Magnetic Markers for Imaging and Surgical Guides

Abstract

Implantable markers for susceptometric imaging and surgical guidance have a total length to diameter ratio of at least about 500 and a surface area of ​​at least about 1×10 -11 m 3 The one or more pieces of ferromagnetic material have a total volume of less than 100 μm. The one or more pieces of ferromagnetic material have a high specific initial permeability (μ r、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 signals received from the excited marker; a magnetic field generator arranged to drive an 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 signal.

Description

Technical Field

[0001] The present disclosure generally relates to the field of magnetic markers for imaging and surgical guides, and more particularly to magnetic susceptibility 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 not physically visible or palpable, such as a small tumor that needs to be excised. Ideally, such markers can be deployed through a thin gauge needle, e.g., 18G - 12G, to reduce trauma to the patient. Typically, such markers are less than 10 mm in length so as to be unobtrusive and minimize trauma. The marker can be placed at the area of interest within the body, such as during a biopsy of a cancerous lesion or other surgical procedure. The marker is placed under the guidance of imaging such as ultrasound or X-ray / mammography. During subsequent surgery, the marker is detected and positioned using a handheld 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]

[0004] ​Additional approaches have been discussed in the applicant's previously published patent applications (e.g., Patent Documents 1, 2, and 3), which use a magnetic field and magnetic markers with high magnetic susceptibility. A handheld susceptometry probe generates an alternating magnetic field that excites the magnetic-responsive markers and detects the response magnetic field. This approach has been found to be very effective for deeper sensing. However, this system has the drawback that artifacts are generated in large MRI settings compared to the markers themselves.

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

[0006] Ferromagnetic materials are known to cause MRI distortion, and these are widely described in the scientific literature. For example, Non-Patent Document 1 explains that although some ferromagnetic materials may be safe for MRI, they still produce significant artifacts. The artifacts are mainly generated by the component (B y ) of the magnetic field generated by the ferromagnetic object that is in the same direction as the main magnetic field generated by the MRI device. The effect of B y is to shift the local Larmor frequency of the protons near the object, and if that shift is large enough, those protons do not appear in the correct slice reconstructed by the MRI device.

[0007] Accordingly, the Applicant has identified the need for small ferromagnetic markers for susceptibility-based detection that have acceptable response isotropy, a long sensing distance, and exhibit small MRI artifacts. The MRI artifacts of such markers should not impair the evaluation of tumor size by medical personnel, as monitoring the reduction in tumor size provides a positive option in the management of cancer patients. In this regard, the breast cancer stage is evaluated using several criteria such as tumor size, whether the tumor has spread to lymph nodes, and whether the cancer has spread (metastasized) to other parts of the body. In early-stage cancer where breast-conserving surgery using tumor excision is envisioned, preferably the tumor size is 2 cm or less. Non-Patent Document 2 shows that smaller tumor sizes represent favorable prognostic factors, and residual tumors > 2 cm are associated with a high local tumor recurrence rate after neoadjuvant chemotherapy. Non-Patent Document 3 shows that tumors with a size of 2 cm or less are classified as T1 and typically correspond to cancer stage 1 or 2 where breast-conserving surgery can be envisioned. Larger tumors are more likely to require more radical surgeries such as mastectomy.

[0008] Accordingly, it is desirable to be able to size the tumor under MRI when it exceeds 2 cm in diameter and to enable an evaluation to observe whether the tumor has shrunk to a level that enables breast-conserving surgery. According to the present disclosure, a marker that provides an artifact of about 2 cm still enables sufficient radiological diagnosis to determine whether the tumor is larger than 2 cm and requires further neoadjuvant treatment.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Literature

[0010]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present disclosure is to provide an improved magnetic marker with reduced MRI artifacts that overcomes or at least reduces the above-mentioned drawbacks.

Means for Solving the Problems

[0012] According to a first aspect of the present disclosure, an implantable marker for imaging and surgical guidance is provided, the marker comprising one or more fragments of a ferromagnetic material having a total length to diameter ratio of at least 50 and a total volume of less than 1×10 -10 m 3 .

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

[0014] Preferably, the ferromagnetic material may have a total volume of less than about 1×10 -11 m 3 and preferably less than about 6×10 -12 m 3 .

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

[0016] When the term "length" is used, unless otherwise explicitly stated, one of ordinary skill in the art will understand that this means the length of the non-linear marker shape when the marker extends linearly. For example, if the marker is helical, the length means the length of the marker when it is straightened and stretched linearly. If the marker includes a plurality of fragments of the ferromagnetic material, the length can include the combined length of the plurality of fragments.

[0017] In some embodiments, one or more fragments of the ferromagnetic material can have a circular cross-section with an easily measurable diameter. In some embodiments, one or more fragments of the ferromagnetic material can have a non-circular cross-section; for example, one or more fragments of the ferromagnetic material can include a strip having a generally rectangular cross-sectional shape. Thus, "diameter" as used herein also means the width (e.g., maximum width) in the case of a non-circular fragment of the 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 fragment.

[0018] Markers with a large length-to-diameter ratio and a small volume as defined herein have been found to provide a good balance between good sensing response and small MRI artifacts. By increasing the length-to-diameter ratio of at least one ferromagnetic material piece, the sensing response of the marker is improved. By reducing the volume of the ferromagnetic material, the MRI artifacts generated by the marker are reduced.

[0019] The marker can be detectable by a magnetic susceptibility probe as described in International Publication No. WO 2014 / 140566. The magnetic susceptibility probe generates 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 of generation, and can produce a magnetic field strength of about 0.04 mT to about 0.4 mT within about 5 mm of the probe. Suitably, this enables the detection of the markers of the present disclosure in 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 depends to some extent on its configuration, as described herein.

[0020] The overall length to diameter ratio of one or more fragments 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 overall length to diameter ratio of one or more fragments 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 overall length to diameter ratio of one or more fragments of ferromagnetic material may be about 2400.

[0021] The total volume of one or more fragments of ferromagnetic material is 5×10 -11 m 3 less than, 3×10 -11 m 3 less than, or 1×10 -11 m 3 less than. In some embodiments, one or more fragments of ferromagnetic material can have a low total volume of 1×10 -12 m 3 of.

