permeability (μ r,i ) is the value of μ r when H is small, and its relationship with the initial magnetic susceptibility is μ r = 1 + χ.

[0078] The apparent relative magnetic permeability (μ app) is the relative magnetic permeability of a material with a specific geometry. That is, it is μ after considering the demagnetization factor. r .

[0079] The demagnetizing field, also known as the stray field, is the magnetic field (H) generated by magnetization (M). It creates shape anisotropy in a ferromagnetic material with a single magnetic domain and magnetic domains in a larger ferromagnetic material.

[0080] The demagnetization factor is a number that describes the magnetic field strength generated by an object with a specific geometry compared to an object with an infinite extent. It must be used to determine the demagnetizing field. The total magnetic field of a magnetic object of any shape varies with the internal position of the object and can be difficult to calculate. This makes it very difficult to determine the magnetic properties of a material, such as how the magnetization of the material varies with its shape and the magnetic field.

[0081] Magnetic anisotropy describes the variation of magnetic properties with the orientation of the material relative to an externally applied magnetic field.

[0082] The magnetic moment, also known as the magnetic dipole moment, is a vector that describes the magnetic strength and orientation of a magnet or other object (such as a current loop that generates a magnetic field H).

[0083] MRI metal artifacts are distortions of MR images, characterized by signal void regions (black) or bright streaks near metal objects. They occur at the interface between tissues and metal with different magnetic susceptibilities, causing local magnetic field distortions of the external magnetic field. This distortion changes the precession frequency in the tissue, resulting in an incorrect spatial mapping of information. Detailed Description

[0084] The present disclosure relates to an improved magnetic marker that allows surgical guidance and provides MRI artifacts small enough (preferably less than 2 cm) to allow effective radiological diagnosis. Surprisingly, it has been found that using ferromagnetic material filaments with a high aspect ratio (as defined above) greater than 50, preferably at least about 500, more preferably at least 650, at least 750 or at least 1000 as defined herein and a small volume less than about 1x10 -10 m 3 creates markers that provide satisfactory sensing performance, balanced with small MRI artifacts. The markers of the present disclosure can be further improved by selecting ferromagnetic materials with a low saturation induction intensity, which can further limit the size of the MRI artifacts. The markers of the present disclosure can be further improved by selecting ferromagnetic materials with a high initial magnetic permeability, which can improve the sensing performance. Various shapes for such markers have also been developed, which provide improved magnetic susceptibility isotropy.

[0085] When an object changes the magnetic field in an MRI machine, "artifacts" are produced on the MRI image. Thus, markers of ferromagnetic materials will produce significant artifacts, reducing their attractiveness as long-term markers for patients undergoing treatments such as neoadjuvant therapy prior to surgical resection. This artifact is mainly produced by the magnetic field component (B y ) generated by the ferromagnetic object, which is in the same direction as the main field (referred to as the y-axis here) generated by the MRI machine. The effect of B y is to change the local Larmor frequency of the protons near the object. If this change is large enough, these protons will not appear in the correct slice reconstructed by the MRI machine. That is, the points where |B y |≥B crit will not appear in the expected slice, where B crit is the magnitude of the y-component of the magnetic flux density B at which the voxel is mapped to a different slice, and its value depends on the MRI scan parameters.

[0086] At distances large compared to the object, the field generated by a ferromagnetic object can be described by a dipole model. Along the magnetization axis, in this model, the magnetic flux density is given by , where m is the magnetic dipole moment of the ferromagnetic material and y is the distance from the object to the point of interest. In an MRI machine, ferromagnetic objects usually saturate, so its magnetic dipole moment is given by . Combining these two equations gives where B marker,MRI is the field generated by the ferromagnetic material when in the MRI field. That is, if B is the total field and B 0 is the field applied by the MRI machine, then B = B 0 +B marker,MRI . Thus, it has been found that the magnetic field strength generated by a ferromagnetic object in an MRI machine depends on the volume of the ferromagnetic material, its saturation induction strength, and the distance from the ferromagnetic material.

[0087] If we now consider the edge of the MRI artifact, at this point B marker,MRI = B crit , and y describes the distance from the center of the artifact to its edge. At this point, using the above equation, we get Thus If we define the "diameter" of the artifact (although the artifact may not be circular) along the y-axis as a measure of its extent, such as D artefact,y = 2y, then it can be obtained that

[0088] In summary, the saturation induction strength (B s ) and the volume (V) of the magnetic material determine the size of the MRI artifact as follows:

[0089]

[0090] This constraint on the maximum volume of the magnetic material that can be used makes it difficult to fabricate markers with an effective sensing distance, good isotropy, and small artifacts using magnetic materials. The markers of the present disclosure solve this problem.

[0091] To apply this discovery to ferromagnetic materials that maintain a good magnetic field magnitude under sensing, the magnetic susceptibility related to shape was also studied.

