Improvements in or relating to implantable ferromagnetic markers - Patents.com

Abstract

An implantable susceptometry marker (1001) for use in a surgical guide includes one or more ferromagnetic elements (1004a, 1004b, 1004c) and at least one diamagnetic element (1003), the one or more ferromagnetic elements being formed from at least one ferromagnetic material having a specific initial permeability of at least about 10,000 and a saturation induction Bs of less than about 1.5 T, and the at least one diamagnetic element having a specific initial permeability of at least about -0.16 x 10 -4 and a total volume of said diamagnetic material within said marker is about 100 to 10,000 times greater than a total volume of said ferromagnetic material.

Description

[Technical field]

[0001] The present disclosure relates to implantable markers for use in surgical guides; in particular, to implantable markers having one or more ferromagnetic elements detectable with a susceptometry probe that emits a magnetic field. The present disclosure also relates to methods of manufacturing such markers and detection devices including at least one such implantable marker. [Background technology]

[0002] Markers are used to guide the surgeon to areas of interest during surgery that are not physically visible or palpable, e.g., small tumors that require resection. Preferably, such markers should be deployable through a fine gauge needle, e.g., 18G-12G, to reduce trauma to the patient. Typically, such markers are less than 10 mm in length to be unobtrusive and minimize trauma. Markers can be placed during biopsy or other surgical procedures of internal sites of interest, e.g., cancer lesions. Markers are placed under imaging guidance, such as ultrasound or x-ray / mammography. During subsequent surgery, the markers are detected and located using a handheld probe that provides audio, visual, or other feedback to the surgeon to guide the surgery. Typically, the markers are resected along with the surrounding tissue.

[0003] A known approach is to use markers containing radioisotopes, such as iodine-125, that can be detected with a handheld gamma ray detection probe. However, the use of radioactive materials is strictly regulated, making it difficult to set up radioactive seeding programs in all but the largest teaching hospital centers.

[0004] A different approach is exemplified by US Pat. Nos. 5,993,333, 5,103,212, and 5,103,366, which are incorporated herein by reference, and which uses a magnetic field and a ferromagnetic marker with high magnetic susceptibility. A handheld susceptometry probe generates an alternating magnetic field ("sensing magnetic field") that excites a magnetically responsive marker that generates a responsive magnetic field detected by the probe. Preferably, the probe is configured to generate a sensing magnetic field having a strength at the source of about 0.2 mT to about 1.2 mT, resulting in a magnetic field strength of about 40 μT to about 400 μT within about 5 mm of the probe. This approach has been found to be very effective for deeper sensing to localize tumors, typically having a diameter of less than about 20 mm, and avoids the drawbacks of the RF approach. However, in MRI settings using much stronger magnetic fields, for example 1.5 T or 3 T, this approach can lead to the generation of undesirable artifacts that are large compared to the marker itself and can obscure the MRI image.

[0005] MRI is used to image lesions not visible on ultrasound or mammography in invasive breast cancer, and MRI monitoring is increasingly used for the evaluation of neoadjuvant therapy before surgical resection, allowing the size of the tumor to be tracked after neoadjuvant therapy and before surgery. MRI artifacts of such markers should not impair the assessment of the size of the tumor by the medical practitioner, since a reduction in the size of the tumor provides a positive option in the management of cancer patients. In this regard, breast cancer stage is typically 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 lumpectomy may be envisaged, the tumor size is preferably 2 cm or less. Non-Patent Document 1 showed that smaller tumor size represents a good prognostic factor, and residual tumors >2 cm are associated with a high local tumor recurrence rate after neoadjuvant chemotherapy. Non-Patent Document 2 indicates that tumors with a size of 2 cm or less are classified as T1, which typically corresponds to cancer stage 1 or 2, when breast-conserving surgery can be envisaged. Larger tumors are more likely to require more radical surgery, such as mastectomy. It is therefore highly desirable to be able to size tumors under MRI when their diameter exceeds 2 cm, allowing assessment of whether the tumor has shrunk to a size that allows breast-conserving surgery.

[0006] Ferromagnetic materials are known to produce MRI distortions, and these are widely documented in the scientific literature. For example, "Magnetic MRI: A New Approach to Magnetic Resonance Imaging" (2011) explains that some ferromagnetic materials may be MRI-safe, but still produce significant artifacts. The artifacts are caused by the component of the magnetic field (B y ) is mainly generated by yThe effect of is to shift the local Larmor frequency of protons near the object, and if the shift is large enough, those protons will not appear in the correct slice in the xz plane reconstructed by the MRI machine.

[0007] An option to reduce the size of MRI artifacts caused by metal implants made of paramagnetic materials, such as cylindrical hip joints and aneurysm clips, by coating the metal implants with diamagnetic materials has been investigated by et al., 2011, pp. 1171-1176 (2012).

[0008] Plewes et al., US Patent No. 5,369, 2003, discloses imaging markers composed of glass and iron-containing aluminum microspheres in a gel matrix that show uniformly good contrast in MR, US and X-ray imaging. The magnetic susceptibilities of all of these materials are reasonably close to those of tissue, but can further include controlled doping with ferromagnetic or paramagnetic materials selected for particularly desirable T1 and T2 properties in MR. US Patent No. 5,369, 2003, discloses that the markers are small and can be easily introduced into tissue through a 12-gauge biopsy needle. The concentration and size of the glass microspheres determine the contrast in US imaging. The contrast seen in MRI resulting from magnetic susceptibility loss is determined by the number of iron-containing aluminum microspheres; however, the marker artifacts also depend on its shape, orientation and echo time. US Patent No. 5,369, 2003 also discloses that by optimizing the size, iron concentration and gel binding, implantable tissue markers are created that are clearly visible in all three imaging modalities.

[0009] On the other hand, US Pat. No. 5,399,993 to Rahmer et al. discloses a multimodal fiducial marker for registration of multimodal data, the multimodal fiducial marker comprising a first portion comprising a magnetic material visible in MPI data obtained by a magnetic particle imaging method and a second portion comprising a second material visible in image data obtained by another imaging method, the image data being registered with said MPI data. The first and second portions are configured or additional measures are provided such that the first portion does not adversely affect the other imaging method and its image data and the second portion does not adversely affect the MPI method and MPI data. In one embodiment, the multimodal fiducial marker further comprises a third portion arranged between or within the first and second portions. This third portion thus separates the first and second portions to avoid adverse effects on each other. Preferably, said third portion is configured as a diamagnetic shell separating the first portion from the second portion. It is thus achieved that the external magnetic field of the marker is zero, i.e. the paramagnetic properties of the magnetic material of the first part are cancelled out. Furthermore, said third part is preferably made of a diamagnetic material, in particular bismuth or graphite.

[0010] These options rely on the fact that paramagnetic and diamagnetic materials have magnetic susceptibilities of comparable magnitude. However, they are unlikely to be used with implantable magnetic markers, which typically contain ferromagnetic materials with magnetic susceptibilities that are 10 million to 1 billion times greater than those of diamagnetic materials, because it would require the use of impractically large amounts of diamagnetic material to achieve any useful reduction in the net magnetic moment of the marker, and therefore the MRI artifact size. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2011 / 067576 [Patent Document 2] International Publication No. 2014 / 013235 [Patent Document 3] International Publication No. 2013 / 140567 [Patent Document 4] US Patent Application Publication No. 2006 / 0293581 [Patent Document 5] US Patent Application Publication No. 2015 / 0011861 [Non-patent literature]

[0012] [Non-Patent Document 1] Shashla(Neoadjuvant chemotherapy in breast cancers, September 2016, DOI: 10.1177 / 1745505716677139) [Non-Patent Document 2] Koh et al. (Introduction of a New Staging System of Breast Cancer for Radiologists: An Emphasis on the Prognostic Stage, January 2019, DOI: 10.3348 / kjr.2018.0231) [Non-Patent Document 3] Hargreaves et al. (Metal Induced Artifacts in MRI, August 2017, DOI: 10.2214 / AJR.11.7364) [Non-Patent Document 4] Gao et al. (Reduction of artefact of metallic implant in magnetic resonance imaging by combining paramagnetic and diamagnetic materials, May 2010, DOI: 10.1063 / 1.3352582) Summary of the Invention [Problem to be solved by the invention]

[0013] It is also known that different shapes of magnetic materials affect the size of MRI artifacts.Therefore, there is a need in the art for small ferromagnetic markers that have good isotropy of sensing response, long sensing range, and small MRI artifacts.The present disclosure seeks to provide an improved magnetic marker with reduced MRI artifacts that overcomes or at least mitigates at least some of the above-mentioned shortcomings. [Means for solving the problem]

[0014] Thus, according to a first aspect of the present disclosure, there is provided an implantable marker for use in a surgical guide, in particular an implantable marker detectable by susceptometry. The implantable marker comprises one or more ferromagnetic elements and at least one diamagnetic element. The one or more ferromagnetic elements have a specific initial permeability of at least about 10,000 and a saturation induction B of less than about 1.5 T. S At least one diamagnetic element is formed from at least one ferromagnetic material having a magneto-resistance of at least about −0.16×10 -4 Preferably, the diamagnetic material is formed from at least one diamagnetic material having a bulk magnetic susceptibility in the range of about −0.16×10 -4 ~Approx.-3×10 -4 The total volume of diamagnetic material in the marker is approximately 100 to 10,000 times greater than the total volume of ferromagnetic material.

[0015] As described herein, ferromagnetic materials have a high relative initial permeability and reach saturation of induction above a threshold applied magnetic field. One or more ferromagnetic elements of the markers of the present disclosure have a relative initial permeability of at least 10,000. In some embodiments, one or more ferromagnetic elements may have a relative initial permeability of more than 50,000. Diamagnetic materials, on the other hand, may have a relative initial permeability at least seven orders of magnitude lower than that of the ferromagnetic material and do not saturate. A typical diamagnetic material has a relative initial permeability of about 1×10 -4It has been found, in accordance with the present disclosure, that by using appropriate relative amounts of ferromagnetic and diamagnetic materials, the above properties of these materials can be advantageously utilized to provide an implantable marker in which: in a sensing magnetic field, one or more ferromagnetic elements are substantially more magnetized than at least one diamagnetic element, producing a response magnetic field large enough to allow the marker to be detected in tissue with a handheld probe; and in an MRI magnetic field, one or more ferromagnetic elements are saturated, thereby increasing their magnetization to a saturation induction B S at least one diamagnetic element, the magnetization of which is limited by saturation but not by saturation, has a degree of magnetization strong enough to offset at least a substantial proportion of the induced magnetization of the one or more ferromagnetic elements, thereby minimizing the size of artifacts produced by the marker, in particular MRI artifacts produced in MRI images on the xz plane of the MRI scanner.

[0016] Thus, in the sensed magnetic field, the amplitude of the magnetic moment generated by the one or more ferromagnetic elements may be 1,000 to 1,000,000 times greater than the magnetic moment generated by the at least one diamagnetic element.

[0017] It will be appreciated that, in accordance with the present disclosure, the amount of diamagnetic material should be selected to minimize the net magnetization of the marker in the MRI magnetic field without "overcompensating" for the ferromagnetic material, thereby not producing unacceptably large artifacts due to the diamagnetic material. At the time of writing, MRI devices are available in a variety of magnetic field strengths; typically ranging from about 0.5T to about 3T (although magnetic fields up to about 7T are known for clinical applications). Thus, in some embodiments of the present disclosure, the marker may include relative amounts of ferromagnetic and diamagnetic material that together produce acceptably small artifacts at two or more different MRI magnetic field strengths; particularly within the range of about 0.5-10T, and preferably about 1-5T; for example, about 1.5T and about 3T. For example, the marker may include amounts of ferromagnetic and diamagnetic material that have nearly no net magnetization at one MRI magnetic field strength, while having net magnetization at another MRI magnetic field strength and still causing acceptably small artifacts. Alternatively, the marker may include relative amounts of ferromagnetic and diamagnetic material optimized to produce acceptably small artifacts at two or more different MRI magnetic field strengths. As used herein, "acceptably small" means less than about 30 mm, preferably less than about 20 mm, particularly in an MRI image on the xz plane in an MRI machine.

[0018] Preferably, in an MRI magnetic field, the smaller of the opposing magnetic moments generated by the one or more ferromagnetic elements or at least one diamagnetic element can have an amplitude that is at least 25%, preferably at least 50%, of the larger of the magnetic moments generated by the at least one diamagnetic element or one or more ferromagnetic elements; thereby, artifacts generated by the marker in an MRI magnetic field can be less than about 30 mm in its longest dimension; preferably less than about 20 mm.

[0019] Thus, according to a second aspect of the present disclosure, an implantable marker may include one or more ferromagnetic elements formed from at least one ferromagnetic material having a relative initial permeability of at least about 10,000, and at least one diamagnetic element formed from at least one diamagnetic material; the one or more ferromagnetic elements and the at least one diamagnetic element are co-located, the at least one diamagnetic material having an apparent magnetic susceptibility, and in an MRI magnetic field, the one or more ferromagnetic elements and the at least one diamagnetic element generate opposing magnetic moments, the smaller of which has an amplitude that is at least about 25% of the larger of the other.