[0022] As an example, one or more fragments of ferromagnetic material can have an overall length of 50 mm and a diameter of 15 μm. In such an example, the overall length to diameter ratio of one or more fragments of ferromagnetic material may be about 3333, and the volume may be about 9×10 -12 m 3 and can be.

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

[0024] In a preferred embodiment, 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. Preferably, the wire or strip can be formed into one or more fragments as described herein.

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

[0026] A ferromagnetic material can have a low saturation induction, for example, of 1 T or less. By providing a ferromagnetic material with a low saturation induction, when the marker is exposed to an MRI magnetic field strength greater than the magnetic field strength required for the ferromagnetic material to saturate its magnetization, the size of the MRI artifacts generated by the material can be limited.

[0027] The ferromagnetic material can have a high initial permeability ratio, for example, (μ r、i ) > 1000. Preferably, the ferromagnetic material can have a high initial permeability ratio of more than 10,000. By providing a ferromagnetic material with a high initial permeability ratio, the sensing performance of the marker can be improved.

[0028] Preferred materials having the properties required for the marker according to 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 can be flexible such that at least one piece can be formed into a desired configuration; for example, to reduce or minimize the magnetic anisotropy 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, such as a cylindrical wire having a circular cross-section, a flat wire or a strip, and the marker can include one or more pieces of the 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 otherwise indicated by the context.

[0030] Preferred embodiments of the markers according to the present disclosure may include one or more wires or strips according to a 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 to define a meandering path that extends in a plurality of different directions and / or includes twists, bends, or turns, either individually or in combination, to reduce the magnetic anisotropy ratio of the marker. Embodiments of the 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 multi-helix, such as a triple or quadruple helix, the individual helices preferably do not contact each other.

[0031] The helical coil 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. In 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 magnetic signal to the weakest magnetic signal generated by the marker at a fixed distance in different orientations of the marker with respect to the probe. Since the calculated distance between the marker and the probe depends relatively weakly on the magnetic sensing response, the marker may preferably have an anisotropy ratio of less than 7 (i.e., 1 to 7), preferably less than 5, and more preferably less than 3.

[0033] A particularly preferred arrangement of the one or more wires is shown in FIG. 7 of the accompanying drawings.

[0034] The ferromagnetic material configured in the required shape can be encapsulated within a cylindrical housing. The cylindrical housing is preferably injectable to enable the placement of markers. Thus, suitably, the housing can have a maximum diameter such that it can be deployed through a narrow gauge needle, for example, from 18G to 12G. The marker may be packaged within another material or a coating may be applied to the marker to ensure that the marker is biocompatible and robust. The marker may be encapsulated, for example, within a tube made of nitinol, titanium, stainless steel, or other biocompatible alloy, and the material is preferably non-magnetic and has a relatively low conductivity. The low conductivity may include a conductivity of less than 10 6 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, and the wires may extend in different directions within the same or different planes. In another example, the wire arrangement may include two, three, four, or more curved or bent wires, and the curved or bent wires may extend in a single plane, for example, a ring-shaped wire, an L-shaped wire, or across a series of planes, for example, a helical wire. 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, for example, planes orthogonal to each other.

[0036] In one embodiment, the arrangement of wires or strips within the housing is provided as offset parallel rods, substantially perpendicular rods, and / or rods arranged end to end, preferably spaced from each other by at least one diameter length of the rod. More preferably, two or more rods may intersect at an angle to each other; for example, two rods can be made to intersect substantially at right angles to each other. The markers may include an arrangement in which a plurality of such intersecting rods are stacked. The stacked intersecting arrangements may align or rotate the intersections relative to each other; for example, each intersection is rotated by substantially 45 degrees relative to an adjacent stacked intersection. In some embodiments, each intersection may be arranged in a respective plane that is substantially perpendicular to an axis defined by the housing; for example, the longitudinal axis of a cylindrical housing of the type described above. In some embodiments, each intersection may be arranged in a respective plane that is inclined relative to such an axis defined by the housing. The planes may preferably be spaced along the axis. Thus, the intersections may be arranged in two or more respective parallel planes that are perpendicular to or inclined to the housing axis.

[0037] Alternative configurations of the rods may be provided, for example, as one or more groups of parallel rods provided 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; for example, the longitudinal axis of a cylindrical housing. Thus, the groups of parallel rods may be arranged in a series of respective planes spaced along the longitudinal axis of the housing. As described above, the planes may be spaced along the axis. The rods of each group may be aligned and / or rotated relative to at least one other group of rods.

[0038] In some embodiments, each group of parallel rods can rotate about 15 to 90° relative to each other's groups; for example, four groups of parallel rods may be arranged such that each group rotates about 45°, about 60°, and about 90° relative to each of the other groups. In another configuration, the inclined rods extend in respective planes that are substantially orthogonal to an axis defined by the housing, particularly the longitudinal axis, and the planes are spaced along the axis and rotated at an angle of about 10 to 45° relative to one or more adjacent rods to form a twist ladder configuration; for example, the arrangement may comprise eight linear rods, each of which is rotated by about 11.25° relative to each of the adjacent rods.

[0039] Optionally, one or more longitudinal rods are provided through the housing, for example through its center, or independently from the cylinder casing, in a shape (such as a tetrahedron having three or four sides, an isolated circle connected to a vertical rod, a "Jack" shape or a snake shape) that provides the same rod orientation as described in UK Patent Application Publication No. 2582123, the content of which is incorporated herein by reference; for example, as shown in FIGS. 11 to 19. In some embodiments, one or more transverse rods may extend in one or more planes that are substantially orthogonal to the axis of the housing, for example the longitudinal axis of a cylindrical housing, and be provided through the housing.

[0040] 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 rings, and optionally includes one or more linear longitudinal rods extending through the helix or ring.

[0041] In a preferred embodiment, the marker is provided as a single helix combined with one longitudinal wire aligned parallel to the longitudinal axis of the helix, or as a multi-helix, such as a double, triple or quadruple helix. Preferably, the pitch of the helical coil 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, a detection system for identifying the position of an implanted marker is provided, the system comprising: an implanted 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 the 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.