[0092] As described above, the magnitude of the magnetic flux density B of a ferromagnetic object along the magnetization axis is In a magnetic field much weaker than the magnetic field generated by an MRI machine (e.g., the magnetic field generated by a magnetic susceptibility measurement probe such as that described in WO 2014 / 140566A1), the magnetization of the material is M = χ app H, where χ app is the apparent initial magnetic susceptibility. By definition, its magnetic dipole moment m = MV, so m = χ app HV, which in turn gives the following expression for the magnetic field generated by the object when stimulated by a weak field:

[0093]

[0094] The last equation shows that the intensity of the sensing response will be proportional to (a) the volume (V) of the magnetic material; (b) the intensity (H) of the applied field; and (c) the apparent magnetic susceptibility (χ app ) of the magnetic material. For slender magnetic materials, the last quantity is much larger, as shown in Figure 1a and Figure 1b The equation also shows that the intensity of the sensing response will decrease with distance from the marker (inversely proportional to the cube of the distance).

[0095] It has been found that certain shapes of markers containing ferromagnetic materials are not suitable for their intended use. For example, for the required sensing distance, a sphere cannot give the expected artifact size because the magnetic susceptibility is low for any diameter. It has been found that for MRI artifacts with a diameter less than 10 mm in a 1.5 T MRI field, the diameter of the sphere cannot exceed 0.18 mm, which is too small to be handled during manufacturing and also cannot be seen by the surgeon after extracting the tumor. On the other hand, to sense beyond 40 mm, the sphere would need to be more than 1.1 mm, and the resulting artifacts would be far greater than the acceptable range.

[0096] Example 1: Physical properties of the markers according to the present disclosure.

[0097] As described above, during sensing, the marker is affected by a small oscillating field. Its magnetic response is characterized by its magnetic permeability μ ror the magnetic susceptibility χ (where μ r = 1 + χ). If the initial magnetic susceptibility or the initial relative permeability is known, the magnetic response of the marker can be predicted. It has been determined that the apparent initial magnetic susceptibility depends on the material, its shape, and the frequency of the applied field.

[0098] It can be inferred that increasing the aspect ratio of the magnetic material (L / D, where L is the length of the cylinder of the material and D is its diameter) significantly improves its sensing performance in the direction of its central axis. Figure 1a and Figure 1b This is illustrated as follows: as the ratio L / D increases, the apparent permeability μ app of the object also increases, which in turn increases the distance at which it can be sensed. This phenomenon is due to the demagnetization effect and can be intuitively understood as follows: if the object is substantially perpendicular to the applied magnetic field, the microscopic magnetic dipole fields generated in the object will mostly cancel each other out. Conversely, if the object is substantially parallel to the applied magnetic field (such as a long and thin rod aligned with the magnetic field), the microscopic dipoles generated in the object will interact constructively, resulting in a stronger magnetic field, which in turn allows the marker to be detected more easily.

[0099] Under an AC magnetic field, an additional phenomenon occurs: eddy currents induced in the material generate an additional magnetic field that partially shields the material from the external field, thereby reducing the sensing performance. Eddy currents can cause a significant difference when the object under the action of the field has a large area perpendicular to the field. In contrast, for a very thin rod the eddy currents actually do not significantly affect the sensing performance of the magnetic wire. For a significantly thicker rod if L / D > 1, the eddy currents are very significant. Therefore, in order to reduce or eliminate the influence of eddy currents on the sensing performance of the magnetic wire, it is preferably thin.

[0100] For a cylinder, the aspect ratio is the most important factor.

[0101] For a rod with an aspect ratio L / D < 10, the initial relative permeability (μ r,i ) as long as > 1,000 makes little difference, as can be seen from Figure 1a and Figure 1b . However, for a rod with a larger aspect ratio, a higher initial relative permeability is beneficial: for example, for a rod with L / D = 400, μ r,i increasing from 1,000 to 50,000 makes μ app increase by about 7 times.

[0102] The magnitude of the induced magnetic field of ferromagnetic materials under MRI determines the size of MRI artifacts. During MRI, the markers are subjected to a large constant field, and the magnetization saturates at B s = μ 0 M s ("saturation induction intensity"). The range of B s for most ferromagnetic materials is ~0.25–1.5 T. Thus, the MRI field (1.5–3.0 T) is strong enough to saturate these materials, and thus the magnetization of ferromagnetic markers in MRI can be simply calculated as M s B s = B s / μ 0 . Therefore, to minimize the artifact size, materials with low B s are required.

[0103] This is illustrated in Figure 2 of the accompanying drawings.

[0104] This results in a limited range of properties that the markers need to satisfy to provide a satisfactory sensing response and reduce MRI artifacts. The minimum volume of magnetic material should be used, the aspect ratio should be high, and preferably the markers should have a high apparent initial magnetic susceptibility, and the material should have a low saturation induction intensity, preferably less than about 1.0 T.