[0020] As used herein, "co-located" means, for example, that one or more ferromagnetic elements and at least one diamagnetic element may be configured and arranged to occupy and extend across substantially the same space (or volume) within the marker.

[0021] As disclosed herein, a sufficient volume of diamagnetic material may be used to generate a magnetic moment having an amplitude that is at least 75% or less than the amplitude of the opposing magnetic moment generated by one or more ferromagnetic elements, i.e., the magnetic moment generated by the diamagnetic material has an amplitude that is within a range of about 25% to about 175% of the amplitude of the opposing magnetic moment generated by one or more ferromagnetic elements.

[0022] In some embodiments, the marker may include relative amounts of ferromagnetic and diamagnetic materials such that the magnetic moment generated by at least one of them under at least two different MRI magnetic fields is within about 75%, preferably within about 50%, of the corresponding magnetic moment generated by the other, respectively, separately. Thus, in some embodiments, the magnetic moment generated by the diamagnetic material may have an amplitude that is within about 25% to about 175%, preferably within about 50% to about 150%, of the corresponding amplitude of the opposing magnetic moment generated by one or more ferromagnetic elements, respectively, separately, under at least two different MRI magnetic fields. Thus, suitably, the magnetic moment generated by at least one diamagnetic element under at least two different MRI magnetic fields may be at least 25% or more of the corresponding magnetic moment generated by one or more ferromagnetic elements, respectively, separately. In this way, the amount of ferromagnetic and diamagnetic materials in the marker may be optimized to target acceptably small artifacts under two or more different MRI magnetic fields, particularly in the range of about 0.5 to 10 T, preferably 1 to 5 T, e.g., 1.5 T and 3 T.

[0023] As noted above, the sensing magnetic field may suitably have a strength of about 0.1 mT to about 2.0 mT, preferably about 0.2 mT to about 1.2 mT at the source, producing a field strength of about 40 μT to about 400 μT within about 5 mm of the probe. Advantageously, this allows the marker to be detected at a range of up to about 50 mm, about 60 mm, about 70 mm, or even up to about 80 mm from the probe.

[0024] Thus, according to a third aspect of the present disclosure, there is provided a detection system for locating an implantable marker, the system comprising at least one implantable marker according to the present disclosure, at least one drive coil arranged to excite the marker with an alternating magnetic field, at least one sense coil arranged to detect a signal received from the excited marker, a magnetic field generator arranged to drive the alternating magnetic field through the at least one drive coil, and at least one detector arranged to receive a signal from the sense coil and detect one or more harmonics of the drive frequency in the received signal. In particular, the detection system may be a susceptometry detection system.

[0025] On the other hand, an MRI magnetic field may typically have a strength of 1.5 T. Suitably, the one or more ferromagnetic elements may be constructed and arranged to generate a response magnetic field as disclosed herein that is large enough to enable detection of the marker in tissue with a handheld susceptometry probe in a sensing magnetic field that is at least 200,000 times weaker than the MRI magnetic field, preferably at least 400,000 times weaker, and in some embodiments up to 800,000 times or more weaker.

[0026] Suitably, the ferromagnetic element or elements have a saturation induction B of less than about 1.5 T, preferably less than about 1 T. S Thus, in some embodiments, the one or more ferromagnetic elements may have a B of the one or more ferromagnetic elements as disclosed herein. S The marker may be constructed and arranged to generate a response magnetic field large enough to enable detection of the marker in tissue using a handheld susceptometry probe at a sensing magnetic field that is at least 1,000 times weaker than the marker in the tissue.

[0027] Suitably, the at least one diamagnetic element may have a total volume that is about 100 to 10,000 times, preferably about 500 to 3,000 times, greater than the volume of the one or more ferromagnetic elements.

[0028] In some embodiments, the one or more ferromagnetic elements are about 1×10 -10 m 3 Less than about 5×10 -11 m 3 , 3×10 -11 m 3 , or 1 × 10 -11 m 3 In some embodiments, the one or more ferromagnetic elements may have a total volume of less than about 1×10 -12 m 3 It may have a small total volume of .

[0029] Typically, the total volume of the at least one diamagnetic element is about 1×10 -9 m 3 ~1.5×10 -7 m 3 , typically up to about 1 × 10 -8 m 3 It could be.

[0030] Advantageously, it has been found that markers containing volumes of ferromagnetic and diamagnetic material within these ranges can be presented in a form having dimensions suitable for implantation, typically by injection. For example, the markers may have widths ranging from about 0.8 mm to about 3 mm, preferably about 1 to 1.5 mm. The markers may have lengths ranging from about 2 to 10 mm.

[0031] British Patent Application No. 2115827.4, the contents of which are incorporated herein by reference, describes a fibrous membrane having a length to diameter ratio of at least about 50, preferably at least about 650, and a length to diameter ratio of about 1×10 -10 m 3 less than about 5×10 -11 m 3Disclosed herein is an implantable marker comprising one or more pieces of ferromagnetic material having a total volume of less than 1000 nm. As disclosed therein, it has been found that increasing the length-to-diameter ratio of at least one piece of ferromagnetic material improves the sensing response of the marker, thereby allowing the use of a smaller volume of ferromagnetic material for a given response magnetic field, resulting in less MRI artifacts. Advantageously, according to the present disclosure, therefore, one or more ferromagnetic elements may have a total length-to-diameter ratio of at least about 50.

[0032] GB 2115827.4 also discloses how one or more pieces of ferromagnetic material may be configured to optimize the isotropy of the response magnetic field generated by the marker. One or more ferromagnetic elements of a marker of the present disclosure may be configured according to the disclosure of the present application to achieve a ratio of magnetic flux anisotropy of less than 7, preferably less than 5. Suitably, one or more ferromagnetic elements of a marker of the present disclosure may be configured as disclosed herein, for example as a helix or multiple helix.

[0033] Those skilled in the art will appreciate that, to obtain maximum benefit from the use of a sufficient volume of diamagnetic material having a magnetization in the MRI magnetic field comparable to that of the one or more ferromagnetic elements, the at least one diamagnetic element may advantageously be configured and arranged to produce an artifact in the MRI magnetic field having a similar shape to the artifact produced by the one or more ferromagnetic elements, but of opposite polarity. In some embodiments, the one or more ferromagnetic elements and the at least one diamagnetic element may be co-located.

[0034] The appropriate configuration and arrangement of the ferromagnetic and diamagnetic elements can be empirically determined by using appropriate mathematical modeling or computer-aided engineering (CAE) software, such as that available under the trademark COMSOL Multiphysics® from Comsol AB, Sweden, or that available under the trademark ANSYS® from Ansys, Inc., Canonsburg, PA, to generate simulated contour maps of respective artifacts produced by one or more ferromagnetic elements and at least one diamagnetic element in an MRI magnetic field, and iteratively adjust the configuration and arrangement of the elements until the contour maps substantially match.

[0035] Preferably, the at least one diamagnetic element may be configured as disclosed herein, for example as a cylinder, and the one or more ferromagnetic elements may be wound around the outer surface of the cylinder as a spiral or multiple spirals, in some implementations of the present disclosure.

[0036] Thus, according to a fourth aspect of the present disclosure, there is provided a method of manufacturing an implantable magnetic marker for use in surgery, comprising: S forming one or more ferromagnetic elements from at least one ferromagnetic material having a ferromagnetic constant; forming at least one diamagnetic element from at least one diamagnetic material, wherein the at least one diamagnetic material has a ferromagnetic constant of at least about −0.16×10 -4 and a total volume of the diamagnetic material is about 100-10,000 times greater than the total volume of the ferromagnetic material; and thereafter, assembling the one or more ferromagnetic elements and at least one diamagnetic element, wherein the at least one diamagnetic element is co-located with the one or more ferromagnetic elements and configured to generate, in an MRI magnetic field, an artifact having a size and shape that at least partially corresponds to the size and shape of the artifact generated by the one or more ferromagnetic elements.

[0037] Preferably, artifacts produced by at least one diamagnetic element in an MRI magnetic field may at least partially overlap with artifacts produced by one or more ferromagnetic elements.

[0038] In some embodiments, the one or more ferromagnetic elements and at least one diamagnetic element can generate opposing magnetic moments, the smaller of which has an amplitude that is at least 25% of the larger of the other.

[0039] The one or more ferromagnetic elements and the at least one diamagnetic element may comprise respective volumes of ferromagnetic and diamagnetic materials selected such that in a sensing magnetic field, the one or more ferromagnetic elements are substantially more magnetized than the at least one diamagnetic element, generating a response magnetic field large enough to enable the marker to be detected in tissue using a handheld susceptometry probe. In an MRI magnetic field, the at least one diamagnetic element has a degree of magnetization strong enough to offset at least a substantial percentage of the magnetization of the one or more ferromagnetic elements, thereby minimizing the size of artifacts generated by the marker as disclosed herein.

[0040] Preferably, the one or more ferromagnetic elements may be constructed and arranged to maximize the strength and isotropy of a response magnetic field generated in response to a sense magnetic field.

[0041] At least one diamagnetic element may be configured and arranged to produce an artifact in an MRI magnetic field having a size and shape that matches to a sufficient extent the artifact size and shape of the artifact produced by one or more ferromagnetic elements, e.g., as disclosed above, particularly in the xz plane defined by the MRI device in which the main magnetic field is oriented along the y-axis, and to reduce the maximum dimension of the artifact produced by the marker to less than about 30 mm.

[0042] As disclosed in International Patent Application No. PCT / GB2022 / 052775, the contents of which are incorporated herein by reference, it has been found that the manufacture of markers having the above-mentioned properties can be facilitated by the use of diamagnetic materials having a relatively high (negative) magnetic susceptibility (with respect to the diamagnetic material). Thus, in some embodiments of the present disclosure, at least one diamagnetic element advantageously has a magnetic susceptibility of about 0.16×10 -4 More than or about 1×10 -4 The magnetic material may be formed from a diamagnetic material having a (negative) bulk magnetic susceptibility of greater than about 1×10. In some embodiments, the diamagnetic material may be formed from a diamagnetic material having a (negative) bulk magnetic susceptibility of greater than about 1×10. -4 ~Approx. 3×10 -4 or more. Suitable diamagnetic materials include pyrolytic graphite, graphite, and bismuth. Pyrolytic graphite has a bulk susceptibility of about 2.7×10 -4 It has a (negative) bulk magnetic susceptibility of about 1.6×10, is biocompatible, and can be machined or deposited directly into the rod. -4 (negative) bulk magnetic susceptibility, is non-toxic, and can be cast or extruded into wire.

[0043] Surprisingly, graphite, which has a substantially isotropic grain structure, exhibits a magnetic field strength of approximately 1.2 × 10 when one or more ferromagnetic elements are arranged side by side. -4 It has been found that graphite having a substantially isotropic grain structure can have an apparent (negative) volume susceptibility of 0.01 to 0.01 mm. Furthermore, graphite having a substantially isotropic grain structure provides acceptable isotropic susceptibility, yet is inexpensive, easily machineable into shapes, and has good biocompatibility properties. Graphite having a substantially isotropic grain structure can be formed by isostatic pressing.

[0044] Preferably, the graphite should have a high purity. Isostatically pressed graphite can be conveniently produced in suitable grades with less than 300 ppm impurities. In some embodiments, the graphite can have less than 5 ppm impurities.

[0045] Advantageously, isotropic graphite may have a high density which has been found to increase its susceptibility. Thus, in some embodiments, the graphite has a viscosity of at least about 1.75 g.cm -3 , for example, about 1.85 g.cm -3 In some embodiments, the graphite may have a density of up to about 1.95 g.cm -3 A density in this range indicates low porosity.

[0046] In some embodiments, the compatibility of the graphite material may be further enhanced by heat treatment at temperatures above about 2,200° C. The heat treatment may occur simultaneously with pressing or after pressing. The heat treatment may advantageously reduce the number density of voids or impurities in the graphite, which may include paramagnetic particles.

[0047] Thus, according to a fifth aspect, the present disclosure encompasses the use of graphite having a substantially isotropic grain structure in an implantable marker for detection by susceptometry that includes one or more ferromagnetic elements to reduce the net magnetic moment of the marker in an MRI magnetic field, thereby minimizing the size of artifacts produced by the marker.

[0048] Thus, according to this aspect of the disclosure, an implantable marker may include one or more ferromagnetic elements and at least one diamagnetic element formed from graphite having a substantially isotropic grain structure, such as isostatically pressed graphite.

[0049] In some embodiments, it is envisioned that alternative diamagnetic materials, such as diamagnetic metamaterials, may be used that may have advantageous magnetic susceptibility, thereby allowing smaller volumes of diamagnetic material to be used within the marker.

[0050] It will be understood that features described herein with respect to one aspect of the disclosure may be incorporated in other aspects of the disclosure, for example, a method of the disclosure may incorporate features described with reference to a marker of the disclosure, and vice versa.