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

Brief Description of the Drawings

[0044]

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DETAILED DESCRIPTION OF THE INVENTION

[0045] Definition: 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.

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

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

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

[0049] Hard magnetic materials have a high coercive force. These are also called permanent magnets.

[0050] Soft magnetic materials have a low coercive force. 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] Magnetic saturation of induction is the state reached when the magnetization M of a material cannot be further increased by an increase in the applied external magnetic field H. In this state, the total magnetic flux density that occurs is called saturation induction (B S ), and the magnetization is saturation magnetization (M S ).

[0053] The initial magnetic susceptibility (χ) is an indicator of how much a material with infinite size is magnetized in a small applied magnetic field. It is defined as χ = M / H for small H, or equivalently as follows.

Equation

[0054] 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 geometric shape in a small applied magnetic field. That is, it is χ after considering the demagnetization factor (see below).

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

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

[0057] Ferromagnetic materials have a variable relative magnetic permeability (μ r ) that increases up to a maximum with respect to a magnetic field. Many ferromagnetic materials have a maximum relative magnetic permeability that can exceed 100,000.

[0058] Paramagnetic materials have a constant relative magnetic permeability (μ that is slightly greater than 1.r ) has.

[0059] The diamagnetic material has a constant relative permeability (μ r ) that is slightly less than 1. Diamagnetism causes a repulsive effect by generating a small magnetic field against the externally applied magnetic field.

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

[0061] The apparent relative permeability (μ app ) is the relative permeability of a material of a specific shape. That is, it is μ r after considering the demagnetization factor.

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

[0063] The demagnetization factor is a number representing the intensity of the magnetic field generated by an object of a specific geometric shape compared to an object of infinite extent. This must be used to determine the demagnetizing field. A magnetic object of any shape has a total magnetic field that varies depending on the position within the object, and it is extremely difficult to obtain by calculation. This makes it very difficult to determine the magnetic properties of a material, such as how the magnetization of the material changes depending on its shape and magnetic field.

[0064] Magnetic anisotropy represents the change in magnetic properties according to the material orientation with respect 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 of MR images characterized by signal voids (black) or bright fringing regions near metallic objects. This occurs at the interface with metal having a different magnetic susceptibility from tissue, causing the local magnetic field to distort the external magnetic field. This distortion changes the precession frequency within the tissue, leading to spatial mis-mapping of information.

[0067] The present disclosure relates to improved magnetic markers that enable surgical guides and provide MRI artifacts small enough (preferably less than 2 cm) to enable effective wireless diagnostics. Using thin wires of ferromagnetic materials as defined herein, having a high length-to-diameter ratio (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 low volume of less than about 1×10 -10 m 3 It has surprisingly been found that markers can be created that provide satisfactory sensing performance, balanced with small MRI artifacts. The markers of the present disclosure can be further improved by selecting ferromagnetic materials having a low saturation induction that can further limit the MRI artifact size. The markers of the present disclosure can be further improved by selecting ferromagnetic materials having a high initial permeability that can improve the sensing performance. Various shapes of such markers have also been developed that improve the isotropy of the magnetic susceptibility.

[0068] "Artifacts" can be generated on MRI images when an object changes the magnetic field within the MRI device. Thus, markers of ferromagnetic materials create significant artifacts, reducing their attractiveness for use as long-term markers for patients undergoing treatments such as neoadjuvant therapy prior to surgical resection. Artifacts are mainly generated by the component (B y ) of the magnetic field generated by ferromagnetic objects in the same direction as the main magnetic field generated by the MRI device (referred to herein as the y-axis). B yThe effect is to shift the local Larmor frequency of the protons near the object, and if the shift is large enough, those protons do not appear in the correct slice reconstructed by the MRI device. That is, the point where |B y | ≧ B crit does 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 another slice, and its value depends on the MRI scanning parameters.

[0069] At distances large 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

Equation

Equation

Equation

[0070] When considering the edge of the MRI artifact here, at that point B marker、MRI = B critwhere y represents the distance from the center of the artifact to its edge. At that point, using the above equation,

Number

Number

Number

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

Number

[0072] This constraint on the maximum volume of the available magnetic material makes it difficult to fabricate markers from magnetic materials with an effective sensing distance, good isotropy, and small artifacts. The markers of the present disclosure address this problem.

[0073] The magnetic susceptibility with respect to shape has also been studied in order to apply this finding to ferromagnetic materials that maintain a magnetic field of a good size during sensing.

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

Number

Equation

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

[0076] The specific shape of the marker containing ferromagnetic material has been found to be unsuitable for the purpose. For example, a sphere has a low magnetic susceptibility for any diameter and thus cannot provide the expected artifact size for the required sensing distance. In the case of an MRI artifact with a diameter of 10 mm or less under a 1.5 T MRI magnetic field, the diameter of the sphere cannot exceed 0.18 mm, which is too small to handle during manufacturing and too small for the surgeon to see after tumor removal. On the other hand, to sense beyond 40 mm, the sphere would need to exceed 1.1 mm, which gives an artifact much larger than what is considered acceptable.

[0077] Example 1: Physical properties of the marker according to the present disclosure. As described above, during sensing, the marker is exposed to a small oscillating field. Its magnetic response is described by the permeability μ r or the magnetic susceptibility χ (μ r(where \(χ = 1\)). When the initial magnetic susceptibility or the relative initial 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, shape, and the frequency of the applied magnetic field.

[0078] It is estimated that by increasing the aspect ratio (L / D, where L is the length of the cylinder of the material and D is its diameter) of the magnetic material, its sensing performance in the direction of its central axis is dramatically increased. This is shown in Figure 1: as the ratio L / D increases, the apparent permeability μ of the object app also increases, and the distance at which the object can be sensed increases. This phenomenon is due to the demagnetizing effect and can be intuitively understood as follows: when the object is substantially perpendicular to the applied magnetic field, the microscopic magnetic dipole fields generated within the object mostly act to cancel each other out. Conversely, when the object is substantially parallel to the applied magnetic field (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 making it possible for the marker to be detected more easily.