[0105] It has been surprisingly found that slender ferromagnetic material wires can provide the required apparent magnetic susceptibility property of greater than or equal to 1,000. Figure 3a is a simulation that confirms the feasibility of detecting straight wires that can be detected in a useful range while showing small MRI artifacts. The dashed line shows the minimum length required to be sensed at 40 mm for each wire diameter, assuming a magnetic susceptibility χ = 72,000 of the wire material. The dash-dotted line shows the maximum length allowed for each wire diameter such that the diameter of the MRI artifact of the wire is less than 10 mm, assuming the wire material has a saturation induction intensity B s of 1 T. The shaded area in the upper left corner of the graph corresponds to wire sizes that can be detected at 40 mm or farther and produce MRI artifacts with a diameter of 10 mm or less. This figure shows that the wire length must be much greater than the wire diameter to satisfy both conditions simultaneously.

[0106] Figure 3b shows the same simulation data as Figure 3a , but with a narrower range of wire diameters and for more sensing distances and saturation induction intensities. The dashed and dash-dotted lines are the same as Figure 3ahas the same meaning. The dash and solid lines correspond to the additional sensing distances and saturation induction intensity values shown in the legend. This figure shows that a wide range of wire sizes can be used if a lower sensing distance (30 mm instead of 40 mm) is accepted; or if the material has a lower saturation induction intensity (0.5 T instead of 1 T).

[0107] Low saturation magnetization produces smaller ferromagnetic dipoles in an MRI scanner, while a higher initial permeability means that a small volume of material will produce a larger sensing response on a probe (e.g., a susceptibility measurement probe such as that described in WO 2014 / 140566A1, the content of which is incorporated herein by reference).

[0108]

[0109] The sensing response in a susceptibility measurement probe field and the MRI artifacts of ferromagnetic materials depend on different variables. It has been recognized that in a small oscillating field (e.g., the oscillating field produced by Sentimag sold by Endomagnetics Ltd, UK), the sensing performance depends almost entirely on the aspect ratio and volume, and has a weaker dependence on the relative initial permeability μ TM (the initial gradient of the B–μ r,i H curve). In contrast, the magnitude of the magnetic field produced by a marker in an MRI machine and thus the size of the MRI artifacts depend on the saturation induction intensity B 0 and the volume of the material. This means that small MRI artifacts of the required size can be produced with very thin ferromagnetic materials with low saturation induction intensity that can still be sensed at a satisfactory distance, as shown in Table 1 below, where the material has χ = 72,000 and B s = 0.5 T: s

[0110]

[0111] Table 1

[0112] It has been found that markers of ferromagnetic materials with low saturation induction intensity and a large aspect ratio can be sufficiently sensed while producing lower MRI artifacts. The marker preferably has an aspect ratio of at least 50, more preferably at least 60, especially at least 100, and even more especially at least about 500, and has a low overall volume, such as a length of at least 3 mm, preferably at least 6 mm, and a diameter less than 100 μm, preferably equal to or less than 50 μm, especially equal to or less than 30 μm.

[0113] This is shown in Figures Figure 3a and Figure 3b which show the MRI performance depending on the rod length and diameter. For a given B s ​, any portion below the contour will produce acceptable artifacts.

[0114] Example 2: Study of the preferred materials for the magnetic markers according to the present disclosure.

[0115] The markers described in Example 1 are further studied to allow the selection of a preferred magnetic material that will produce the required high initial relative magnetic permeability μ r,i > 1000, which can form very fine ribbons or wires to allow the construction of a large aspect ratio but small volume, and have a low saturation induction intensity B s , desirably having a low B of less than 1 T s .

[0116] The preferred materials found to have the required properties are specific metals, amorphous metals, and ceramic ferrites, preferably cobalt-based amorphous metals, such as those sold under the trade names Yshield MCE61 TM , Metglas 2705M TM and Metglas 2714A TM ; manganese-zinc ceramic ferrites, such as those sold under the trade names Fair-Rites 31 TM , 76 TM and 78 TM ; 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 TM , 20 TM and 43 TM ; more preferably cobalt-based amorphous metals, such as Yshield TM and Metglas 2714A TM .

[0117] Although ceramics have a low saturation induction intensity, they are less likely to form wires or flat wires and are therefore less suitable for the markers according to the present disclosure.

[0118] Figure 4 is a plot of the saturation induction intensity versus the initial relative magnetic permeability of various different materials. The materials that can form suitable markers are included in the upper left region of the graph, showing a low saturation induction intensity and a high relative initial magnetic permeability.

[0119] Example 3: Study of the optimized design of the magnetic markers according to the present disclosure.

