Improvements in or relating to implantable ferromagnetic markers

Abstract

An implantable marker for use in a surgical guide is provided, the implantable marker including one or more ferromagnetic elements formed from at least one ferromagnetic material and at least one diamagnetic element formed from at least one diamagnetic material, the at least one diamagnetic material including graphite having a substantially isotropic grain structure, and the one or more ferromagnetic elements juxtaposed with the at least one diamagnetic element.

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 by susceptometry using a probe that emits a magnetic field. The present disclosure also relates to methods of making such markers. [Background technology]

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

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

[0004] A different approach, exemplified by U.S. Patent Nos. 5,629,999, 5,749,963, 5,769,973, and 5,823,526, uses a magnetic field and a ferromagnetic marker with high initial magnetic susceptibility. A handheld probe generates an alternating driving magnetic field ("sensing field") that excites the magnetically responsive marker, generating a responsive magnetic field that can be detected by the probe using susceptometry. Preferably, the probe is configured to generate a sensing field with a source strength 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 highly effective for deeper sensing to localize tumors, typically less than about 20 mm in diameter, and avoids the drawbacks of RF approaches. However, in MRI settings using much stronger magnetic fields, such as 1.5 T or 3 T, this approach can lead to the generation of undesirable artifacts as a result of the ferromagnetic material, which is large compared to the marker itself and can obfuscate MRI images.

[0005] MRI is used to image invasive breast cancer lesions not visible on ultrasound or mammography. MRI monitoring is increasingly being used to evaluate neoadjuvant therapy before surgical resection, allowing tumor size to be tracked after neoadjuvant therapy and before surgery. MRI artifacts from such markers should not impair medical professionals' assessment of tumor size, as a reduction in tumor size provides a positive option in the management of cancer patients. In this regard, breast cancer stage is typically assessed using several criteria, including tumor size, whether the tumor has spread to lymph nodes, and whether the cancer has spread (metastasized) to other parts of the body. For early-stage cancer, where breast-conserving surgery using lumpectomy may be considered, tumor size is preferably 2 cm or less. Non-Patent Document 1 indicates that smaller tumor size represents a favorable prognostic factor, and residual tumors >2 cm are associated with a high rate of local tumor recurrence after neoadjuvant chemotherapy. Non-Patent Document 2 indicates that tumors 2 cm or less in size are classified as T1, which typically corresponds to cancer stage 1 or 2, in which breast-conserving surgery can be considered. Larger tumors are more likely to require more radical surgery, such as mastectomy. Therefore, it is highly desirable to be able to determine the size of tumors under MRI when the diameter of the tumor is greater than 2 cm, allowing for evaluation of whether the tumor has shrunk to a size that allows breast-conserving surgery.

[0006] Ferromagnetic materials are well known to produce MRI distortions, and these are widely documented in the scientific literature. For example, [3] explains that some ferromagnetic materials may be MRI-safe, but will still produce significant artifacts. The artifacts are caused by the component of the magnetic field (B) produced by a ferromagnetic object that is in the same direction as the principal y-axis magnetic field produced by the MRI machine, as explained in more detail below. y ) is mainly produced by B 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] Non-Patent Document 4 has investigated options for reducing 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. These options rely on the fact that paramagnetic and diamagnetic materials have similar magnetic susceptibilities, so that the effect of a given volume of paramagnetic material can be offset by a similar volume of diamagnetic material. However, they are not promising for use with implantable magnetic markers, which typically contain ferromagnetic materials with magnetic susceptibilities 10 to 100 million times greater than diamagnetic materials.

[0008] Bismuth, a well-known diamagnetic material, has a magnetic field strength of approximately -1.66 × 10 -4 , but is unsuitable for use in implantable markers due to toxicity concerns and difficulty in machining (it is relatively soft and inflexible). Graphite, on the other hand, has a volume magnetic susceptibility of about -0.16 x 10 -4 It has been reported that [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2011 / 067576 [Patent Document 2] International Publication No. 2014 / 013235 [Patent Document 3] International Publication No. 2013 / 140567 [Non-patent literature]

[0010] [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]

[0011] Therefore, there is a need in the art for an implantable ferromagnetic marker that has good isotropy of sensing response, long sensing range, while exhibiting low 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 drawbacks. [Means for solving the problem]

[0012] According to a first aspect, there is provided an implantable marker for use in a surgical guide, comprising one or more ferromagnetic elements formed from at least one ferromagnetic material and at least one diamagnetic element formed from at least one diamagnetic material; the at least one diamagnetic material comprises graphite having a substantially isotropic grain structure (i.e., isotropic graphite).