[0079] Under an AC magnetic field, an additional phenomenon occurs: the eddy currents then induced within the material generate an additional magnetic field that partially shields the material from the external magnetic field, thus reducing the 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 the case of a very thin rod (φ about 50 μm), the eddy currents actually do not have a significant impact on the sensing performance of the magnetic wire. In the case of a significantly thick rod (φ about 500 μm), the eddy currents increase when L / D > 1. Therefore, in order to reduce or eliminate the influence of eddy currents on the sensing performance of the magnetic wire, it is preferable to make the wire thinner.

[0080] In the case of a cylinder, the aspect ratio is the most important factor.

[0081] As is clear from Figure 1, for a rod with an aspect ratio L / D < 10, the relative initial permeability (μ r、i) makes little difference as long as it is >1,000. However, for rods with a higher aspect ratio, a higher initial relative permeability is beneficial: for example, in the case of a rod with L / D = 400, when μ r、i increases from 1,000 to 50,000, μ app increases by about 7 times.

[0082] The magnitude of the magnetic field of the ferromagnetic material induced under MRI determines the size of the MRI artifact. During MRI, the marker is exposed to a large constant magnetic field, and the magnetization saturates at B S = μ0M S ("saturation induction"). For most ferromagnetic materials, the range of B S is about 0.25 - 1.5 T. Therefore, since the MRI magnetic field (1.5 - 3.0 T) is strong enough to saturate these materials, the magnetization of the ferromagnetic marker in MRI can simply be calculated as M S B S = B S / μ0. Therefore, in order to minimize the artifact size, a material with a low B S is required.

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

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

[0085] Surprisingly, it has been found that an elongated wire of ferromagnetic material can provide the necessary property of a magnetic susceptibility of 1,000 or more. Figure 3a is a simulation that shows the feasibility of a straight wire detectable in a useful range while showing a small MRI artifact. The dotted line shows, for each wire diameter, the minimum length required to be sensed at 40 mm, assuming that the wire material has a magnetic susceptibility χ = 72,000. The dashed-dotted line shows, for each wire diameter, the maximum length allowed for the MRI artifact of the wire to have a diameter of less than 10 mm, assuming that the wire material has a saturation induction B S of 1 T. The hatched area in the upper left corner of the graph corresponds to wire dimensions that can be detected simultaneously at 40 mm or more and produces an MRI artifact with a diameter of 10 mm or less. This figure shows that the wire length must be much larger than the wire diameter to simultaneously satisfy both of these conditions.

[0086] Figure 3b shows the same simulated data as Figure 3a, but for a narrower range of wire diameters and for more sensing distances and saturation inductions. The dotted line and the dashed-dotted line have the same meaning as in Figure 3a. The dashed line and the solid line correspond to additional values of sensing distance and saturation induction as shown in the legend. This figure shows that a wide range of wire dimensions 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 (0.5 T instead of 1 T).

[0087] A low saturation magnetization gives a small ferromagnetic dipole in an MRI scanner, and a high initial permeability means that a small volume of material gives a large sensing response on a probe such as a magnetic susceptometry probe as described in International Publication No. WO 2014 / 140566, the contents of which are incorporated herein by reference. TIFF0007706648000011.tif121170

[0088] The sensing response under a magnetic field of a magnetic susceptibility meter probe and the MRI artifacts of ferromagnetic materials depend on different variables. In a small oscillating magnetic field such as that generated by Sentimag® commercially available from Endomagnetics Ltd. in the UK, the sensing performance depends almost only on the aspect ratio and volume, and it is recognized that the dependence on the initial magnetic permeability (μ r、i )(the initial gradient of the B-μ0H curve) is weak. In contrast, the magnitude of the magnetic field generated by the marker within the MRI apparatus, and thus the size of the MRI artifact, depends on the saturation induction B S and the volume of the material. This means that it is possible to generate the required small MRI artifacts using very thin fragments of low-saturation induction ferromagnetic materials that can still be sensed at a satisfactory distance, as shown in Table 1 below for materials with χ = 72,000 and B S = 0.5T:

Table 1

[0089] 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, and more particularly at least about 500, and having a low total volume, for example, markers having a length of at least 3 mm, preferably having a length of at least 6 mm and a diameter of less than 100 μm, preferably 50 μm or less, particularly 30 μm or less, of a low-saturation induction ferromagnetic material piece have been found to be appropriately sensed while generating low MRI artifacts.

[0090] This is shown in FIGS. 3a and 3b of the accompanying drawings showing the MRI performance depending on the length and diameter of the rod. For a given B S , those below the curve give acceptable artifacts.

[0091] Example 2: Study of preferred materials for magnetic markers according to the present disclosure. The markers described in Example 1 were further investigated to provide the required high initial permeability μ r、i >1000, can be formed into very thin strips or wires, allows a large aspect ratio but has a small volume, and has a low saturation induction B S having, ideally, a low B of less than 1 T S enabled the selection of a preferred magnetic material.

[0092] The preferred materials having the required properties were found to be preferably the following specific metals, amorphous metals and ceramic ferrites: for example, cobalt-based amorphous metals sold under the trade names Yshield MCE61 (trademark), Metglas 2705M (trademark) and Metglas 2714A (trademark); for example, manganese-zinc ceramic ferrites sold under the trade names Fair-Rites 31 (trademark), 76 (trademark) and 78 (trademark); for example, nickel-iron soft ferromagnetic alloys sold under the trade names Mu-metal, Permalloy 80, Permalloy C, Permalloy and Supermalloy; for example, nickel-zinc ceramic ferrites sold under the trade names Fair-Rites 15 (trademark), 20 (trademark), and 43 (trademark); and more preferably, cobalt-based amorphous metals, such as Yshield (trademark) and Metglas 2714A (trademark).

[0093] Ceramics have a low saturation induction, but are not very easy to form into wires or flat wires and are therefore not very suitable for the markers according to the present disclosure.

[0094] Figure 4 is a plot of saturation induction against initial permeability for a wide variety of different materials. Materials that can form suitable markers are included in the upper left region of the graph, showing low saturation induction and high relative initial permeability.