[0120] The elongated wire markers discussed in Examples 1 and 2 provide the required initial relative magnetic permeability μr,i > 1000, preferably > 10,000, large aspect ratio but small volume and having a low saturation induction intensity B s However, this type of marker has a high anisotropy ratio and exhibits a strong sensing response only in the direction of its axis.

[0121] From a practical perspective, during surgery using a magnetic probe to detect markers as described in WO2014 / 013235, high anisotropy is not desirable: the magnetic signal at a constant distance will vary according to the orientation of the marker relative to the probe, and such that when approaching from certain orientations, the marker will appear closer, while when approaching from other orientations, the marker will appear farther. Minimizing the anisotropy of the implanted marker improves the surgeon's ability to localize the marker, making it more intuitive, and improves the surgeon's ability to remove the safety margin of the tissue around the lesion. An anisotropy ratio of 1 is ideal, producing a uniform response from any direction. However, in practice, it is challenging to achieve this within the geometric constraints of delivery through a small needle. An anisotropy ratio less than 7 (i.e., between 1 and 7), preferably less than 5 and more preferably less than 3, is desirable. Since the magnetic sensing response strongly depends on distance (under certain conditions, approximately inversely proportional to its sixth power), conversely, the calculated distance depends relatively weakly on the magnetic sensing response. Therefore, an anisotropy ratio less than 2 is close enough to the ideal value for practical use, a ratio of 5 may not be distinguishable from isotropy in practice, and a ratio of 7 can provide sufficient uniformity.

[0122] Two methods have been identified to increase the axial sensing and increase the isotropy of the magnetic susceptibility. It is also desirable to provide a marker that does not require unpacking at the injection site, as the deployable concept requires a consistent unpacking mechanism to allow for accurate placement and complete unpacking to provide the necessary sensitivity and isotropy. Thus, having a marker that does not require unpacking at the injection site will also provide a significant improvement over the prior art. To achieve this, the marker can include a plurality of small ferromagnetic rods that encapsulate the wire in Example 1 within a single cylinder, where all axes are covered. However, this type of marker still faces several challenges in terms of detection sensitivity (since short rods are expected to have a lower axial magnetic susceptibility and some destructive interaction effects), MRI artifacts (since the complexity of the magnetic dipoles will pose the greatest complexity for estimation), safety and regulation, and the manufacturing process and consistency of rod encapsulation.

[0123] Therefore, further configurations have been investigated to optimize the marker according to the present disclosure. For a given artifact size, a constraint on the maximum volume of the magnetic material that can be used for the marker has been determined. Using a magnetic material with a low saturation induction intensity B sThe material will enable more material to be used. The diameter of the wire will determine the total length of wire available, its relative permeability and the aspect ratio of the wire can then be used to calculate the sensing response.

[0124] It has been determined that the key variables that can be modified to improve the design of the marker are the total wire volume and the wire length, since it is the wire diameter that has the greatest relationship with the artifact diameter and therefore the latter is less variable. If the design consists of the wire diameter D, then the allowed length of the wire L is:

[0125]

[0126] Initially, an arrangement comprising multiple filament rods arranged in different orientations was considered to enhance the anisotropy of the marker. It has been unexpectedly found that adjacent rods can have a positive or negative interaction on the total dipole moment, as shown in the figure Figure 5a , Figure 5b and Figure 5c shown.

[0127] Figure 5a shows that for parallel rods placed 0.5 mm apart, the dipole moment is reduced by 5% for a 50 μm diameter rod and by 10% for a 100 μm diameter rod. Figure 5b As shown, two identical rods placed vertically with the ends separated by a length of the rod diameter will increase the total dipole moment by 5%. Figure 5c As shown, the dipole moment of the vertical rod decreases less if the axis is offset.

[0128] Based on these findings, marker configurations with closely spaced parallel rods were ruled out as markers for the present disclosure. However, satisfactory markers for embodiments of the present disclosure are configurations that can offset the placement of these parallel rods, such as Figure 5c A further embodiment is a shape in which the vertical bars can be placed end to end.

[0129] The rods are preferably spaced at least one diameter apart.

[0130] The rod provided in the desired configuration can be encapsulated in a cylindrical housing known in the art. For example, the markers can be packaged in other materials to ensure that they are biocompatible to prevent reaction with body tissue and are strong, or a coating can be applied to the marker. The marker can be enclosed in a tube made of, for example, nitinol, titanium, stainless steel or other biocompatible alloys, which is preferably non-magnetic and has a relatively low electrical conductivity. Suitable coating materials include polymer coatings, such as FEP, parylene, PTFE, ETFE, PE, PET, PVC or silicone or epoxy sealants.

[0131] Given the difficulty of evaluating magnetic dipole moments in complex structures, a method has been developed to determine how different shapes behave and interact. The results are summarized in Figure 6 .