[0051] The following is a description, by way of example only, with reference to the accompanying drawings of embodiments of the present disclosure. [Brief description of the drawings]

[0052] [Figure 1(a)] Schematic side view of a person lying in an MRI scanner showing the magnetic field B gradient on the y-axis of the main magnetic field [Figure 1(b)] Another schematic side view of an MRI scanner, showing how the image slices are cut along the y-axis, and indicating the orientation of the x-, y-, and z-axes [Figure 2(a)] Hysteresis curves showing magnetization as a function of magnetic field H for a typical ferromagnetic material. [Figure 2(b)] Hysteresis loop similar to that in Fig. 2(a) showing magnetic flux B as a function of magnetic field H for a typical ferromagnetic material [Figure 2(c)] Schematic diagram showing the direction of the magnetic moment generated in a ferromagnetic material when a magnetic field H1 is applied. [Figure 3(a)] Graph showing magnetic flux B as a function of magnetic field H for a typical diamagnetic material [Figure 3(b)] Schematic diagram showing the direction of the magnetic moment that occurs in a diamagnetic material when a magnetic field is applied. [Figure 4] FIG. 1 is a schematic illustrating the change in magnetic moment due to an applied magnetic field for a marker including at least one ferromagnetic element and at least one diamagnetic element, according to one embodiment of the present disclosure. [Diagram 5] FIG. 1 is a schematic perspective view of an implantable marker according to a first embodiment of the present disclosure, comprising a cylindrical diamagnetic core and three spaced apart ferromagnetic wires extending substantially parallel to the longitudinal axis of the core and juxtaposed with the outer surface of the core; [Figure 6(a)]FIG. 5 is a contour plot of magnetic flux density B in the xz plane for an MRI scanner of the type shown in FIG. 1(a) and / or FIG. 1(b), showing how B deviates from the applied MRI magnetic field B along the y axis as a result of the presence in the magnetic field of the implantable marker of FIG. 5. [Figure 6(b)] Comparative contour plots of magnetic flux density B in the xz plane of an MRI scanner showing how B deviates from the MRI magnetic field B0 when a ferromagnetic wire of the same configuration as shown in Figure 5 is present in the field but without the diamagnetic core. [Figure 7] FIG. 1 is a schematic perspective view of an implantable marker according to a second embodiment of the present disclosure, comprising a cylindrical diamagnetic core and three spaced apart ferromagnetic wires, each extending through the diamagnetic core substantially parallel to its longitudinal axis; [Figure 8] A contour plot of magnetic flux density B in the xz plane for an MRI scanner of the type shown in Figure 1(a) and / or Figure 1(b), showing how B deviates from the MRI magnetic field B0 as a result of the presence in the field of the implantable marker of Figure 7. [Figure 9] FIG. 13 is a schematic perspective view of an implantable marker according to a third embodiment of the present disclosure, comprising a cylindrical diamagnetic core and a ferromagnetic wire helix extending around the outer surface of the diamagnetic core; [Figure 10(a)] A contour plot of magnetic flux density B in the xz plane for an MRI scanner of the type shown in Figure 1(a) and / or Figure 1(b), showing how B deviates from the MRI magnetic field B0 as a result of the presence in the field of the implantable marker of Figure 9. [Figure 10(b)] Comparative contour plots of magnetic flux density B in the xz plane of an MRI scanner showing how B deviates from the MRI magnetic field B0 when present in the field of a ferromagnetic wire of the same configuration as shown in FIG. 9, but without the diamagnetic core. [Figure 11] FIG. 13 is a schematic perspective view of an implantable marker according to a fourth embodiment of the present disclosure, comprising a cylindrical diamagnetic core and a triple helix formed from ferromagnetic wire extending around the outer surface of the diamagnetic core; [Figure 12(a)]A contour plot of magnetic flux density B in the xz plane for an MRI scanner of the type illustrated in FIG. 1(a) and / or FIG. 1(b), showing how B deviates from the MRI magnetic field B0 as a result of the presence in the field of the implantable marker of FIG. [Figure 12(b)] Comparative contour plots of magnetic flux density B in the xz plane of an MRI scanner showing how B deviates from the MRI magnetic field B0 when present in the field of a ferromagnetic wire of the same configuration as shown in FIG. 10 but without the diamagnetic core. [Figure 13] 1 is a flow chart showing a method for manufacturing an implantable marker according to a fifth embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] definition Magnetic flux density B is a vector field that measures the strength and direction of the magnetic field around a magnet or electric current.

[0054] Magnetic field strength, or magnetic field H, is a vector field that describes the magnetic effects on moving charges, electric currents, and magnetic materials.

[0055] Magnetization or magnetic polarization M is a vector field that represents the density of permanent or induced magnetic dipole moments in a magnetic material.

[0056] Saturation of induction is the state reached when the magnetization M of the material cannot be further increased by increasing the applied external magnetic field H. In this state, the total magnetic flux density produced is equal to the saturation induction B S The magnetization is called the saturation magnetization M S It is.

[0057] Magnetic susceptibility, χ, is a measure of how magnetized a material is in an applied magnetic field and is defined as χ=M / H.

[0058] Bulk magnetic susceptibility is a measure of the magnetic susceptibility of a material in its bulk form when placed in a magnetic field.

[0059] Apparent volume (diamagnetic) susceptibility is a measure of the magnetic susceptibility of a diamagnetic material in its bulk form when placed in a magnetic field in the presence of one or more shaped ferromagnetic materials.

[0060] Magnetic permeability μ is a measure of a material's resistance to the formation of a magnetic field and is defined as μ=B / H.

[0061] Relative permeability (μ r ) is the ratio of magnetic permeability to the permeability of free space (μ0); that is, μ r =μ / μ0). μ r It can be related to χ by the formula =1+χ.

[0062] Initial magnetic susceptibility (χ i ) is a measure of how much an infinite material can be magnetized in a small applied magnetic field. It is known that for small H (e.g., less than 0.01 mT), χ i =M / H, or equivalently, is less than or equal to

number

[0063] Apparent magnetic susceptibility is a measure of the magnetic susceptibility of a material with a particular shape when placed in a magnetic field.

[0064] Apparent initial magnetic susceptibility (χ app ), also known as the effective magnetic susceptibility, is the initial magnetic susceptibility of a material of a particular geometry in a small applied magnetic field. That is, χ after taking into account the demagnetization factor i It is.

[0065] Specific initial permeability (μ r,i ) is μ for small H r is the value of μ r,i =1+χ i is related to the initial magnetic susceptibility by

[0066] Apparent relative permeability (μ app ) is the relative magnetic permeability of a material of a particular shape. That is, μ after taking into account the demagnetization factorr It is.

[0067] Ferromagnetic materials have a variable magnetic permeability μ that increases with the magnetic field up to a maximum. Many ferromagnetic materials have a maximum permeability that can exceed 100,000.

[0068] Paramagnetic materials have a constant magnetic permeability μ that is slightly greater than unity.

[0069] Diamagnetic materials have a constant magnetic permeability μ that is slightly less than 1. Diamagnetism causes a repulsive effect by generating a small magnetic field that opposes an externally applied magnetic field.

[0070] Coercivity is the magnetic field H required to completely demagnetize a magnetic material.

[0071] Hard magnetic materials or permanent magnets have a high coercive force.

[0072] Soft magnetic materials have low coercivity and are therefore easily magnetized and demagnetized.

[0073] The demagnetizing or stray field is the magnetic field H inside a magnet that is created by the magnetization M of the magnetic material. It gives rise to shape anisotropy in ferromagnetic materials with a single magnetic domain, and to magnetic domains in larger ferromagnetic materials.

[0074] The demagnetization factor is the quantity that must be used to determine the demagnetization field. A magnetic object of any shape has a total magnetic field that varies with position within the object, which can complicate the calculations. This makes it difficult to determine the magnetic properties of the material, for example, how the magnetization of the material changes with the magnetic field.

[0075] Magnetic anisotropy describes the change in magnetic properties as a function of material orientation.

[0076] The magnetic anisotropy ratio is the ratio of the strongest to the weakest magnetic signal generated by a marker at a fixed distance at different orientations of the marker relative to the probe.

[0077] Magnetic moment is the magnetic strength and orientation of a magnet or other object that produces a magnetic field.

[0078] The magnetic dipole moment is a vector quantity that relates to the magnetic properties of a current loop.

[0079] Magnetic resonance imaging (MRI) is a non-invasive imaging technique that produces detailed anatomical images in three dimensions. A typical MRI scanner 10 is shown diagrammatically in Figures 1(a) and 1(b). A uniform main magnetic field 11, B0, is aligned with the longitudinal y-axis 12 of the scanner. As shown in Figure 1(a), an RF pulse 13, B1, is applied to momentarily perturb the net magnetization M of atomic nuclei in the tissue of a patient 14 lying within the scanner. This RF excitation momentarily tilts the magnetization from the y-axis (i.e., parallel to B0, where no signal can be detected) to the transverse xz plane (i.e., orthogonal to the y-axis), where it can be detected by an appropriate receiving coil. After the RF pulse is turned off, the magnetization of the atoms relaxes and exhibits precession as it returns to the thermal equilibrium configuration. It is possible to detect the magnetization because the transverse component of the process magnetization induces an electromotive force in the receiving coil. This is detected as an NMR signal. The received signal is spatially encoded by the application of a magnetic field gradient 15 superimposed on the main magnetic field, as shown in FIG. 1(b).

[0080] MRI metal artifacts arise at the interface between tissue and metals with different magnetic susceptibility that distort the local magnetic field with the external magnetic field. This distortion changes the precession frequency in the tissue, leading to spatial mismapping of information. crit is defined as the critical change in magnetic flux B in the direction of the main magnetic field generated by the MRI machine at which artifacts caused by metals are produced and voxels are mapped onto the inaccurate slice imaged by the MRI machine. In a typical MRI machine of the type shown in Figures 1(a) and 1(b), the main magnetic field is aligned with the y-axis 12 and aligned with the slice 16. 1 , 16 2 , 16 3 ,...16n are the respective xz planes orthogonal to the principal y-axis 12. Therefore, artifacts in MRI images are generally artifacts in the xz plane.

[0081] It is an object of the present disclosure to provide an implantable marker, in particular a marker adapted for detection by susceptometry, which comprises one or more ferromagnetic elements that generate a detectable response magnetic field in the probe when exposed to a driving magnetic field emitted by a handheld susceptometry probe, and generate artifacts of minimal size when exposed to much stronger magnetic fields in an MRI scanner, in particular in the xz plane of the scanner.

[0082] Thus, in one aspect, the present disclosure provides an implantable marker for use in a surgical guide. The implantable marker comprises one or more ferromagnetic elements and at least one diamagnetic element. The one or more ferromagnetic elements and the at least one diamagnetic element comprise respective amounts of ferromagnetic and diamagnetic materials, and in a sensing magnetic field (at the source) of less than about 0.5 mT, the one or more ferromagnetic elements are substantially more magnetized than the at least one diamagnetic element to generate a response magnetic field large enough to detect the marker in tissue with a handheld probe; and in an MRI magnetic field of 0.5 T or more, typically 1.5 T or more, the at least one diamagnetic element has a degree of magnetization strong enough to offset at least a substantial proportion of the induced magnetization of the one or more ferromagnetic elements. In this way, the marker of the present invention can produce smaller MRI artifacts than a marker comprising the same amount of ferromagnetic material without any diamagnetic material. Thus, for a given volume of ferromagnetic material, the size of the MRI artifact can be reduced to an acceptable size.

[0083] As will be described in more detail below, the one or more ferromagnetic elements advantageously have a magnetic field strength of about 1×10 -11 m 3In some embodiments, the total volume of ferromagnetic material in one or more pieces is less than about 5×10 -11 m 3 In some embodiments, the total volume of the ferromagnetic material in the one or more pieces is less than about 5×10 -11 m 3 Less than 3×10 -11 m 3 Less than or about 1 × 10 -11 m 3 In some embodiments, the one or more ferromagnetic elements may be less than about 1×10 -12 m 3 The composition may have a low total volume.

[0084] To maximize magnetization in the sense magnetic field, the one or more ferromagnetic elements may have a total length (i.e., the sum of the lengths of all ferromagnetic elements when multiple ferromagnetic elements are present) to diameter (or square root of cross-sectional area) ratio of at least about 50, as disclosed in GB Patent Application No. 2115827.4. Thus, in some embodiments, the total length to diameter (or square root of cross-sectional area) ratio of one or more pieces of ferromagnetic material may be at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 650, or at least about 750. In some embodiments, the total length to diameter (or square root of cross-sectional area) ratio of one or more pieces of ferromagnetic material may be at least 1000, at least 2000, or at least 3000.

[0085] As an example, the one or more pieces of ferromagnetic material can have a total length of about 50 mm and a diameter of about 15 μm. In such an example, the one or more pieces of ferromagnetic material can have a total length to diameter ratio of about 3,300 and a volume of about 9×10 -12 m 3In another embodiment, the one or more pieces of ferromagnetic material may have a total length of about 36 mm and a diameter of about 15 μm. In such an example, the one or more pieces of ferromagnetic material may have a total length to diameter ratio of about 2,400 and a volume of about 6.4×10 -12 m 3 It could be.