[0095] Example 3: Investigation of the optimized design of the magnetic marker according to the present disclosure. The elongated wire markers discussed in connection with Examples 1 and 2 provide a required relative initial permeability μ r、i > 1000, preferably > 10,000, have a large aspect ratio, a small volume, and a 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, during surgery to detect markers using the magnetic probe described in WO 2014 / 013235, a high anisotropy is not desirable: 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 moving away from another orientation. By minimizing the anisotropy of the embedded marker, the surgeon's ability to more intuitively localize the marker is improved, and the surgeon's ability to safely excise the tissue around the lesion is enhanced. 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, more preferably less than 3 is desirable. Since the magnetic sensing response strongly depends on distance (under certain conditions, it is approximately inversely proportional to the sixth power of the distance), conversely, the calculated distance depends relatively weakly on the magnetic sensing response. Therefore, when the anisotropy ratio is less than 2, it is a value close to ideal in practice; when it is 5, it is indistinguishable from isotropy in practice; and when it is 7, sufficient uniformity is provided.

[0097] Two methods have been identified to increase the axial perception and increase the anisotropy of the magnetic susceptibility. It is also desirable to provide a marker that does not need to be unpacked at the injection site, because the deployable concept needs to have a consistent unpacking mechanism that allows for accurate placement and complete unpacking to provide the required sensitivity and anisotropy. Therefore, having a marker that does not need to be unpacked at the injection site will also provide a significant improvement over the prior art. To achieve this, the marker may comprise a number of small ferromagnetic rods using the wire of Example 1 encapsulated within a single cylinder that covers all axes. However, this type of marker still faces some challenges with respect to detection sensitivity (short rods are expected to have low axial sensitivity and disruptive interaction effects), MRI artifacts (the complexity of magnetic dipoles is the greatest complexity to estimate), safety and regulation, and the manufacturing process and consistency for encapsulation of the rods.

[0098] Therefore, further configurations of the optimized marker according to the present disclosure were investigated. For a given artifact size, it has been found that there is a constraint on the maximum volume of magnetic material suitable for use in the marker. By using materials with a low saturation induction B S more material can be used. The wire diameter determines the total length of wire that can be used and its relative permeability, and the aspect ratio of the wire can be used to calculate the sensing response.

[0099] Since the diameter of the artifact is most strongly dependent on the wire diameter, an important variable has been identified that can be modified to improve the design of the marker as the total wire volume and the length of the wire, and thus the latter does not vary much. If the design consists of a wire diameter D, the allowable length L of the wire is as follows:

Equation

[0100] Initially, an arrangement comprising a plurality of rods of thin wires arranged in different directions was thought to enhance the anisotropy of the markers. Unexpectedly, as shown in FIGS. 5a, 5b and 5c of the accompanying drawings, it has been found that adjacent rods can have a positive or negative interaction with respect to the total dipole moment.

[0101] FIG. 5a shows that parallel rods arranged 0.5 mm apart from each other reduce the dipole moment by 5% for rods with a diameter of 50 μm and by 10% for rods with a diameter of 100 μm. Conversely, as seen in FIG. 5b, when two identical rods are arranged vertically and the ends are separated by the length of the rod diameter, the total dipole moment increases by 5%. Further, as seen in FIG. 5c, vertical rods show a smaller decrease in their dipole moments when offset axially.

[0102] Based on these findings, marker configurations with closely spaced parallel rods were excluded as markers of the present disclosure. However, satisfactory markers forming embodiments of the present disclosure were configurations that were capable of offsetting the arrangement of these parallel rods, as shown in FIG. 5c. Further embodiments are those in which the vertical rods can be arranged end to end.

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

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

[0105] Considering that it is difficult to evaluate the magnetic dipole moment of complex structures, a methodology has been developed to establish how different shapes behave and interact. The findings are summarized in Figure 6.

[0106] It was concluded that a design with a higher aspect ratio, either a longer rod or a larger ring, produces a design with much better sensing performance than MRI artifacts. In this regard, it was found that a rod 5 mm in length is approximately 8 times better than one 1 mm in length per unit volume, and that a ring is better than two perpendicular rods per unit volume. Ring or coil-based designs were also identified as being better than two perpendicular rods for generating a sensing response in two directions.

[0107] In this regard, referring to Figure 6 of the accompanying drawings, the quantity m Z / V indicates how much sensing response the marker generates per unit volume. A 5 mm straight rod produces a stronger response per unit volume than a ring (m Z / V is for the rod 54 and the ring 42), the rod produces a magnetic response only along its axis, while the ring produces it in two dimensions covered by its plane. Thus, the correct performance index of the ring is 2×42 = 84, that is, it is about 50% better than the rod.

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

[0109] This figure also emphasizes the spiral shape, ring, and offset parallel or perpendicular rod arrays, which are preferred embodiments of the present disclosure. These provide the best performance per volume of material used.

[0110] Example 4: Further investigation of the spiral coil marker according to an embodiment of the present disclosure. Considering the ease of manufacturing the spiral shape, the optimization of this shape was further investigated as a preferred marker according to the present disclosure.

[0111] Two different types of spiral designs have been demonstrated to produce acceptable sensing responses with respect to both minimum sensing distance and isotropy. As shown in Figures 8a - 9b respectively, these are (i) a single spiral combined with one longitudinal wire aligned parallel to the axis (Figures 8a and 8b), and (ii) a multi - spiral consisting of double or triple spirals (Figures 9a and 9b). In Figures 8a and 8b, the longitudinal wire is aligned parallel and co - axial with the axis. In another arrangement, the longitudinal wire is not co - axial with the axis but is located on the side of the spiral.

[0112] Markers with a single helix design obtain a lateral response from their helical coil and most of the axial response from their axial rod, while markers with a triple helix design use a larger pitch to obtain both lateral and axial responses from their helical coil (a larger pitch means the coil is more axially oriented). In the context of triple helix and other multi-helixes, the term "pitch" as used herein means the pitch of the individual coils of each component of the multi-helix, unless the context clearly indicates otherwise.

[0113] As shown in Table 2 below, the sensing distance was predicted using a combination of standard physics simulation software (COMSOL), a custom computer model, 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 simulations, it can be concluded that it is desirable to use a smaller diameter and one long rod instead of two short rods.