[0132] The conclusion is that larger aspect ratio designs, whether longer rods or larger loops, will result in designs with better sensing performance for MRI artifacts. In this regard, per unit volume, a 5 mm long rod is about eight times better than a 1 mm long rod, and a loop is better than two perpendicular rods per unit volume. In terms of generating induced responses in two directions, loop- or coil-based designs have also been determined to be better than two perpendicular rods.

[0133] In this regard, referring to Figure 6 of the accompanying drawings, the quantity m z / V indicates how much sensing response is generated per unit volume of the marker. Although the 5 mm straight rod generates a stronger response per unit volume than the loop (the m z / V of the rod is 54 while the m z / V of the loop is 42), the rod only generates a magnetic response along its axis, while the loop generates a magnetic response in two dimensions covered by its plane. Therefore, the correct quality factor of the loop is 2×42 = 84, i.e., about 50% better than the rod.

[0134] of the accompanying drawings Figure 7 illustrates the configurations of multiple markers according to embodiments of the present disclosure, and it is found that these markers generate the desired low MRI artifacts and have good sensing responses in multiple directions. Figure 7 provides the sensing distance at 200 mA for an artifact with a diameter of 10 mm. The material parameters are: μ r = 72,000, B s = 0.55 T, the diameter of the wire is 30 μm, and the maximum total length is 21 mm.

[0135] The figure also emphasizes the preferred embodiments of the present disclosure, which are helical shapes, loops, and offset parallel or perpendicular rod arrangements. These provide the best performance for the material used per volume.

[0136] Example 4: Further study on the helical coil marker according to an example of the present disclosure.

[0137] Considering that the helical shape is easy to manufacture, the optimization of this shape as a preferred marker according to the present disclosure was further studied.

[0138] The study shows that two different helical designs both produce acceptable induced responses in terms of minimum sensing distance and isotropy. As shown respectively in Figures 8a to 9b , they are (i) a single helix combined with one longitudinal wire arranged parallel to the axis core ( Figure 8a andFigure 8b ), and (ii) a multi-helix consisting of a double helix or a triple helix Figure 9a and Figure 9b ). In Figure 8a and Figure 8b , the longitudinal filaments are arranged parallel and coaxial to the core. In an alternative arrangement, the longitudinal filaments are located on one side of the helix rather than coaxial with the core.

[0139] Markers using a single helix design obtain a transverse response from their helical coils and most of the axial response from their axial rods, while markers using a triple helix design use a larger pitch to obtain both transverse and axial responses from their helical coils (a larger pitch means the coils are more pointed in the axial direction). In the context of triple and other multi-helices, the term "pitch" as used herein refers to the pitch of the individual coils that make up the multi-helix, unless the context clearly indicates otherwise.

[0140] Using a combination of standard physical simulation software (COMSOL), custom computer models, and experiments, the sensing distances were predicted for one or several of the axial rods used and for two diameters, as shown in Table 2 below.

[0141]

[0142] Table 2

[0143] 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 simulation results, it can be concluded that it is desirable to use a smaller diameter and a longer rod rather than two shorter rods.

[0144] For a single helix design where the longitudinal filaments are arranged parallel to the core axis ( Figure 8a and Figure 8b ), it has been determined that it is necessary to use the thinnest possible filaments (see Example 1 above) and the longest possible filament length. The diameter of the coil should also be maximized in order to provide a stronger transverse sensing response for the same volume of material, as Figure 6 shown. Figure 8b An optional housing or tube 80 located around the helical coil is shown in dashed lines. The marker can be placed in a tube made of, for example, nitinol, titanium, stainless steel, or other biocompatible alloy, which material is preferably non-magnetic and has a relatively low electrical conductivity. Suitable coating materials include polymer coatings such as FEP, parylene, PTFE, ETFE, PE, PET, PVC, or silicone or epoxy-based sealants.

[0145] Surprisingly, the plot of pitch versus transverse sensing distance does not show a sharp peak near the optimum value, and the pitch must be balanced against the increase in axial sensing to reach the optimum point. Figures 10a to 10cIt is shown that the pitch that maximizes the lateral sensing performance is approximately equal to the coil diameter - which is the optimal pitch for a single helix design where the helical coil must only produce a lateral sensing response and the axial component comes from the axial wire. While the pitch that produces isotropic sensing performance is approximately 1.6 times the coil diameter, this pitch is useful for a multi-helix design that does not include an axial wire, so both the axial and lateral sensing responses must be produced by the helical coil. Figures 10a to 10c The sensing distance (mm) versus pitch (mm) is illustrated for 1 mm diameter markers, 1.15 mm diameter markers, and 1.3 mm diameter markers, respectively.

[0146] Other design options with multiple helices to avoid the need for an axial rod were further investigated. 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.