[0086] In some embodiments, the marker may comprise a wire or strip of ferromagnetic material having a length of at least about 3 mm, about 6 mm, about 10 mm, about 30 mm, 50 mm, or about 100 mm. The wire may have a diameter of less than about 100 μm, or about 50 μm or less, about 30 μm or less, about 15 μm or less, or about 10 μm or less. The marker may comprise a wire or strip of ferromagnetic material having an overall length of about 3 mm, about 6 mm, about 10 mm, about 30 mm, about 50 mm, or about 100 mm or less. Suitably, the wire or strip may be formed into one or more pieces as described herein.

[0087] Preferably, the ferromagnetic material may have a relative initial permeability of at least about 10,000. In some embodiments, the ferromagnetic material may have a relative initial permeability of at least about 50,000 or at least about 70,000. In some embodiments, the ferromagnetic material may have a relative initial permeability of about 100,000 or greater.

[0088] Furthermore, as described below, the ferromagnetic material may have a saturation induction that is weaker than a non-typical MRI magnetic field. Thus, suitably, the ferromagnetic material has a saturation induction B of less than about 1.5 T, preferably less than about 1.0 T; more preferably less than about 0.7 T. S may have:

[0089] The at least one diamagnetic element may suitably comprise a total volume of diamagnetic material that is about 100-10,000 times greater, preferably about 500-3,000 times greater, such as about 950-1,050 times greater, or about 500-950 times greater, or about 500-1,050 times greater, than the total volume of ferromagnetic material of the one or more ferromagnetic elements. Thus, the at least one diamagnetic element may comprise a total volume of diamagnetic material that is about 1×10 -9 m 3 ~1.5×10 -7 m 3 By selecting the respective amounts of ferromagnetic and diamagnetic material within these ratios and / or volumes, and by saturation of the induction of the ferromagnetic material in the MRI magnetic field, the amplitudes of the opposing magnetic moments generated by the one or more ferromagnetic elements and the at least one diamagnetic element in the MRI magnetic field can be of the same order of magnitude. Preferably, the amplitude of the smaller of the magnetic moments generated in the MRI magnetic field by the one or more ferromagnetic elements or the at least one diamagnetic element can be at least 25%, preferably at least 50%, of the amplitude of the larger magnetic moment generated by the at least one diamagnetic element or the one or more ferromagnetic elements, respectively. In this way, the artifact size of the marker in the MRI magnetic field, especially in the xz plane of the MRI scanner as defined herein, can be acceptable, i.e., its longest dimension can be less than about 30 mm, preferably less than about 20 mm. Furthermore, the total volume of ferromagnetic and diamagnetic material allows the production of a marker that is small enough to be deployable through a narrow gauge needle, for example 18G to 12G.

[0090] The one or more ferromagnetic elements and the at least one diamagnetic element may be suitably constructed and arranged to generate mutually opposing magnetic moments in the presence of an applied magnetic field. In particular, when the marker is placed within an applied magnetic field H, the one or more ferromagnetic elements have a magnetic moment m ferromagnet and at least one diamagnetic element has an opposing magnetic moment m diamagnet Therefore, the net magnetic moment of the marker mtotal m total =mf erromagnet -m diamagnet In a sensed magnetic field (at the source) of less than about 0.5 mT, the net magnetic flux generated by the marker determines the strength of the signal generated by the marker. In an MRI magnetic field, the magnetic flux generated by the marker affects the size of the artifacts produced in the MRI image.

[0091] As those skilled in the art will appreciate, MRI magnetic fields typically have strengths of between 0.5T and 10T or more, particularly between about 1.5T and 7T.

[0092] In the field of the present disclosure, handheld sensitive probes can be used by surgeons to detect and locate markers after implantation. Suitably, the probes can be those described in WO 2014 / 140566, the contents of which are incorporated herein by reference; for example, the Sentimag™ probe, commercially available from Endomagnetics Ltd, UK.

[0093] The probe may generate a sensing magnetic field having a strength at the source of about 0.1 mT to about 2.0 mT, preferably about 0.2 mT to about 1.2 mT, for example about 0.3 mT. This may produce a magnetic field strength of about 25 μT to about 500 μT, preferably about 40 μT to about 400 μT, within about 5 mm of the probe, which may be determined by the B S The sensing magnetic field may be at least 1,000 times weaker than the sensing magnetic field. Typically, the sensing magnetic field may be an oscillating magnetic field. Thus, the sensing magnetic field may oscillate with an amplitude at the source of 0.1 mT to 2.0 mT, preferably about 0.2 mT to about 1.2 mT.

[0094] In use, when the sensing probe is in proximity to the marker, the sensing magnetic field generates a magnetic moment in the ferromagnetic material, and the marker generates a detectable response magnetic signal. Under the type of sensing magnetic field described, it is desirable that the marker is easily detectable. It is desirable that the marker has a relatively strong net magnetic moment and generates a relatively high magnetic flux density (B) within the range of the sensing magnetic field. It is desirable that the magnetic flux is suitably isotropic (in practice, a magnetic anisotropy ratio of less than 7, preferably less than 5, may be sufficient) so that the marker can be consistently detected from a reasonably large distance and from any direction. As described in more detail below, under the sensing magnetic field, the magnetic signal generated by the marker is dominated by at least one ferromagnetic element. Fields of the magnitude described in the previous paragraph may typically allow the markers of the present disclosure to be detected at a range of up to about 50 mm, about 60 mm, about 70 mm, or about 80 mm from the probe.

[0095] FIG. 2(a) is a hysteresis curve 1 showing magnetization M as a function of applied magnetic field H for a typical ferromagnetic material. Ferromagnetic materials typically have a high initial magnetic susceptibility and develop a strong magnetization M when exposed to a low applied magnetic field H, as shown by dashed line 3. FIG. 2(b) is a similar hysteresis curve 101 showing magnetic flux density B as a function of applied magnetic field H for a typical ferromagnetic material. Ferromagnetic materials typically reach magnetic saturation (saturation induction B) under a relatively low applied magnetic field (H). S 2(c), the magnetic moment of the ferromagnetic material 7 is in the same direction as the applied magnetic field 9.

[0096] The magnetic moment m of one or more ferromagnetic elements in the sensed magnetic field ferromagnet m ferromagnet =χ app.ferromagnet H.V. ferromagnet The magnetic flux density (B) or magnetic field generated by all the ferromagnetic material in the marker is approximately given by:

number

[0097] FIG. 3(a) is a graph 201 showing magnetic flux B as a function of magnetic field H for a typical diamagnetic material. As shown in FIG. 3(a), diamagnetic materials typically have a low initial magnetic susceptibility and exhibit a linear increase in magnetization 211 up to relatively high magnetic fields without reaching saturation. As a diamagnetic material, the magnetic flux B is less than that of free space, as shown by the dashed line 203 shown for reference, since the induced magnetization faces the magnetic field H. As shown in FIG. 3(b), when the diamagnetic material is exposed to an applied magnetic field, a magnetization or magnetic moment 207 is induced that faces the direction of the applied magnetic field 209. As described herein, at least one diamagnetic element of the present disclosure has a magnetization of 1×10 when exposed to a magnetic field less than 0.01 mT. -3 Less than 3 × 10 -4 The magnetic moment m of at least one diamagnetic element in the sense magnetic field may be less than diamagnet m diamagnet =χ app.diamagnet H.V. diamagnet The magnetic flux density (B) generated by a diamagnetic element is given by:

number

[0098] In the sensed magnetic field, the magnetic moment of the one or more ferromagnetic elements is higher than the opposing magnetic moment of the at least one diamagnetic element. The magnetic moment of the one or more ferromagnetic elements may be at least 1,000 to 1,000,000 times greater than the opposing magnetic moment of the at least one diamagnetic element.

[0099] The magnetic fields commonly used in MRI machines are several orders of magnitude stronger than the sensing fields mentioned above, with the most common clinical MRI machines at the time of this writing being 1.5 T or 3 T. Thus, in some embodiments of the present disclosure, the MRI magnetic field may be typically 1-5 T, but in some embodiments may be as high as 7 T or higher.

[0100] As mentioned above, the one or more ferromagnetic elements can reach saturation of induction at magnetic field strengths well below typical MRI magnetic field strengths. The one or more ferromagnetic elements of the present disclosure can reach saturation of induction B at 1.5 T or less. S and thus may be saturated when exposed to the MRI magnetic field. In this case, using the dipole approximation, the magnetic moment m of one or more ferromagnetic elements when subjected to a relatively strong MRI magnetic field ferromagnet is:

number

[0101] When exposed to MRI magnetic fields, the induced magnetic moment of the at least one diamagnetic element may also be significant, given the upper limit of magnetization due to saturation of the one or more ferromagnetic elements, and the rather large volume of diamagnetic material used in the at least one diamagnetic element. Although the magnetic moment per unit volume of the at least one diamagnetic element is typically much weaker than the magnetic moment of the one or more ferromagnetic elements, a large volume of diamagnetic material relative to the volume of ferromagnetic material may generate a magnetic moment that significantly counteracts the magnetic moment of the ferromagnetic material. When exposed to a typical MRI magnetic field, the magnetic moment m from the at least one diamagnetic element is diamagnet is:

number

[0102] As an example, the total magnetic moment of at least one diamagnetic element in a 1.5 T MRI field is approximately -1 × 10 -6 Am 2 where the negative sign indicates that the magnetic moment is in the opposite direction to the MRI field.

[0103] Because the magnetic moment from the at least one diamagnetic element opposes the magnetic moment of the one or more ferromagnetic elements, the magnetic moment from the at least one diamagnetic element reduces the net magnetic moment of the entire marker when exposed to an MRI magnetic field. Thus, preferably, the marker has a net magnetic moment of about 1×10-6 Am 2 In particular, the marker can have a net magnetic moment of less than about 1×10 when exposed to a magnetic field of 0.5 T to 7 T, preferably about 1 T to 5 T; more preferably about 1.5 T to 3 T. -6 Am 2 The magnetic moment may be less than 0.1.

[0104] 4 illustrates a schematic representation of the change in magnetic moment with an applied magnetic field H of a marker comprising one or more ferromagnetic elements and at least one diamagnetic element, according to one embodiment of the present disclosure. The magnetic moment as a function of the applied magnetic field is shown for one or more ferromagnetic elements 301, at least one diamagnetic element 303, and the total magnetic moment 305 of the marker. At intermediate magnetic field strengths, below the strength of a typical MRI magnetic field but above the strength of the sensing field, the one or more ferromagnetic elements have reached saturation 307 and the magnetic moment m of the one or more ferromagnetic elements ferromagnet is relatively high. Meanwhile, at least one diamagnetic element has an opposing magnetic moment that is substantially smaller than the magnetic moment of the ferromagnetic element or elements under the sense magnetic field, but increases linearly with the applied field. At such intermediate magnetic fields, the magnetic moment of the ferromagnetic element or elements still exceeds the total magnetic moment m marker 305, but at larger magnetic field strengths of the kind used in MRI scanners, the opposing magnetic moment of at least one diamagnetic element may represent a significant proportion, e.g., at least 25%, preferably at least 50%, of the larger magnetic moment of the ferromagnetic element or elements.

[0105] In some embodiments, at a certain applied magnetic field strength, indicated by point A, the amplitude of the (negative) magnetic moment of the at least one diamagnetic element may be substantially equal to the (positive) magnetic moment of the at least one ferromagnetic element, and thus the total or net magnetic moment of the marker may be zero or close to zero. At even higher applied magnetic fields, the amplitude of the magnetic moment of the at least one diamagnetic element may be even greater than the amplitude of the magnetic moment of the one or more ferromagnetic elements, and the total or net magnetic moment of the marker may be negative.

[0106] Considering the constraints on the marker of the present disclosure, its size and shape, as well as the magnetic properties of available materials, the need to co-locate the magnetic dipoles induced in the one or more ferromagnetic elements and the at least one diamagnetic element so that they at least partially cancel each other, and the strength of the MRI magnetic field, it will be appreciated that in practice the magnetic moments of the one or more ferromagnetic elements and the at least one diamagnetic element may not completely cancel each other. However, as long as the magnetic moments of the one or more ferromagnetic elements and the at least one diamagnetic element cancel each other sufficiently to reduce artifacts caused by the marker under MRI to an acceptable size, preferably less than about 30 mm in its longest dimension, more preferably less than 25 mm, and even more preferably less than about 20 mm, the objectives of the present disclosure can be met.

[0107] Thus, in an MRI magnetic field, the smaller of the opposing magnetic moments generated by the one or more ferromagnetic elements or at least one diamagnetic element can have an amplitude that is at least 25%, preferably at least 50%, of the amplitude of the larger magnetic moment generated by the at least one diamagnetic element or the one or more ferromagnetic elements. In some embodiments, the magnetic moment generated by the at least one diamagnetic element in an MRI magnetic field can have an amplitude that is at least 27% of the amplitude of the larger magnetic moment generated by the one or more ferromagnetic elements, preferably at least 50% of the amplitude of the magnetic moment generated by the one or more ferromagnetic elements.