[0115] In the case of a single helix design (Figs. 8a and 8b) having a longitudinal wire aligned parallel to the axis of the core, it was determined that it is necessary to use the thinnest possible wire (see Example 1 above) having the maximum possible length. As shown in Fig. 6, it is necessary to maximize the diameter of the coil to provide a stronger lateral sensing response for the same volume of material. Fig. 8b shows an optional housing or tube 80 of a dotted line located around the helical coil. The marker may be encapsulated, for example, in a tube made of nitinol, titanium, stainless steel, or other biocompatible alloy, and the material is preferably non-magnetic and has a relatively low conductivity. Suitable coating materials include polymer coatings such as FEP, Parylene, PTFE, ETFE, PE, PET, PVC, or silicone, or epoxy-based encapsulants.

[0116] Surprisingly, the graph of pitch versus lateral sensing distance does not show a sharp peak near the optimum value, and the pitch needs to be balanced with the increase in axial sensing to reach the sweet spot. Figs. 10a - 10c show that the pitch that maximizes the lateral sensing performance is approximately equal to the helical diameter - this is the optimal pitch for a single helix design where the helical coil needs to generate only the lateral sensing response and the axial component is provided by the axial wire. The pitch that generates isotropic sensing performance is approximately equal to 1.6 times the helical diameter, but this pitch is useful for a multi-helix design that excludes the axial wire, and thus, both the axial and lateral sensing responses need to be generated by the helical coil. Figs. 10a - 10c show the sensing distance (mm) versus pitch (mm) for a marker with a diameter of 1 mm, a marker with a diameter of 1.15 mm, and a marker with a diameter of 1.3 mm, respectively.

[0117] Other design options with multiple helices were further investigated to avoid the need for an axial rod. Table 3 below shows that when the total length of the wire is the same, 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 higher pitches, which was expected to improve axial detection. Surprisingly, as shown in Table 4 below, there was only a slight effect on lateral detection, and even more surprisingly, an increase in lateral detection was found. An unexpectedly large discovery was also the non-destructive effect on sensitivity by intertwining the helices close to each other without contact.

[0119] In conclusion, for a given amount of material and marker length, it was found that a single helix exhibited a short pitch and a combination with a ferromagnetic rod might be required. Alternatively, a double or triple helix incorporated into a marker with the same amount of material for the same length required the helix to be stretched so that the pitch increased, which helped to move the coil more axially, but surprisingly, the lateral detection did not decrease.

[0120] When stronger sensing performance is required in a more compact shape, higher-order helices can be used to provide more coils per unit length. However, when too many coils are crowded (at intervals less than one coil diameter), destructive interactions begin.

[0121] The marker size in all cases of Table 4 was a diameter of 1.15 mm and a length of 8.0 mm.

Table 4

[0122] As can be seen from Table 4 above, when the pitch is decreased and the number of turns is increased, the lateral sensing performance improves, but the axial sensing performance decreases. Also, the total length of the wire used increases, and the size of the MRI artifact increases. When the pitch is increased and the number of turns is decreased, the lateral sensing performance decreases, but the axial sensing performance improves. Also, the total length of the wire used decreases, and the MRI artifact size decreases. For each type of multi-helical marker, there is an optimal pitch that produces isotropic sensing performance (for example, in the case of a triple helix, a pitch of about 2.0 mm for a marker with a diameter of 1.15 mm using a 15 μm Co-Fe amorphous metal wire).

[0123] Example 5: Investigation of alternative ferromagnetic materials for the markers according to the present disclosure. All of the markers disclosed above use the thin wire described in connection with Example 1 above to manufacture markers of optimized design. However, the required high initial relative permeability μ r、i > about 1000, preferably > 10,000, and a preferred magnetic material having a low saturation induction B S 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 shows an iron-based metal alloy having μ r、i ≧ 15,000, which meets the requirements of the markers according to the present disclosure and can be provided in the form of a roll sheet before being cut into wires or strips.

Table 5

[0125] Marker designs can be created from these thin sheets using known manufacturing techniques such as etching or laser cutting. These manufacturing techniques are aimed at creating wires, whether or not they 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 markers according to the present disclosure provide small ferromagnetic markers having good isotropy of magnetic susceptibility and sensing distance and exhibiting small MRI artifacts.

[0127] Example 6: Use of the markers according to the present disclosure in the monitoring and treatment of breast cancer. The markers according to the present disclosure are particularly suitable for the monitoring and treatment of breast cancer and are aimed at enabling the tracking of tumor size during preliminary neoadjuvant therapy to reduce the tumor size to less than 2 cm in length or to a size that is sufficiently small compared to the whole (BCS) at least.

[0128] Patients presenting breast cancer tumors that are more than 2 cm but less than 5 cm and do not spread further than the nearby lymph nodes (often classified as "stage 2" breast cancer) can undergo BCS, which generally requires neoadjuvant therapy to reduce the tumor to about 2 cm or less. In parallel, healthcare providers also need to evaluate the exact nature of the tumor and typically need to perform a biopsy to sample a portion of the tumor tissue.

[0129] The markers according to the present disclosure can be placed within cavities formed by tissue sampling in order to identify the location of tumors using magnetic susceptibility probes such as the probes described in WO 2014 / 140566. This enables the location of tumors to be identified during future evaluation of tumor progression and / or for resection of the tumor. A susceptibility detection system for positioning the marker is shown in FIG. 20, and the marker 20 according to the present disclosure is shown together with a magnetic susceptibility probe 22, which probe 22 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 enable tracking of the tumor response to adjuvant therapy, for example by means of regular examinations under MRI, by minimizing the size of the artifacts generated by the markers under the MRI magnetic field, ideally to a length of 2 cm or less. In this regard, the markers are too large for BCS (essentially about 2 cm, but in some cases more), but do not interfere with the assessment of tumor size.

[0131] Thus, the markers of the present disclosure are particularly suitable for the protocols normally pursued by medical personnel when tracking the progression of breast cancer under MRI, since they can enable a significant reduction in the size of MRI artifacts due to their low induced saturation and low mass per unit volume. Once the tumor has shrunk to a size allowing BCS, medical personnel can identify the location of the tumor by means of the marker. The marker can be detected by a magnetic susceptibility probe positioned at least 3 cm and up to 5 cm away, enabling the location of tumors several centimeters below the surface of the skin to be identified. This enables medical personnel to determine the best route to access and remove the tumor by resection before incising the tissue.