[0147]

[0148] Table 3

[0149] To maintain the same marker length and diameter, the double and triple helices have a higher pitch, which is expected to provide better axial detection. However, surprisingly, as shown in Table 4 below, the lateral detection is only slightly affected, and more surprisingly, it is found that the lateral detection increases. A significant unexpected finding is that the helices are closely intertwined with each other without touching, having a non-destructive effect on the magnetic susceptibility.

[0150] In summary, it has been found that for a given amount of material and marker length, a single helix will exhibit a short pitch and may require combination with a ferromagnetic rod. Alternatively, incorporating a double or triple helix into a marker of the same amount of material of the same length will require stretching the helix to increase the pitch, which helps move the coil in a more axial direction, but surprisingly does not reduce the lateral detection.

[0151] If stronger sensing performance is needed in a more compact shape, higher-order helices can be used to provide more coils per unit length. However, if too many coils are packed closely together (spacing less than 1 times the coil diameter), they will start to interact destructively with each other.

[0152] The marker size in all cases in Table 4 is 1.15 mm in diameter and 8.0 mm in length.

[0153]

[0154] Table 4

[0155] As shown in Table 4 above, decreasing the pitch and increasing the number of turns will improve the transverse sensing performance but will reduce the axial sensing performance. It will also increase the total length of the wire used, thus increasing the size of the MRI artifact. Increasing the pitch and reducing the number of turns will reduce the transverse sensing performance but will improve the axial sensing performance. It will also reduce the total length of the wire used, thus reducing the size of the MRI artifact. For each type of multi-helical marker, there is an optimal pitch to produce isotropic sensing performance (e.g., for a triple helix, the pitch of a 1.15 mm diameter marker using 15 um Co-Fe amorphous metal wire ~2.0 mm).

[0156] Example 5: Study of alternative ferromagnetic materials for the markers according to the present disclosure.

[0157] All of the markers disclosed above use the thin wires as described above with respect to Example 1 to produce an optimized design of the marker. However, a preferred magnetic material that will produce a desired high initial relative permeability μ r,i > 1000, preferably > 10,000 and having a low saturation induction strength B s can also be formed into a strip, flat wire having an elliptical cross-section for providing a marker according to the present disclosure.

[0158] For example, Table 5 below illustrates iron metal alloys that have a μ r,i ≥ 15,000, meet the requirements for the markers according to the present disclosure and can be provided in the form of a rolled plate before being cut into wires or strips.

[0159]

[0160] Table 5

[0161] (*) An indicator of the amount of material available for a given artifact size. More material should produce a stronger signal response.

[0162] Marker designs can be created from these sheets using known manufacturing techniques (e.g., etching or laser cutting). The purpose of these manufacturing techniques is to produce wires that may or may not produce a flat shape. In the case of flat wires, the diameters described in other parts of this application essentially correspond to the average radial length of the wire.

[0163] It is readily apparent from the above description that the implantable markers according to the present disclosure provide small ferromagnetic markers having good magnetic susceptibility isotropy, sensing distance and showing small MRI artifacts.

[0164] Example 6: Use of the markers according to the present disclosure in the monitoring and treatment of breast cancer.

[0165] The markers according to the present disclosure are particularly suitable for the monitoring and treatment of breast cancer, enabling the tracking of the size of the tumor during initial neoadjuvant treatment, with the aim of reducing the size of the tumor to less than 2 cm in length or at least to a size small enough compared to overall (BCS).

[0166] Patients with breast cancer tumors greater than 2 cm but less than 5 cm and not yet spread to adjacent lymph nodes (commonly classified as "stage 2" breast cancer) can undergo BCS, but this typically requires neoadjuvant treatment to reduce the tumor to about 2 cm or smaller. At the same time, healthcare providers also need to evaluate the exact nature of the tumor, usually requiring a biopsy to sample some tumor tissue.

[0167] The markers according to the present disclosure can be placed in the cavity created by tissue sampling in order to localize the tumor using a susceptibility measurement probe (such as the probe described in WO 2014 / 140566 A1). This enables the localization of the tumor during future evaluation of tumor progression and / or ablation of the tumor. Figure 20 A susceptibility measurement detection system for localizing the marker is shown, in which the marker 20 according to the present disclosure and a susceptibility measurement probe 22 are shown. The probe 22 includes a drive coil 24 arranged to excite the marker using 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 signals.

[0168] The markers of the present disclosure also enable the tracking of the tumor's response to adjuvant treatment through regular examinations (such as under MRI), since the size of the artifacts generated by the markers under the MRI field is kept to a minimum, ideally not exceeding 2 cm in length. In this regard, when the tumor size is too large for BCS (basically around 2 cm, but possibly larger), the markers should not interfere with the assessment of the tumor size.