[0108] When exposed to the MRI magnetic field, one or more ferromagnetic elements produce artifacts on the MRI image, which cause localized changes in the magnetic field within the MRI machine. The artifacts are generated by ferromagnetic elements B that are in the same direction as the main magnetic field generated by the MRI machine (referred to herein as the y-axis). y This is mainly caused by the component of the magnetic flux generated by B y The effect of |B is to shift the local Larmor frequency of protons in the tissue near the marker, and if the shift is large enough, those protons will not show up in the correct slices reconstructed by the MRI machine. y |≧B crit The point where B crit is the magnitude of the y-component of the magnetic flux density B at which a voxel is mapped onto another slice, and its value depends on the MRI scan parameters.

[0109] Amount of ferromagnetic material, saturation induction B S, and the size and shape of the ferromagnetic element(s) affect the size of the artifact. At distances large compared to the size of the ferromagnetic element(s), the magnetic flux density generated by the ferromagnetic element(s) can be approximated by a dipole model. Under that model, along the axis of magnetization, the magnetic flux density generated by the ferromagnetic element is given by:

number

number

number

[0110] If we consider the edges of MRI artifacts, then at that point,

number

number

number

number

[0111] According to the present disclosure, the size of the artifacts produced by the marker may be reduced by the presence of at least one diamagnetic element, since the net magnetic moment of the marker is at least reduced by the presence of at least one diamagnetic element. For the entire marker, when exposed to an MRI magnetic field, the size of the artifacts produced can be calculated as follows:

number

number

[0112] From this equation, in order to reduce or minimize the diameter of the artifact produced by the marker, B MRI χ V diamagnet is B S ·V ferromagnet It is understood that the value must be equal to the typical exemplary value. MRI =1.5T, B S = 0.6T, and χ = 5 × 10 -4In the case of , the volume of the at least one diamagnetic material should be at least about 1000 times larger than the volume of the one or more ferromagnetic elements to minimize the diameter of the artifact. However, as discussed in more detail below, the volume of diamagnetic material required to balance the magnetic moment of the one or more ferromagnetic elements will be smaller under stronger MRI magnetic fields, e.g., 3 T. In some embodiments, a volume of diamagnetic material less than about 10,000 times, e.g., less than 5,000 times or less than 2,500 times, e.g., about 1,000 times larger than the volume of the one or more ferromagnetic elements may be suitable.

[0113] Large artifacts generated during MRI imaging are problematic and can lead to mismapping of spatial information. It is therefore important to minimize the size of the artifacts generated by the marker in the MRI field while still allowing the marker to be sensed in the sensing field.

[0114] In order for a marker to be sensed in a sensing magnetic field, the magnetic moment of the ferromagnetic element or elements must dominate the net magnetic moment when the marker is exposed to the sensing magnetic field.

[0115] In order that artifacts produced by the marker in a typical MRI magnetic field are relatively small, the magnetic moment of the at least one diamagnetic element should at least partially cancel out the magnetic moment of the one or more ferromagnetic elements so that the net magnetic moment of the marker is as small as possible. Furthermore, the size and shape of the artifacts produced by only the one or more ferromagnetic elements should at least approximate the size and shape of the artifacts produced by only the at least one diamagnetic element, such that when combined closely together in the marker, they will overlap and therefore cancel each other out at least to some extent, as described herein.

[0116] The size of the artifacts produced by the markers of the present disclosure when exposed to an MRI magnetic field depends on the volume and shape of the one or more ferromagnetic elements and the volume and shape of the at least one diamagnetic element. Using large amounts of ferromagnetic material can result in undesirably large artifacts. Increasing the volume of diamagnetic material can lead to smaller artifacts.

[0117] However, if a volume of diamagnetic material is used that is much larger than required to offset the volume of ferromagnetic material, the "negative" artifacts produced by the at least one diamagnetic element may dominate the artifacts produced by the one or more ferromagnetic elements, which may lead to an undesirable increase in the mar artifact size. Therefore, it may be desirable to optimize the volume ratio between the one or more ferromagnetic elements and the at least one diamagnetic element to reduce the size of the mar artifact size for a given MRI magnetic field strength.

[0118] The size of the artifacts produced in the MRI magnetic field also depends on the B S Since it depends on B, the lower S If a ferromagnetic material having a B in the range of 0.25 T to 1.5 T is used, a larger volume of ferromagnetic material may be used. S may have:

[0119] The volume of diamagnetic material required to offset the magnetization of one or more ferromagnetic elements in an MRI magnetic field may depend on the strength of the MRI magnetic field. In particular, a smaller amount of diamagnetic material may be required to offset the saturation magnetization of one or more ferromagnetic elements in a stronger magnetic field. MRI scanners are available with different MRI magnetic field strengths, which means that the opposing magnetic moments of a marker comprising one or more ferromagnetic elements and at least one diamagnetic element may be substantially equal in magnitude under a certain strength of MRI magnetic field, but not equal under a different MRI magnetic field. Suitably, the respective volumes of ferromagnetic material and diamagnetic material in the marker of the present disclosure are capable of producing MRI artifacts of acceptable size over a range of MRI magnetic fields, for example, 0.5-10T, preferably 1-7T, more preferably 1.5-3T.

[0120] In some embodiments, the respective volumes of ferromagnetic and diamagnetic material in the marker may be such that they generate magnetic moments of substantially equal amplitude under one MRI magnetic field, e.g., 1.5 T, thereby minimizing artifact size, while still producing acceptably small artifacts under a different MRI magnetic field, e.g., 3 T. Preferably, to minimize the volume of material used in the marker, the amount of diamagnetic material present may be such that the amplitude of the magnetic moment generated by at least one diamagnetic element is substantially equal to the amplitude of the magnetic moment generated by one or more ferromagnetic elements under a first MRI magnetic field, e.g., 3 T, but still produces artifacts of acceptable size under a second MRI magnetic field that is weaker than the first, e.g., 1.5 T.

[0121] In some embodiments, the respective volumes of ferromagnetic and diamagnetic materials in the marker may be such that they generate magnetic moments of different amplitudes in two or more different MRI magnetic fields, but the artifact size under each different MRI magnetic field is of an acceptable size. Thus, in some embodiments, the marker may include relative amounts of ferromagnetic and diamagnetic materials such that the opposing magnetic moment generated by at least one is within about 75% of the other, preferably within about 50% of the other, under at least two different MRI magnetic fields. In this sense, the respective amounts of ferromagnetic and diamagnetic materials in the marker may be optimized to target acceptably small artifacts under two or more different MRI magnetic fields, particularly in the range of about 0.5-10 T, preferably 1-5 T, e.g., 1.5 T and 3 T. The shape and dimensions of each ferromagnetic element and at least one diamagnetic element may also affect the size and shape of the artifacts and the ease with which the marker can be sensed.

[0122] As disclosed in GB 2115827.4, for a given volume of ferromagnetic material, a ferromagnetic element with a large aspect ratio may be more easily detectable in the sensing magnetic field. Increasing the aspect ratio (L / D, e.g., where L is the length of the element and D is the diameter or width or the square root of the cross-sectional area in the case of elements with non-circular cross sections) of a magnetic element may increase its sensing performance in the direction of its major axis. As the ratio increases, the apparent permeability μ app also increases, and as a result the sensed distance can be increased. This phenomenon is due to the demagnetization effect.

[0123] Suitably, the or each one or more ferromagnetic elements may comprise at least one wire or strip. The wire may comprise a cylindrical wire having a substantially circular cross section. Alternatively, the wire may be a flat wire or strip. The one or more ferromagnetic elements may comprise a plurality of wires and / or strips.

[0124] In some implementations, one or more ferromagnetic elements in the form of multiple wires or strips may be configured, individually or in combination, to extend in several different directions and / or define one or more serpentine paths that include twists, bends or turns in order to optimize the isotropy of the magnetic response of the marker, as described herein and in GB Patent Application No. 2115827.4.

[0125] One or more ferromagnetic elements of a marker of the present disclosure may suitably have a length to diameter (or width / square root of cross-sectional area) (L / D) ratio of at least about 50, preferably at least about 650 or at least about 1000.

[0126] The ferromagnetic element or elements preferably have a magnetic field of 1×10 -10 m 3 less than about 5×10 as described above -11 m 3 The total volume may be less than 1000 μm.

[0127] Unless expressly stated otherwise, the term "length", when used herein in the context of an individual magnetic element, refers to the length of the element when it extends linearly. For example, in the case of a helical ferromagnetic element, the length of the element is the length of the wire forming the helix. In contrast, the term "total length" is used herein, unless otherwise stated, to refer to the length of one or more magnetic elements in the configuration in which they are formed into a marker. In the latter context, "length" generally refers to the size of one or more elements in the direction of the longest dimension of the marker. On the other hand, "total diameter" or "total width" refers to the diameter or width, respectively, of an assembly of one or more magnetic elements in a direction transverse to the longest dimension.

[0128] Ferromagnetic elements with high aspect ratios and low volumes attempt to balance useful sensing response with acceptably small MRI artifacts; by reducing the volume of ferromagnetic material, the MRI artifacts produced by the ferromagnetic elements can be reduced. On the other hand, increasing the aspect ratio of at least one ferromagnetic element for a given volume of ferromagnetic material can improve the sensing response of the marker.

[0129] In some embodiments, the aspect ratio of the or each ferromagnetic element may be at least 100, at least 200, at least 300, at least 400, at least 500, at least 650, or at least 750. In some embodiments, the aspect ratio of the or each ferromagnetic element may be at least 1000, at least 2000, or at least 3000. This allows the volume of ferromagnetic material, and therefore MRI artifact size, to be reduced while maintaining sensing response. In some embodiments, one or more ferromagnetic elements have an aspect ratio of at least 1×10 -11 m 3 The total volume may be less than 1000 .mu.m.

[0130] Increasing the aspect ratio of the material of the ferromagnetic element can dramatically increase its sensing performance in the direction of its longest dimension. As the aspect ratio increases, the apparent magnetic permeability μ app also increases, which increases the distance at which the marker can be sensed as a result of the demagnetizing effect.

[0131] A straight ferromagnetic wire has a high aspect ratio and generates a strong magnetic flux density in the direction of its longitudinal axis. This can lead to practical sensing performance in a sensed magnetic field parallel to this axis. However, such elements may be less easy to detect in a direction perpendicular to the longitudinal axis, i.e., they may have an anisotropic sensed response, which may result in a large variation in the magnetic response of the element depending on its orientation relative to the sensed magnetic field, which may make it difficult to calibrate the magnetic response detected by the probe to its proximity to the marker. Using one or more ferromagnetic elements with a large aspect ratio can result in good sensing performance using a relatively small volume of ferromagnetic material, which has the advantage of producing small artifacts in the MRI image.

[0132] The sensing response and MRI artifact size of a ferromagnetic element under a sensing magnetic field may depend on different variables. Under a sensing magnetic field such as that generated by a Sentimag™ probe, the sensing performance may depend almost exclusively on the aspect ratio and volume of the ferromagnetic material, and on the relative initial permeability μ r,i (initial slope of the B-μH curve). In contrast, the magnitude of the magnetic field produced by a ferromagnetic element when exposed to an MRI magnetic field, and therefore the MRI artifact size, depends only on the saturation induction B S and the volume of ferromagnetic material. This means that it is possible to limit the size of the MRI artifacts by using very thin, low saturation induction pieces of ferromagnetic material that can still be sensed at a sufficient distance.

[0133] It has been found that coiled ferromagnetic wires can have a more isotropic response in the sensed magnetic field than straight wires while still having a low volume and a high aspect ratio. Thus, coiled ferromagnetic wires can be detected in the sensed magnetic field from an improved range of directions, with less change in their magnetic response with orientation relative to the sensed magnetic field, while still producing acceptably small artifacts in the MRI magnetic field.

[0134] Thus, in some embodiments, the one or more ferromagnetic elements may comprise a coiled ferromagnetic wire or strip, or a plurality of spaced apart rings that may be substantially coaxial with one another. Optionally, the one or more ferromagnetic elements may further include one or more straight rods extending through the coils or rings. In some implementations, at least one ferromagnetic element may comprise a helical wire coil.

[0135] In some embodiments, the one or more ferromagnetic elements may include at least one single helix; optionally combined with one or more straight wires arranged substantially parallel to the longitudinal axis of the helix.

[0136] In some embodiments, the two or more ferromagnetic elements can be configured as multiple helices, for example, a two-helix, a three-helix, or a four-helix.

[0137] In the case of a combination of a ferromagnetic element having the form of a single helix and one or more ferromagnetic elements having the form of straight wires or strips aligned substantially parallel to the longitudinal axis of the helix, the transverse magnetic response of the marker may arise primarily from the helix and the longitudinal response may arise primarily from the one or more straight wires or strips.