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

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

[0134] In FIG. 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] In FIGS. 14a and 14b, the marker comprises a length of magnetic marker material having a straight central portion 6h and two further portions 6i, 6j bent orthogonally to each other and to the central portion at each end. In a further aspect, the radius of bend 6k may be larger to enable the marker to be more easily inserted into the outer tube.

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

[0137] In FIG. 16, the marker includes a magnetic marker material 6n of elliptical or oval length, and the wire ends 6o are joined to each other or are adjacent but not joined. Two portions of the ellipse or oval at the ends of its major axis are bent at approximately 90° to the plane of the ellipse. The bent portion occupies approximately one-quarter to one-third of the area of the ellipse or oval.

[0138] In FIG. 17, the marker includes three lengths of magnetic marker materials 6t, 6u, 6v arranged orthogonally to each other so as to form substantially orthogonal three legs or vertices of a rectangular parallelepiped. The three lengths are joined at a joint 6w that allows the lengths to be parallel to each other before deployment and then redeployed to form an orthogonal tripod.

[0139] In FIGS. 18a and 18b, the marker includes three lengths of magnetic marker materials 6x, 6y, 6z arranged to form a tripod having a non-orthogonal angle between the legs. The three lengths are joined at a joint 6w that allows the lengths to be parallel to each other before deployment and then redeployed to form a 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 characteristics: [Table 6]

[0141] 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 the three legs equally spaced.

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

[0143] In the foregoing description, where an integer or element having known, obvious, or predictable equivalents is recited, such equivalents are incorporated herein as if individually set forth. The claims should be referred to in order to determine the true scope of the present disclosure, and the claims should be construed to embrace any such equivalents. Also, integers or features of the present disclosure described as preferred, advantageous, convenient, or the like are optional and will be understood by the reader not to limit the scope of the independent claims. Further, it should be understood that such optional integers or features may be advantageous in some embodiments of the present disclosure but not desirable and thus may not be present in other embodiments. Other Embodiments 1. An implantable marker for imaging and surgical guidance, comprising: one or more fragments 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 m 3 , wherein the one or more fragments of the ferromagnetic material have a high specific initial permeability (μ r、i ) > about 1000 . The implantable marker is characterized by this. 2. An implantable marker for imaging and surgical guidance, comprising: one or more fragments of a ferromagnetic material having a total length to diameter ratio of at least about 650, preferably at least about 750 or at least about 1000 and a total volume of less than about 1×10 -11 m 3 . The implantable marker is characterized by this. 3. The marker according to embodiment 1 or 2, characterized in that the total length to diameter ratio of the one or more fragments of the ferromagnetic material is at least about 2000. 4. The marker according to any one of embodiments 1 to 3, characterized in that the total volume of the one or more fragments of the ferromagnetic material is less than about 6×10 . -12 m 3 5. The marker according to any one of embodiments 1 to 4, characterized in that the one or more fragments of the ferromagnetic material have a low saturation induction of about 1 T or less. 6. The marker according to any one of embodiments 1 to 5, characterized in that the one or more fragments of the ferromagnetic material are wires or strips. 7. The marker according to any one of embodiments 1 to 6, characterized in that the marker comprises a wire or strip of a ferromagnetic material having a length of at least about 10 mm. 8. The marker according to any one of embodiments 1 to 7, characterized in that the marker comprises a wire or strip of a ferromagnetic material having a length of at least about 20 mm. 9. The marker according to any one of embodiments 1 to 8, characterized in that the marker comprises a wire of a ferromagnetic material having a diameter of less than about 100 μm. 10. The marker according to any one of embodiments 1 to 9, characterized in that the marker comprises a wire of a ferromagnetic material having a diameter of about 30 μm or less. ​ 11. The marker according to any one of Embodiments 1 to 10, wherein the marker generates an MRI artifact of less than about 2.5 cm in a magnetic field of about 1.5 T or more. 12. The ferromagnetic material is cobalt-based amorphous metal (e.g., Yshield MCE61 (trademark), Metglas 2705M (trademark), and Metglas 2714A (trademark)); manganese-zinc ceramic ferrite (e.g., Fair-Rites 31 (trademark), 76 (trademark), and 78 (trademark)); nickel-iron-based soft ferromagnetic alloy (e.g., Mu-metal, Permalloy 80, Permalloy C, Permalloy, and Supermalloy); and nickel-zinc ferrite (e.g., Fair-Rites 15 (trademark), 20 (trademark), and 43 (trademark)); and, more preferably, is selected from cobalt-based amorphous metals (e.g., Yshield (trademark) and Metglas 2714A (trademark)), the marker according to any one of Embodiments 1 to 11. 13. The marker according to any one of Embodiments 1 to 12, wherein the ferromagnetic material includes one or more wires or strips configured in the form of one or more rods, helical coils, and / or rings. 14. One or more fragments of the ferromagnetic material are configured to define a meandering path that extends in a plurality of different directions, and / or includes twists, bends, or curves, individually or in combination, the marker according to any one of Embodiments 1 to 13. 15. One or more fragments of the ferromagnetic material include one or more wires or strips that extend 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, the marker according to any one of Embodiments 1 to 14. 16. One or more fragments of the ferromagnetic material include one or more wires or strips of the ferromagnetic material arranged as offset parallel rods, rods that are substantially perpendicular to each other, and / or rods that are arranged end-to-end without contacting each other, the marker according to any one of Embodiments 1 to 15. 17. One or more fragments of the ferromagnetic material include a plurality of pairs of rods that intersect each other substantially at right angles, and the marker includes a stacked arrangement of the plurality of pairs of intersecting rods, according to any one of embodiments 1 to 16. 18. The pairs of intersecting rods are aligned or rotated with respect to each other, and each pair is preferably rotated by substantially about 45 degrees with respect to an adjacent pair, according to the marker of embodiment 17. 19. One or more fragments of the ferromagnetic material include one or more groups of parallel rods, and the parallel rods are in different groups extending in the same or different directions within the housing; or form a twist ladder configuration, according to any one of embodiments 1 to 18. 20. One or more fragments of the ferromagnetic material further include one or more longitudinal or transverse rods extending through the housing, according to any one of embodiments 16 to 19. 21. One or more fragments of the ferromagnetic material include one or more helical coils, according to any one of embodiments 1 to 20. 22. One or more fragments of the ferromagnetic material include a plurality of spaced-apart rings, according to any one of embodiments 1 to 21. 23. One or more fragments of the ferromagnetic material include one or more straight rods extending through a helical coil or a plurality of spaced-apart rings, according to the marker of embodiment 21 or 22. 24. One or more fragments of the ferromagnetic material include a single helical coil combined with a straight wire aligned parallel to the helical coil axis, according to any one of embodiments 1 to 23. 25. One or more fragments of the ferromagnetic material include a multi-helical coil forming, for example, a double or triple helix, according to any one of embodiments 1 to 24. 26. The pitch of each helical coil is about 1.0 to 1.5 of the diameter of the coil, according to any one of embodiments 21 or 23 to 25. 27. The marker further comprises an outer housing, and the ferromagnetic material is encapsulated within the housing; the outer housing is configured and dimensioned for injection, for example, via an 18G to 12G gauge needle. The marker according to any one of Embodiments 1 to 26. 28. A detection system for identifying the position of an implantable marker, an implantable marker according to any one of Embodiments 1 to 27; at least one drive coil arranged to excite the marker using 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 a drive frequency within the received signal The detection system comprising.