[0169] Thus, the markers of the present disclosure are particularly suitable for the protocol typically employed by healthcare providers when tracking breast cancer progression under MRI, due to their low saturation induction intensity and low mass per volume, which allows for a significant reduction in the size of MRI artifacts. Once the tumor has shrunk to a size allowing BCS, healthcare providers are able to localize the tumor with the aid of the markers. These markers can be detected by a susceptibility measurement probe located at least 3 cm and at most 5 cm away, enabling the localization of tumors that may be several centimeters beneath the skin surface. This enables healthcare providers to determine the optimal path for approaching and removing the tumor by ablation before incising the tissue.

[0170] In Figure 11a and Figure 11b as well as Figure 19In [reference], the marker 6 includes a section of magnetic marker material that is bent to depict 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. On the other hand, the radius of the bend 6d can be configured (e.g., by making them larger) to allow the marker to be more easily loaded into the outer tube before deployment.

[0171] In Figure 12 the marker includes a section of magnetic marker material that is bent into a part of a circle 6e, where one end 6f is bent radially towards the center and then bent substantially 90° out of the plane of the circle 6e to form a part 6g along or parallel to the axis of the circle.

[0172] In Figure 13 the marker 6 includes multiple sections of magnetic marker material arranged along three orthogonal axes x, y, and z to form the shape of a "jack" (also known as a jackstone or knucklebone).

[0173] In Figure 14a and Figure 14b the marker includes a section of magnetic marker material having a straight central section 6h and two additional sections 6i, 6j that are bent orthogonally to each other and to the central section at their respective ends. On the other hand, the radius of the bend 6k can be larger to allow the marker to be more easily inserted into the outer tube.

[0174] In Figure 15 the marker 6 includes a section of magnetic marker material in a circular standing wave shape, i.e., forming a uniform wave shape and then bent to connect the ends and form a circle in a plan view.

[0175] In Figure 16 the marker includes a section of elliptical or oval magnetic marker material 6n, where the filament ends 6o are connected or are close to each other but not connected. Two parts of the ellipse or oval at the ends of its major axis are bent to approximately 90° of the plane of the ellipse. The bent parts include approximately one-fourth to one-third of the area of the ellipse or oval.

[0176] In Figure 17 the marker includes three sections of magnetic marker material 6t, 6u, 6v arranged orthogonally to each other to substantially form the vertices of an orthogonal tripod or a cube. These three sections are connected by a connecting section 6w that allows the three sections to be parallel to each other before deployment and then redeployed to form an orthogonal tripod.

[0177] In Figure 18a and Figure 18bIn this case, the marker includes three segments of magnetic marker material 6x, 6y, 6z, which are arranged to form a tripod with non-orthogonal angles between the legs of the tripod. These three segments are connected by a connecting section 6w, which allows the three segments to be parallel to each other before deployment and then redeployed to form a tripod.

[0178] In one embodiment, the magnetic marker may include a wire in the form of a helical coil made of a ferromagnetic material, having the following properties:

[0179] Standard Magnetic marker Wire length 36 mm Wire diameter 0.015 mm Total wire length-to-diameter ratio 2400 Volume of ferromagnetic material <![CDATA[6.4x10 -12 m 3 > Total marker length (excluding heat shrink and capsule) 5 mm Pitch 1.6 mm Number of coils 3 coils Core diameter 1.2 mm Core length 5 mm Core volume 5.65x10-9 m3 Diamagnetic / ferromagnetic volume 883

[0180] Preferably, the angle between the legs is selected such that the harmonic magnetic response is as uniform as possible from any direction. The tripod is uniform with three equally spaced legs.

[0181] Although the markers of the present disclosure have been described and illustrated with reference to specific embodiments, those of ordinary skill in the art will understand that the markers themselves have many different variations that are not specifically illustrated herein.

[0182] When a whole or element is referred to in the foregoing description as having known, obvious or foreseeable equivalents, then such equivalents are incorporated herein as if set forth individually. The true scope of the present disclosure should be determined with reference to the claims, which should be construed to cover any such equivalents. The reader should also understand that the wholes or features described as preferred, advantageous, convenient or the like in the present disclosure are optional and do not limit the scope of the independent claims. Further, it should be understood that such optional wholes or features, while they may be beneficial in some embodiments of the present disclosure, may not be desirable in other embodiments and may therefore be absent.

Claims

1. An implantable marker for imaging and surgical guidance, the marker comprising one or more pieces of ferromagnetic material having a total aspect ratio of at least 500 and a total volume of less than 1 x 10-11 m3, wherein, the one or more pieces of ferromagnetic material have a high initial relative permeability μr,i > 1000.

2. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material have a total aspect ratio of at least 650.

3. The marker according to claim 2, wherein, the one or more pieces of ferromagnetic material have a total aspect ratio of at least 750.

4. The marker according to claim 3, wherein, the one or more pieces of ferromagnetic material have a total aspect ratio of at least 1000.