[0138] If the marker includes multiple ferromagnetic elements, the individual ferromagnetic elements can be arranged so that they do not contact each other to avoid destructive interactions between the elements. In some embodiments, the ferromagnetic elements can be held apart by one or more spacers, or by being fixed to at least one diamagnetic element or another component of the marker, such as a housing or other non-magnetic support. Thus, in a multiple helical arrangement, for example, each individual helical ferromagnetic element can be disposed within a helical gap defined by the turns of one or more other helical ferromagnetic elements.

[0139] It has been found that the shape and size of MRI artifacts produced by coiled magnetic wires may depend on the coil pitch and / or coil diameter of the wire: larger pitches may typically produce longer, thinner artifacts, whereas shorter, wider coils may typically produce thicker, shorter artifacts.

[0140] Suitably, the wires may have a diameter of less than about 100 μm, 50 μm, 30 μm, 15 μm, or 10 μm; preferably, the wires may have a diameter of about 15 μm.

[0141] The helical ferromagnetic element formed from the ferromagnetic wire may have a helix diameter (i.e., diameter of the helix) of about 0.8 mm to 3 mm, preferably about 1.0 mm to 1.5 mm, and more preferably about 1.15 mm to 1.30 mm. It has been found that a larger coil diameter can produce a stronger transverse sensing response in the sensing magnetic field.

[0142] Suitably, the helical ferromagnetic element may have a pitch of about 0.5 mm to 3 mm, preferably about 1.0 to 2.0 or 1.0 to 1.5 mm, for example about 1.6 mm. A larger pitch may improve the sensing response of the helix in its axial direction. This is believed to be due to the longer length of the helical coil protruding in the axial direction.

[0143] Preferably, the pitch of the helix may be approximately equal to the diameter of the helix. In some embodiments, the pitch of the helix may be 1.0-2.0 or 1.0-1.5 times the diameter of the helix, for example about 1.33 times. This may help to maximize the lateral response of the helix in the sensed magnetic field.

[0144] Decreasing the pitch and increasing the number of turns of the helical ferromagnetic element may increase the lateral sensing performance of the marker, but decrease its axial sensing performance. They also increase the overall length of the wire used, which may increase the MRI artifact size for a given gauge of wire. On the other hand, increasing the pitch and decreasing the number of turns of the helical ferromagnetic element may decrease the lateral sensing performance of the marker, but increase its axial sensing performance. This may also reduce the total volume of wire used for a given wire gauge, which may advantageously serve to decrease the MRI artifact size of the marker. It has been found that there may be an optimal pitch to produce isotropic sensing performance for each type of multi-helical marker. For triple helices, a pitch of about 2.0 mm for each individual helix may be optimal for a marker of about 1.15 mm diameter using about 15 μm metal wire.

[0145] In some embodiments, the one or more ferromagnetic elements may include at least one helical ferromagnetic element having a helix length (i.e., end-to-end length of the helix) of about 2 mm to 10 mm, preferably about 6 mm to 8 mm, for example about 4 mm or about 5 mm. It has been found that a longer helix can increase the aspect ratio of the marker and result in an improved sensing response. Suitably, the helical ferromagnetic element may be formed from a wire having an overall length of at least about 3 mm, 6 mm, 10 mm, 30 mm, 50 mm, or 100 mm.

[0146] As described above, the at least one diamagnetic element may be configured and arranged to minimize the net magnetic moment of the marker in the MRI magnetic field. The at least one diamagnetic element may generate a "negative" artifact in the MRI magnetic field. The artifact generated by the at least one diamagnetic element may be calculated to reduce the size of the artifact generated by the marker as a whole, as described above, preferably at two or more MRI magnetic field strengths. Preferably, the at least one diamagnetic element may be configured and arranged to generate an "inverse" artifact in the MRI magnetic field having a shape and size similar to the artifact generated by the one or more ferromagnetic elements.

[0147] In order for at least one diamagnetic element to most effectively cancel the fields from one or more ferromagnetic elements, and therefore reduce the size of the resulting MRI artifacts, the ferromagnetic and diamagnetic elements should (i) generate magnetic fields of similar strength (but opposite direction) in the MRI magnetic field; and (ii) be co-located as closely as possible.

[0148] The above objective (i) can be achieved according to the present disclosure by using respective volumes of ferromagnetic and diamagnetic materials as disclosed herein, such that the two induction field strengths in the MRI magnetic field are similar. As disclosed herein, at least one diamagnetic element can typically include a significantly larger volume of material than one or more ferromagnetic elements. Using a significantly larger volume of diamagnetic material compared to the total volume of ferromagnetic material means that the total magnetic moment of the marker, and therefore the size of the artifacts generated by the marker, can be reduced.

[0149] The volume of the at least one diamagnetic element may be about 100 to 10,000 times larger than the total volume of the one or more ferromagnetic elements, preferably about 500 to 3,000 times larger than the total volume of the one or more ferromagnetic elements, for example about 1,000 times larger.

[0150] The total volume of ferromagnetic material forming one or more ferromagnetic elements is less than 5 × 10 -11 m 3 , 3×10 -11 m 3 , or 1 × 10 -11 m 3 It may be less than.

[0151] Typically, the volume of the at least one diamagnetic element is about 1×10 -9 m 3 ~1.5×10 -7 m 3 It can be

[0152] Objective (ii) can be achieved by distributing one or more ferromagnetic elements and at least one diamagnetic element in a similar manner in space. In general, the magnetic field generated by a given volume of diamagnetic material is weaker than the magnetic field generated by the same volume of ferromagnetic material, and therefore a larger volume of diamagnetic material is required. For this reason, and because it may be impossible to perfectly co-locate the two materials, the magnetic fields generated by the two materials may not typically completely cancel each other in the MRI magnetic field. While it may be most beneficial to align the dipole components of the two magnetic fields, aligning higher order components (quadrupoles, octopoles, etc.) may result in diminishing returns. The appropriate configuration and arrangement of the ferromagnetic and diamagnetic elements can be empirically determined by using a suitable computer mathematical modeling program to generate contour plots of the magnetic flux changes individually generated in the MRI magnetic field by one or more ferromagnetic elements and at least one diamagnetic element, and iteratively adjusting the configuration and arrangement of the elements until the contour plots substantially match. The shape and size of the artifacts produced by one or more pieces of ferromagnetic or diamagnetic material in an MRI magnetic field are determined by the B crit , which, as noted above, is the magnitude of the y-component of the change in magnetic flux density B for a given MRI magnetic field, where a voxel maps to a different slice due to the presence of one or more pieces in the field.

[0153] The one or more ferromagnetic elements and the at least one diamagnetic element may suitably be juxtaposed to one another within a common space that may be defined by the one or more ferromagnetic elements and / or the at least one diamagnetic element. As mentioned above, this may be particularly advantageous when graphite having a substantially isotropic grain structure is used as the diamagnetic material, since it has surprisingly been found that the proximity of the one or more ferromagnetic elements increases the apparent susceptibility of the graphite. Suitably, the one or more ferromagnetic elements and the at least one diamagnetic element may be configured and arranged such that the center, e.g., box center (i.e., the center of a notional rectangular box that fits as closely as possible around the object) or geometric center, of a theoretical artifact generated by the one or more ferromagnetic elements coincides with the center, e.g., box center or geometric center, of a theoretical artifact generated by the at least one diamagnetic element. In some embodiments, the center of mass of the one or more ferromagnetic elements may substantially coincide with the center of mass of the at least one diamagnetic element.

[0154] In some implementations, the at least one ferromagnetic element can extend along or around an outer surface of the at least one diamagnetic element. In some implementations, the at least one ferromagnetic element can be wrapped around the at least one diamagnetic element.

[0155] Conveniently, the at least one diamagnetic element may form the core of the marker. The at least one diamagnetic element may comprise an elongated body having an outer surface. Advantageously, the elongated body may be substantially cylindrical. The elongated body may form a support or mandrel for at least one of the one or more ferromagnetic elements. In some implementations, at least one of the one or more ferromagnetic wires may be wound around the elongated body of the diamagnetic element to form a single or multiple helix, as described above. Alternatively, the at least one diamagnetic element may be juxtaposed to the single or multiple helix formed by at least one of the one or more ferromagnetic wires; for example, in the form of an elongated rod extending substantially parallel to the longitudinal axis of the helix or around the helix in the form of a hollow cylinder.

[0156] It has been found that the size of artifacts produced by a marker can be advantageously minimized when the overall length of one or more ferromagnetic elements is the same as or similar to the overall length of at least one diamagnetic element, and / or when the overall diameter or width of one or more ferromagnetic elements is the same as or similar to the overall diameter or width of at least one diamagnetic element.

[0157] Thus, preferably, the one or more ferromagnetic elements may individually or collectively extend along at least 80% of the total length of the at least one diamagnetic element. In some embodiments, the at least one diamagnetic element may have a total length of about 2 mm to 10 mm, preferably about 4 mm, 5 mm, or 6 mm to 8 mm. In some implementations, the total length of the at least one diamagnetic element may be approximately the same as the total length of the one or more ferromagnetic elements; for example, the length of the helix where the one or more ferromagnetic elements form the helix. The total length of the at least one diamagnetic element may be within 5% of the total length of the one or more ferromagnetic elements. The total length of the at least one diamagnetic element may be within about 2% of the total length of the one or more ferromagnetic elements.

[0158] Suitably, the marker may be sized to fit within a particular needle gauge, for example between 12G and 18G, preferably between 16G or 18G. Thus, in some embodiments, the marker may have a diameter ranging from about 0.514mm to about 1.803mm, preferably from about 0.838mm to about 1.194mm. Once the total volume required for the ferromagnetic and diamagnetic materials is determined, the percentage of each material within the marker can be calculated. The diameter, length, and spatial arrangement of the one or more ferromagnetic elements and at least one diamagnetic element may then be determined based on the available diameters within a particular needle gauge, taking into account in some embodiments the need to accommodate a housing or outer coating for the ferromagnetic and diamagnetic elements.

[0159] In general, the at least one diamagnetic element may have an overall diameter or width of about 0.03 to 3 mm. Taking into account the inner diameter of a particular needle gauge and leaving sufficient space for the housing or outer coating, as discussed in the previous paragraph, in some embodiments, the at least one diamagnetic element may have an overall diameter or width of about 0.45 mm to 1.8 mm, more preferably about 0.80 mm to 1.2 mm. It has been found that in many cases, making the overall diameters of the one or more ferromagnetic elements and the at least one diamagnetic element as similar to one another as possible may lead to the best artifact size reduction. Thus, in some embodiments, the overall diameter of the at least one diamagnetic element may be approximately the same as the overall diameter of the one or more ferromagnetic elements; for example, the helix diameter where the one or more ferromagnetic elements form a helix. The overall diameter of the at least one diamagnetic element may be within about 5% of the overall diameter of the one or more ferromagnetic elements. The overall diameter of the at least one diamagnetic element may be within about 2% of the overall diameter of the one or more ferromagnetic elements. However, if a very strong diamagnetic material (e.g., pyrolytic carbon) is used or if the wire diameter is very thin, only a small amount of diamagnetic material may be needed to balance the ferromagnetic magnetic moment. In such cases, the overall diameter of the at least one diamagnetic element may be smaller than the overall diameter of the one or more ferromagnetic elements. Preferably, the similarity of the aspect ratio of the diamagnetic material to the one or more ferromagnetic elements is preserved when the diameter of the diamagnetic element is small.

[0160] Thus, the one or more ferromagnetic elements and at least one diamagnetic element may be configured and arranged as disclosed herein such that the artifacts generated by the marker in an MRI magnetic field are less than about 30 mm in maximum length, preferably less than about 20 mm in maximum length. The size of the MRI artifacts may vary depending on the strength of the MRI magnetic field. The artifacts generated by the marker in an MRI magnetic field may be less than 20 mm in length in a magnetic field of less than 3 T. The artifacts generated by the marker in an MRI magnetic field may be less than 20 mm in length in a magnetic field of less than 5 T. The artifacts generated by the marker in an MRI magnetic field may be less than 20 mm in length in a magnetic field of less than 7 T.

[0161] For markers according to embodiments of the present disclosure, the one or more ferromagnetic elements have low saturation induction (B S ), for example less than 1.5 T. Furthermore, the ferromagnetic element or elements may have a high relative initial permeability, for example greater than 10,000 for a magnetic field of 0.1 mT to 0.5 mT. In some embodiments, the ferromagnetic element or elements may have a relative initial permeability of greater than 50,000 or even greater than 100,000.