Claims

1. An implantable marker for imaging and surgical guidance, At least about 500 overall length to diameter ratio and about 1×10 －１１ m ３ including one or more fragments of a ferromagnetic material having a total volume of less than One or more fragments of the ferromagnetic material have a high initial relative permeability (μ ｒ、ｉ ) > about 1000 characterized by the implantable marker.

2. The marker according to claim 1, characterized in that the ratio of the total length to the diameter of one or more fragments of the ferromagnetic material is at least about 650.

3. The marker according to claim 2, characterized in that the ratio of the total length to the diameter of one or more fragments of the ferromagnetic material is at least about 2000.

4. The total volume of one or more fragments of the ferromagnetic material is less than about 6×10 －１２ m ３ The marker according to any one of claims 1 to 3, characterized in that it is less than

5. The marker according to claim 1, characterized in that one or more fragments of the ferromagnetic material have a low saturation induction of about 1 T or less.

6. The marker according to claim 1, characterized in that one or more fragments of the ferromagnetic material are wires or strips.

7. The marker according to claim 1, characterized in that the marker includes a wire or strip of ferromagnetic material having a length of at least about 10 mm.

8. The marker according to claim 7, characterized in that the marker includes a wire or strip of ferromagnetic material having a length of at least about 20 mm.

9. The marker according to claim 1, characterized in that the marker includes a wire of ferromagnetic material having a diameter of less than about 100 μm.

10. The marker according to claim 9, characterized in that the marker includes a wire of ferromagnetic material having a diameter of about 30 μm or less.

11. The marker according to claim 1, characterized in that the marker generates an MRI artifact of less than about 2.5 cm in a magnetic field of about 1.5 T or more.

12. The marker according to claim 1, characterized in that the ferromagnetic material is selected from cobalt-based amorphous metals; manganese-zinc ceramic ferrites; nickel-iron-based soft ferromagnetic alloys; nickel-zinc ferrites; and cobalt-based amorphous metals.

13. The marker according to claim 1, characterized in that the ferromagnetic material includes one or more wires or strips configured in the form of one or more rods, helical coils, and / or rings.

14. The marker according to claim 1, characterized in that one or more fragments of the ferromagnetic material are configured to define a meandering path that extends in multiple different directions and / or includes twists, bends, or curves, individually or in combination.

15. One or more fragments of the ferromagnetic material include one or more wires or strips extending in different directions in the same or different planes, and the marker is arranged such that the marker has a signal anisotropy ratio of less than about 7. The marker according to claim 1, characterized in that.

16. One or more fragments of the ferromagnetic material include one or more wires or strips of ferromagnetic material arranged as offset parallel rods, rods substantially perpendicular to each other, and / or rods arranged end-to-end without contacting each other. The marker according to claim 1, characterized in that.

17. One or more fragments of the ferromagnetic material include a plurality of pairs of rods intersecting substantially at right angles to each other, and the marker includes a stacked arrangement of the plurality of pairs of intersecting rods. The marker according to claim 1, characterized in that.

18. The pairs of intersecting rods are aligned or rotated with respect to each other, or rotated substantially about 45 degrees with respect to adjacent pairs. The marker according to claim 17, characterized in that.

19. One or more fragments of the 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. The marker according to claim 1, characterized in that.

20. One or more fragments of the ferromagnetic material further include one or more longitudinal or transverse rods extending through the housing. The marker according to claim 19, characterized in that.

21. One or more fragments of the ferromagnetic material further include one or more longitudinal or transverse rods extending through the housing. The marker according to any one of claims 16 to 18, characterized in that.

22. One or more fragments of the ferromagnetic material include one or more helical coils. The marker according to claim 1, characterized in that.

23. One or more fragments of the ferromagnetic material include one or more straight rods extending through the one or more helical coils. The marker according to claim 22, characterized in that.

24. One or more fragments of the ferromagnetic material include a plurality of spaced rings. The marker according to claim 1, characterized in that.

25. The marker according to claim 24, wherein one or more fragments of the ferromagnetic material comprise one or more straight rods extending through the plurality of spaced-apart rings.

26. The marker according to claim 1, wherein one or more fragments of the ferromagnetic material comprise a single helical coil combined with a straight wire aligned parallel to the helical coil axis.

27. The marker according to claim 1, wherein one or more fragments of the ferromagnetic material comprise a multi-helical coil forming, for example, a double or triple helix.

28. The marker according to 22, 23, 26 or 27, wherein the pitch of each helical coil is about 1.0 to 1.5 times the diameter of the coil.

29. The marker further comprises an outer housing, the ferromagnetic material is enclosed within the outer housing; the outer housing is configured and dimensioned for injection via an 18G to 12G gauge needle. The marker according to claim 1.

30. A detection system for identifying the position of an implantable marker, The implantable marker according to claim 1; At least one drive coil arranged to excite the marker using 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 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 A detection system comprising.

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