5. The marker according to claim 4, wherein, the one or more pieces of ferromagnetic material have a total aspect ratio of at least 2000.

6. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material have a total volume of less than 6 x 10-12 m3.

7. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material have a low saturation induction intensity equal to or less than 1 T.

8. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material are wires or ribbons.

9. The marker according to claim 1, wherein, the marker comprises a wire or ribbon of ferromagnetic material having a length of at least 10 mm.

10. The marker according to claim 9, wherein, the marker comprises a wire or ribbon of ferromagnetic material having a length of at least 20 mm.

11. The marker according to claim 1, wherein, the marker comprises a wire of ferromagnetic material having a diameter of less than 100 μm.

12. The marker according to claim 11, wherein, the marker comprises a wire of ferromagnetic material having a diameter equal to or less than 30 μm.

13. The marker according to claim 1, wherein, the marker produces an MRI artifact of less than 2.5 cm in a field of 1.5 T or greater.

14. The marker according to claim 1, wherein, the ferromagnetic material is selected from: cobalt-based amorphous metals, manganese-zinc ferrite nickel-iron-based soft ferromagnetic alloys, or nickel-zinc ferrite.

15. The marker according to claim 1, wherein, the ferromagnetic material comprises one or more wires or ribbons configured in the form of one or more rods, helical coils, and / or rings.

16. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material are configured to individually or collectively define one or more tortuous paths extending along several different directions and / or including twists, bends, or turns.

17. The marker according to claim 1, wherein, the one or more pieces of ferromagnetic material comprise one or more wires or ribbons extending in different directions in the same or different planes such that the marker has a signal anisotropy ratio of less than 7.

18. The marker according to claim 17, wherein, The one or more ferromagnetic materials include one or more wires or ribbons extending in different directions in the same or different planes such that the marker has a signal anisotropy ratio of less than 5.

19. The marker according to claim 1, wherein, the one or more ferromagnetic materials include one or more ferromagnetic material wires or ferromagnetic material ribbons, and the ferromagnetic material wires or ferromagnetic material ribbons are arranged as offset parallel rods, substantially perpendicular rods to each other, and / or rods placed end to end without contacting each other.

20. The marker according to claim 1, wherein, the one or more ferromagnetic materials include multiple pairs of rods crossing each other substantially at right angles, and the marker includes a stacked arrangement of multiple pairs of crossing rods.

21. The marker according to claim 20, wherein, the multiple pairs of crossing rods are collinear or rotated relative to each other.

22. The marker according to claim 21, wherein, the multiple pairs of crossing rods are rotated relative to each other, and each pair is rotated substantially 45 degrees relative to an adjacent pair.

23. The marker according to claim 1, wherein, the one or more ferromagnetic materials include one or more groups of parallel rods, and the parallel rods in different groups extend in the same or different directions within the housing; or form a twisted ladder structure.

24. The marker according to claim 23, wherein, the one or more ferromagnetic materials further include one or more longitudinal or transverse rods extending through the housing.

25. The marker according to any one of claims 19 to 22, wherein, the one or more ferromagnetic materials further include one or more longitudinal or transverse rods extending through the housing.

26. The marker according to claim 1, wherein, the one or more ferromagnetic materials include one or more spiral coils.

27. The marker according to claim 26, wherein, the one or more ferromagnetic materials include one or more straight rods extending through the one or more spiral coils.

28. The marker according to claim 1, wherein, the one or more ferromagnetic materials include multiple spaced-apart rings.

29. The marker according to claim 28, wherein, the one or more ferromagnetic materials include one or more straight rods extending through the multiple spaced-apart rings.

30. The marker according to claim 1, wherein, the one or more ferromagnetic materials include a single spiral coil combined with straight wires, and the straight wires are arranged parallel to the axis of the spiral coil.

31. The marker according to claim 1, wherein, the one or more ferromagnetic materials include multiple spiral coils.

32. The marker according to claim 31, wherein, the multiple spiral coils form a double helix or a triple helix.

33. The marker according to claim 26, 27, 30, 31 or 32, wherein, the pitch of the spiral coil or each spiral coil is 1.0 to 1.5 times the diameter of the spiral coil.

34. The marker according to claim 1, wherein, The marker further includes an outer housing, and the ferromagnetic material is encapsulated within the outer housing; wherein, the outer housing is configured and dimensioned to be injectable through a needle of 18G to 12G gauge.

35. A detection system for localizing an implantable marker, the system comprising: An implantable marker according to any one of claims 1 to 34; At least one drive coil and at least one sense coil, the at least one drive coil being arranged to excite the marker with an alternating magnetic field, the at least one sense coil being 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 one drive coil; and At least one detector arranged to receive a signal from the at least one sense coil and to detect one or more harmonics of the drive frequency in the received signal.

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