[0162] The or each ferromagnetic element may suitably comprise a ferromagnetic metal. At least one ferromagnetic element may comprise an amorphous metal. At least one ferromagnetic element may comprise a ceramic ferrite. Suitable ferromagnetic materials include cobalt-based amorphous metals, for example sold under the trade names Yshield MCE61™, Metglas 2705M™ and Metglas 2714A™. Suitable ferromagnetic materials also include manganese-zinc ceramic ferrites, for example sold under the trade names Fair-Rites 31™, 76™ and 78™. Suitable ferromagnetic materials further include nickel-iron-based soft ferromagnetic alloys, for example sold under the trade names Mu-metal, Permalloy 80, Permalloy C, Permalloy and Supermalloy. Other suitable ferromagnetic materials include nickel-zinc ceramic ferrites, for example sold under the trade names Fair-Rites 15™, 20™, and 43™; preferably cobalt-based amorphous metals, such as Yshield™ and Metglas 2714A™. However, ceramics, although having low saturation induction, are less easily formed into wires or flat wires and are therefore less suitable for markers according to the invention. In some embodiments, metallic ferromagnetic materials may be preferred in view of their ductility for drawing into wires with high aspect ratios and flexibility for forming into rings, spirals, and the like.

[0163] In some embodiments, the at least one diamagnetic element has a magnetic field strength of about 0.16×10 -4 It can be made from diamagnetic materials that have a negative bulk magnetic susceptibility greater than -0.16×10. For example, graphite has a negative bulk magnetic susceptibility of approximately -0.16×10. -4 This is approximately -0.91×10 -5 However, advantageously, at least one diamagnetic element is ferrodiamagnetic, i.e., has a magnetic susceptibility of about 1×10 -4In some embodiments, the at least one diamagnetic element may have a strongly negative magnetic susceptibility of at least about −1×10 -4 In some embodiments, the at least one diamagnetic element may have a volume susceptibility of up to about −3×10 -4 Thus, in some embodiments, at least one diamagnetic element may have a volume susceptibility of about −0.16×10 -4 ~-3×10 -4 In some embodiments, the at least one diamagnetic element may have a bulk magnetic susceptibility of up to about −7×10 -4 A diamagnetic element with a high (negative) magnetic susceptibility can be advantageous because it means that less diamagnetic material is needed to offset the (positive) magnetization of one or more ferromagnetic elements in the MRI magnetic field.

[0164] In some embodiments, at least one diamagnetic element may include graphite. Advantageously, the graphite may have a fine, substantially isotropic grain structure. For example, isostatically pressed graphite may have a higher density, higher strength, and finer grain structure than graphite formed from extrusion or compaction. Furthermore, isostatically pressed graphite may advantageously have more isotropic magnetic properties than graphite formed by extrusion or compaction. Isostatically pressed graphite may also be inexpensive, easily machinable, have good biocompatibility properties, and be manufacturable in grades with less than 300 ppm impurities. Thus, preferably, the graphite may be of high purity, containing greater than 99.9% carbon. In some embodiments, the graphite may have less than 5 ppm impurities. The graphite may have a density of at least about 1.75 g / cm 3 , for example, about 1.85 g / cm 3 In some embodiments, the graphite can have a density of up to about 1.95 g / cm, which can correspond to low porosity. 3Surprisingly, high density, high purity isostatically pressed graphite, in the presence of one or more juxtaposed ferromagnetic elements, may have a density of about -1.2 x 10 -4 It has been found to have an apparent volume magnetic susceptibility of

[0165] Thus, according to a different aspect, the present disclosure encompasses the use of graphite having a substantially isotropic grain structure in an implantable marker including one or more ferromagnetic elements to reduce the net magnetic moment of the marker in an MRI magnetic field, thereby minimizing the size of artifacts produced by the marker. According to this aspect, the implantable marker of the present disclosure may include one or more ferromagnetic elements and at least one diamagnetic element formed from graphite having a substantially isotropic grain structure, for example by isostatic pressing. Suitably, the graphite may be of high purity. The graphite may be heat treated, for example at a temperature of at least about 2,200°C.

[0166] In other embodiments, at least one diamagnetic element may be made from pyrolytic carbon. Pyrolytic carbon is biocompatible and can be machined or evaporated directly onto the rod. Pyrolytic carbon, approximately 2-2.5 g / cm 3 , for example, about 2.25 g / cm 3 Pyrolytic carbon may have a density of about 2.7×10 -4 The magnetic material may have a volume magnetic susceptibility of

[0167] In some embodiments, the at least one diamagnetic element has a magnetic field strength of about -1.6×10 -4 The material may be made from bismuth, which has a volume magnetic susceptibility of 1000 nm. Bismuth is non-toxic and can be cast or extruded into wires.

[0168] Other suitable ferrodiamagnetic materials may be available to one of skill in the art For example, the use of diamagnetic metamaterials may allow for the use of less diamagnetic material.

[0169] According to another aspect, the present disclosure provides a method for manufacturing a magnetic marker. The method can include forming one or more ferromagnetic elements and at least one diamagnetic element, and then assembling the one or more ferromagnetic elements with the at least one diamagnetic element to form a marker. The one or more ferromagnetic elements and the at least one diamagnetic element can include respective volumes of ferromagnetic and diamagnetic materials selected as disclosed herein, such that in a sensing magnetic field, the one or more ferromagnetic elements are substantially more magnetized than the at least one diamagnetic element to generate a response magnetic field large enough to make the marker detectable in tissue using a handheld probe, while in an MRI magnetic field, the at least one diamagnetic element has a degree of magnetization strong enough to offset at least a substantial proportion of the magnetization of the one or more ferromagnetic elements, thereby minimizing the size of artifacts generated by the marker.

[0170] Preferably, the ferromagnetic material has a specific initial permeability of at least 10,000 and a saturation induction B of less than about 1.5 T. S The diamagnetic material may have a magnetic field strength of at least about −0.16×10 -4 The magnetic material may have a volume susceptibility of

[0171] The one or more ferromagnetic elements may be configured and arranged to maximize the strength and isotropy of a response magnetic field generated in response to the sense magnetic field. The at least one diamagnetic element may be configured and arranged to generate an artifact in the MRI magnetic field having a size and shape that matches the artifact size and shape of the artifact generated by the one or more ferromagnetic elements, at least to an extent sufficient to reduce a maximum dimension of the artifact generated by the marker to less than about 30 mm, preferably less than about 20 mm.

[0172] In yet another aspect of the disclosure, a method can include configuring and arranging one or more ferromagnetic elements and at least one diamagnetic element to generate mutually opposing magnetic moments in the presence of an applied magnetic field. The strength of the magnetic moment generated by the at least one diamagnetic element can be negligible in a sense magnetic field relative to the strength of the magnetic moment generated by the one or more ferromagnetic elements to allow the magnetic moment generated by the at least one ferromagnetic element to be detected by a probe, and can be as large as the strength of the magnetic moment generated by the one or more ferromagnetic elements in an MRI magnetic field, thereby minimizing the size of artifacts generated by the marker on an MRI image by canceling or substantially balancing the magnetic moments of the at least one ferromagnetic element.

[0173] In some embodiments, at least one diamagnetic element may be formed from graphite having an isotropic grain structure of the type disclosed herein. Suitably, the graphite may be of high purity and high density as disclosed herein.

[0174] In some embodiments, constructing and arranging one or more ferromagnetic elements and at least one diamagnetic element may include winding one or more ferromagnetic elements around a core or mandrel formed from at least one diamagnetic element. Thus, in one aspect of the disclosure, a method is provided for manufacturing a marker comprising a diamagnetic core received within a coil of one or more ferromagnetic wires or strips. The core may have an initial length that is several times the length of a single marker. One or more ferromagnetic wires or strips may be wound around the diamagnetic core. The ends of the wires or strips may be conveniently secured to the core at the beginning and end of the winding, for example, using an adhesive. The resulting assembly may then be divided into two or more segments, each segment having a length corresponding to the length of the marker. The segments may be divided from one another by cutting, for example, by mechanical, pressure, or thermal means, for example, with a blade, water jet, or laser. Alternatively, the diamagnetic core may be cut into separate segments prior to coil winding.

[0175] 5 is a schematic diagram of an implantable marker 401 according to a first embodiment of the present disclosure. The marker 401 includes three generally straight ferromagnetic wires formed from an iron-cobalt based alloy 403a, 403b, 403c that run along the outside of a diamagnetic core 405. It will be appreciated that in variations of this embodiment, fewer or more ferromagnetic wires may be used. The diamagnetic core 405 has a χ=-1.66×10 -4 The cylinder comprises isostatically pressed graphite and has a diameter of about 1 mm and a length of about 8 mm. The ferromagnetic wires 403a, 403b, 403c have an initial volume susceptibility value of about 72,000. Each wire 403a, 403b, 403c has a diameter of about 16 μm and a length of about 8 mm, and the wires 403a, 403b, 403c extend in a direction substantially parallel to the longitudinal axis of the core 405 such that the length of the wires substantially matches the length of the diamagnetic core 405. In the presence of the ferromagnetic wires, the diamagnetic core has a magnetic susceptibility of about -1.2×10 -4It is found to have an apparent volume magnetic susceptibility value of

[0176] At a sensed magnetic field of less than about 0.5 mT, the magnetic field generated by each of the wires 403a, 403b, 403c is approximately equal to the apparent magnetic susceptibility χ app,wire volume of wire V wire , and the magnetic moment generated by the diamagnetic core 405 is proportional to the apparent magnetic susceptibility χ of the core 405. app,core and its volume V core The quantity χ for the combination of wires 403a, 403b, and 403c is proportional to app,wire .3.V wire is about 4.6 x 10 -8 m 3 It can be calculated that the quantity X for the diamagnetic core 405 is app,core V core is approximately -1.0 x 10 -12 m 3 It can be calculated that the combined magnetic field generated by the ferromagnetic wires 403a, 403b, 403c in the sense magnetic field is therefore approximately 45,000 times larger than the magnetic moment generated by the diamagnetic core 405 (which is negligible in comparison).

[0177] When exposed to a 1.5 T MRI magnetic field, each of the ferromagnetic wires 403a, 403b, 403c reached induction saturation. Thus, the combined magnetic moment of the three wires 403a, 403b, 403c is given by:

number

number

[0178] FIG. 6(a) is a contour plot 507 of the magnetic flux B from a 3T MRI magnetic field B across the xz plane of the MRI scanner. y Deviation in |B-B0| y , which is due to the presence of the marker 401 of FIG. 5 in the MRI magnetic field. The contour lines represent lines of constant magnetic flux density deviation in the vicinity of the marker 401. As mentioned above, B crit is |B-B0| y , above which voxels are mapped to inaccurate slices of the MRI image. Therefore, B crit The contour lines in represent the contours of artifacts that may be produced in the xz plane for the marker 401 of FIG. 5 in an MRI magnetic field, with the axial length of the marker 401 oriented along the y axis. crit A value of B has been found to give reasonably good agreement between theoretical predictions and experimental data, but those skilled in the art may wish to consider crit It will be appreciated that depends on the configuration of the particular MRI device (e.g., slice thickness). Thus, FIG. 6(a) shows that B crit To show how the artifact size changes for different values ​​of |B-B0| y Other contours at different values ​​of are shown.

[0179] For comparison, FIG. 6(b) is a contour plot 511 showing the magnetic flux density B generated in the same MRI magnetic field B for the same configuration of ferromagnetic wirings 403a, 403b, 403c in the absence of the diamagnetic core 405. y Deviation in |B-B0| y Contour line 513 indicates B crit = 0.6 μT. The effect of the diamagnetic core on reducing the size of the artifact in the xz plane of FIG. 6(a) is self-evident.

[0180] 7 is a schematic diagram of a different implantable marker 601 according to a second embodiment of the present disclosure. Similar to the marker 401 of FIG. 5 described above, the marker 601 includes three ferromagnetic wires 603a, 603b, 603c, although in variants fewer or more wires may be used. However, in this embodiment, the ferromagnetic wires 603a, 603b, 603c extend axially through a diamagnetic core 605. The diamagnetic core 605 is substantially the same size and shape as the diamagnetic core 405 of FIG. 5, and has substantially the same properties. The core 605 therefore has a χ=-1,66×10 -4 The ferromagnetic wires 603a, 603b, 603c are substantially the same length and gauge as the wires 403a, 403b, 403c shown in FIG. 5. Thus, the ferromagnetic wires 603a, 603b, 603c have an initial volume susceptibility value of about 72,000. Each wire 403a, 403b, 403c has a diameter of about 16 μm and a length of about 8 mm, with the length of the wires substantially matching the length of the diamagnetic core 405.

[0181] FIG. 8 is a contour plot 707 similar to FIG. 6(a) showing the magnetic flux B from a 3T MRI magnetic field B across the xz plane of the MRI scanner due to the presence of the marker 601 of FIG. 7 in the MRI magnetic field. y Deviation in |B-B0| y 6(a) and 6(b), the axial length of the marker 601 is oriented along the y-axis. critThe contour line 709 at 0.6 μT, which may correspond to , thus represents the contour of an artifact that may be produced in the xz-plane of the marker 601 in an MRI magnetic field. By comparing the artifact of Figure 6(a) with that of Figure 8, it can be seen that the overall size and shape of the artifact in the xz-plane does not change significantly depending on whether the ferromagnetic wires 403a, 403b, 403c; 603a, 603b, 603c are positioned outside or inside the diamagnetic core 405.

[0182] 9 is a schematic diagram of another implantable marker 801 according to a third embodiment of the present disclosure. The marker 801 comprises a substantially cylindrical diamagnetic core 805 of isostatically pressed graphite or another suitable diamagnetic material as disclosed herein, having a diameter of about 1.15 mm and a length of about 8 mm. The diamagnetic core 805 has a magnetic field strength of about -1.2×10 -4 The marker 801 further comprises a ferromagnetic element consisting of a single helical coil wire 803 of an iron-cobalt based alloy. It will be understood that other ferromagnetic materials may be used as disclosed herein. The wire 803 has a diameter of about 15 μm and the helix has a length of about 8 mm (i.e., approximately the same length as the core 805). The helix has a pitch of about 1.2 mm. In a variation of this embodiment, multiple ferromagnetic wires may be wound around the diamagnetic core 805 in the form of multiple helices, for example double or triple helices. This allows for a longer pitch to increase the sensitivity of the marker, even if the same amount of wire is used, as disclosed herein.

[0183] FIG. 10(a) is a contour plot 907 similar to FIGS. 6(a) and 8, showing the magnetic flux B from a 3T MRI magnetic field B across the xz plane of the MRI scanner due to the presence of the marker 801 of FIG. 9 in the MRI magnetic field. y Deviation in |B-B0| y 6(a), 6(b) and 8, the axial length of the marker 801 is oriented along the y-axis. critThe contour line 909 at 0.6 μT, which may correspond to 0.5 μT, thus represents the contour of artifacts that may be generated in the xz plane of the marker 801 in an MRI magnetic field. For comparison, FIG. 10(b) shows the magnetic flux density B generated in the same MRI magnetic field B for the same ferromagnetic helix 803 in the absence of the diamagnetic core 805. y Deviation in |B-B0| y Contour line 913 indicates B crit = 0.6 μT. The effect of the diamagnetic core on reducing the size of the artifact in the xz plane of FIG. 10(a) is self-evident.

[0184] 11 is a schematic diagram of yet another implantable marker 1001 according to a fourth embodiment of the present disclosure. The marker 1001 has a substantially cylindrical diamagnetic core 905 of isostatically pressed graphite, having a diameter of about 1.15 mm and a length of about 8 mm. The diamagnetic core 1005 has a magnetic field strength of about -1.2×10 -4 The diamagnetic core 1005 has a cylindrical outer surface 1006 that supports three ferromagnetic elements 1004a, 1004b, 1004c. Each ferromagnetic element 1004a, 1004b, 1004c comprises a coil of wire of ferromagnetic iron-cobalt based material, the wire having a diameter of about 15 μm. As shown in FIG. 11, the coils are arranged to form a triple helix 1003 in which the respective wires 1004a, 1004b, 1004c do not touch each other. Suitably, the wires may be glued or otherwise held in place on the outer surface 1005. Each coil of the triple helix has a pitch of about 1.80 mm. Each coil of the triple helix 1003 comprises about 4.4 turns of wire, with the total number of turns of the triple helix 1003 being about 14.2. The total length of the ferromagnetic wire used for the triple helix is ​​about 52 mm.

[0185] In an MRI magnetic field of about 1.5 T, the total magnetic moment of the three ferromagnetic wires 1004a, 1004b, and 1004c is about 2.1×10 -6 Am 2 On the other hand, the magnetic moment of the diamagnetic core 1005 is calculated to be about -1.2×10 -6 Am2 Therefore, the net magnetic moment of the marker 1001 of this embodiment in a 1.5 T MRI magnetic field is about 8.7×10 -7 Am 2 FIG. 12(a) is a contour plot 1107 of the magnetic flux density B from a 3T MRI magnetic field B across the xz plane of the MRI scanner due to the presence of the marker 1001 of FIG. 11 in the MRI magnetic field. y Deviation in |B-B0| y The contour lines represent lines of constant magnetic flux deviation in the vicinity of the marker 1001. As mentioned above, B crit is |B-B0| y , above which a voxel will be mapped to an incorrect slice of the MRI image. Therefore, B crit The contour lines in represent contours of artifacts that may be produced in the xz plane for the marker 1001 of FIG. 11 in an MRI magnetic field, with the axial length of the marker 1001 oriented along the y axis. crit A value of B has been found to give reasonably good agreement between theoretical predictions and experimental data, but those skilled in the art may wish to consider crit It will be appreciated that depends on the configuration of the particular MRI device (e.g., slice thickness). Thus, FIG. 12(a) shows that B crit To show how the artifact size changes for different values ​​of |B-B0| y 4 shows other contours at different values ​​of .

[0186] For comparison, FIG. 12(b) shows the magnetic flux density B generated for the same configuration of ferromagnetic wires 1004a, 1004b, 1004c in the same MRI magnetic field B when the diamagnetic core 1005 is not present. y Deviation in |B-B0| y Contour line 1113 indicates B crit = 0.6 μT. The effect of the diamagnetic core on reducing the size of the artifact in the xz plane of FIG. 12(a) is self-evident.

[0187] When using a triple helix 1003, the coils of the helix have a larger component in that direction along the axial length of the marker, allowing the pitch to be longer to increase the axial sensitivity of the marker even if the same amount of wire is used in a given axial length as with a single helix. A pitch of about 1.80 mm has been found to provide sufficient lateral sensing performance while having good axial sensing performance due to the longer pitch. In this embodiment, the marker has an axial sensing distance of about 34 mm and a lateral sensing distance of about 34 mm.

[0188] 13 is a flow chart showing a method 1100 of manufacturing a marker according to a fifth embodiment of the present disclosure. In a first step 1101, the method includes providing at least one ferromagnetic element and at least one diamagnetic element. In a second step 1103, the method includes configuring and arranging the one or more ferromagnetic elements and the at least one diamagnetic element in juxtaposition to each other to generate mutually opposing magnetic moments in the presence of an applied magnetic field. The strength of the magnetic moment generated by the at least one diamagnetic element is relatively very low in a sensing magnetic field of less than about 0.5 mT, thereby allowing the magnetic moment generated by the at least one ferromagnetic element to be detected by the probe, and is relatively high in an MRI magnetic field of 1.5 T or more, thereby minimizing the size of the artifact generated by the marker on the MRI image by canceling the magnetic moment of the at least one ferromagnetic element.

[0189] The ferromagnetic material configured to the required shape may then be enclosed within a cylindrical housing. The cylindrical housing is preferably injectable to allow for placement of the marker. Preferably, the housing may therefore have a maximum diameter such that it is deployable through a narrow gauge needle, for example 18G to 12G, as disclosed above. The marker may be packaged within other materials or may be coated to ensure that the marker is biocompatible and robust. The marker may be enclosed within a tube made, for example, of Nitinol, titanium, stainless steel, or other biocompatible alloys, the material being preferably non-magnetic and having a relatively low electrical conductivity. The low electrical conductivity may be less than 10 6 It may include electrical conductivity below Siemens. Suitable coating materials include polymeric coatings such as Invar, FEP, Parylene, PTFE, ETFE, PE, PET, PVC or silicone, or epoxy-based encapsulants.

[0190] Those skilled in the art will appreciate that features of the above-described embodiments may be combined in other embodiments that are within the scope of the present disclosure.

[0191] In the above description, integers or elements having known obvious or foreseeable equivalents are referred to, and such equivalents are incorporated herein as if set forth individually. Reference should be made to the claims to determine the true scope of the present disclosure, and the claims should be interpreted to encompass any such equivalents. It will also be understood by the reader that integers or features of the present disclosure described as advantageous, convenient, etc. are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that such optional integers or features may be beneficial in some embodiments of the present disclosure, but may not be desirable and therefore may not be present in other embodiments.

Claims

1. 1. An implantable susceptometry marker for use in a surgical guide, comprising one or more ferromagnetic elements and at least one diamagnetic element, the one or more ferromagnetic elements are formed from at least one ferromagnetic material having a specific initial permeability of at least about 10,000 and a saturation induction Bs of less than about 1.5 T; The at least one diamagnetic element has a magnetic field strength of at least about −0.16×10 －４ and formed from at least one diamagnetic material having a volume susceptibility of The total volume of the diamagnetic material within the marker is about 100 to 10,000 times greater than the total volume of the ferromagnetic material. An implantable susceptometry marker comprising:

2. The diamagnetic material has a magnetic field strength of about -0.16×10 －４ ~Approx.-3×10 －４ 2. The implantable susceptometry marker of claim 1, having a volume magnetic susceptibility in the range of

3. The total volume of ferromagnetic material within the marker is approximately 1×10 －１２ m ３ ~1×10 －１０ m ３ The implantable susceptometry marker according to claim 1 or 2, characterized in that

4. The total volume of diamagnetic material within the marker is approximately 1×10 －９ m ３ ~Approx. 1.5×10 －７ m ３ The implantable susceptometry marker according to any one of claims 1 to 3, characterized in that

5. The implantable susceptometry marker according to any one of claims 1 to 4, characterized in that the one or more ferromagnetic elements and the at least one diamagnetic element are co-located.

6. An implantable susceptometry marker according to any one of claims 1 to 5, characterized in that the one or more ferromagnetic elements comprise one or more wires or strips.

7. 7. The implantable susceptometry marker of claim 6, wherein the one or more wires or strips have a total length to diameter (or width or square root of the cross-sectional area of ​​the wire or strip) ratio of at least about 50.

8. The implantable susceptometry marker of any one of claims 1 to 7, wherein the ferromagnetic material and the diamagnetic material are present in respective volumes, and in an MRI magnetic field, the one or more ferromagnetic elements and the at least one diamagnetic element generate opposing magnetic moments, the smaller of which is at least about 25% of the stronger of the amplitudes.

9. The implantable susceptometry marker of any one of claims 1 to 8, wherein the ferromagnetic material and the diamagnetic material are present in respective volumes, and the amplitude of a magnetic moment generated by at least one of the one or more ferromagnetic elements and each of the at least one diamagnetic element is within about 75% of the amplitude of a magnetic moment generated by the other of the at least one diamagnetic element and each of the one or more ferromagnetic elements under at least two different MRI magnetic fields.

10. 10. The implantable susceptometry marker according to any one of claims 1 to 9, characterized in that the at least one ferromagnetic material is selected from cobalt-based amorphous metals, manganese-zinc ceramic ferrites, nickel-iron-based soft ferromagnetic alloys and nickel-zinc ceramic ferrites.

11. 11. An implantable susceptometry marker according to any one of claims 1 to 10, characterized in that the diamagnetic material of the at least one diamagnetic element is selected from pyrolytic graphite, graphite, in particular graphite with a substantially isotropic grain structure, and bismuth.

12. An implantable susceptometry marker according to any one of claims 1 to 11, characterized in that the one or more ferromagnetic elements individually or collectively extend along at least 80% of the length of the at least one diamagnetic element.

13. The implantable susceptometry marker according to any one of claims 1 to 12, characterized in that the length of said at least one diamagnetic element is approximately the same as the overall length of said one or more ferromagnetic elements.

14. The implantable susceptometry marker of any one of claims 1 to 13, characterized in that the diameter of the at least one diamagnetic element is approximately the same as the overall diameter of the one or more ferromagnetic elements.

15. An implantable susceptometry marker according to any preceding claim, characterized in that at least one of the one or more ferromagnetic elements comprises a helical wire coil.

16. 16. The implantable magnetic marker of claim 15, wherein the marker includes a plurality of ferromagnetic elements arranged as multiple helices.

17. An implantable susceptometry marker according to any one of claims 1 to 16, characterized in that the at least one diamagnetic element has the form of a cylinder.

18. 20. The implantable susceptometry marker of claim 17, wherein the one or more ferromagnetic elements comprise one or more wires or strips wrapped around an outer surface of a cylinder in the form of a spiral or multiple spirals.

19. 1. A method of manufacturing an implantable susceptometry magnetic marker for use in surgery, comprising: forming one or more ferromagnetic elements from at least one ferromagnetic material having a specific initial permeability of at least 10,000 and a saturation induction Bs of less than about 1.5 T; forming at least one diamagnetic element from at least one diamagnetic material, the at least one diamagnetic material having a magnetic field strength of at least about −0.16×10 －４ wherein the total volume of the diamagnetic material is about 100 to 10,000 times greater than the total volume of the ferromagnetic material; and thereafter, assembling the one or more ferromagnetic elements and the at least one diamagnetic element, the at least one diamagnetic element being co-located with the one or more ferromagnetic elements and configured to generate, in an MRI magnetic field, an artifact having a size and shape that substantially matches a size and shape of an artifact generated by the one or more ferromagnetic elements. A method comprising:

20. 1. A susceptometry measurement detection system for identifying the location of an implanted marker, comprising: An implantable susceptometry marker according to any one of claims 1 to 18; at least one drive coil arranged to excite the implantable marker with an alternating magnetic field and at least one sense coil arranged to detect signals received from the excited marker; a magnetic field generator arranged to drive an alternating magnetic field through the at least one drive coil; and at least one detector positioned to receive a signal from the sensing coil and detect one or more harmonics of the drive frequency in the received signal; A system comprising:

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