[0013] The one or more ferromagnetic elements can be positioned in juxtaposition with at least one diamagnetic element, meaning that the diamagnetic and ferromagnetic elements are positioned adjacent to one another within the marker. Surprisingly, it has been found that the presence of one or more ferromagnetic elements in close proximity to at least one diamagnetic element increases the apparent volume magnetic susceptibility of graphite. For example, graphite has a magnetic susceptibility of approximately -0.16 x 10 -4 Although it has been reported in the literature to have a bulk magnetic susceptibility of about -1.2 × 10 in the presence of one or more ferromagnetic elements, its apparent bulk magnetic susceptibility is reduced to about -1.2 × 10 -4 It has been found that the magnetic susceptibility increases (becomes more negative) until the magnetic field reaches a certain value. Without wishing to be bound by any particular theory, it is believed that in the presence of a magnetic field, e.g., an MRI field of 1.5 T or greater, one or more ferromagnetic elements enhance the magnetic field in at least one diamagnetic element, resulting in a stronger apparent volume magnetic susceptibility. This surprising effect has been demonstrated in isotropic graphite, but other diamagnetic materials, such as bismuth, and indeed anisotropic graphite, have not demonstrated the same enhancement.

[0014] Furthermore, graphite with a substantially isotropic particle structure has a substantially isotropic magnetic response, making it suitable for use in implantable markers where the orientation of the marker within the body necessarily changes with each procedure. Isotropic graphite exhibits high (negative) volume susceptibility in all directions of observation. As a result, the use of isotropic graphite provides a more predictable reduction in marker artifact size (regardless of the marker's orientation).

[0015] In some embodiments, all or most of the diamagnetic material of the marker may comprise graphite having a substantially isotropic grain structure. Typically, there may be only one diamagnetic material. In other words, the diamagnetic element may be composed solely of graphite having an isotropic grain structure (grains substantially randomly oriented).

[0016] The inventors have discovered that graphite having a substantially isotropic grain structure has magnetic properties suitable for use as a diamagnetic material in the diamagnetic elements of a marker. It has been discovered that the use of graphite as a diamagnetic material enables the manufacture of a marker in which at least one diamagnetic element has a negative magnetic susceptibility large enough to generate a magnetic moment of sufficient amplitude in an MRI magnetic field, and substantially reduces (e.g., to less than about 30 mm) the size of MRI artifacts caused by the magnetization of one or more ferromagnetic elements that have an initial magnetic permeability and are present in a sufficient volume to be detectable under susceptometry with a detection range useful for surgery. Furthermore, graphite in its various forms tends to be biocompatible and easily machined.

[0017] Suitable ferromagnetic materials have a high relative initial permeability and reach inductive saturation above a threshold applied magnetic field. For example, at least one ferromagnetic material can have a relative initial permeability of at least about 1,000. In some embodiments, the ferromagnetic material can have a relative initial permeability of at least about 10,000, at least about 50,000, or at least about 70,000. In some embodiments, the ferromagnetic material can have a relative initial permeability of up to about 100,000 or even higher.

[0018] On the other hand, graphite has an initial relative permeability at least seven orders of magnitude lower than that of ferromagnetic materials and does not saturate. In accordance with the present disclosure, it has been found that the above properties of materials can be advantageously utilized to provide an implantable marker for generating a response magnetic field large enough to enable the marker to be detected by susceptometry in tissue using a handheld probe having a practically useful range, in which one or more ferromagnetic elements are substantially more magnetized than at least one diamagnetic element in a sensing field; and in an MRI magnetic field, one or more ferromagnetic elements saturate, thereby increasing the magnetization to a saturation induced B s , but the at least one diamagnetic element, whose magnetization is not limited by saturation, has a magnetization strong enough to cancel all or at least a significant 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 resulting in MRI images in the x-z plane of the MRI scanner.

[0019] Thus, in the sensing 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.

[0020] It has been found that implantable markers comprising graphite as the diamagnetic material exhibit good reduction in marker MRI artifact size (e.g., in MRI images in the xz plane of an MRI scanner) and can further be manufactured to be suitably small.

[0021] The graphite is advantageously present at a density of about 1.2 to about 1.9 g / cm 3 The density may range from 0.1 to 1000 .mu.m.

[0022] Graphite may have a relatively high bulk magnetic susceptibility compared to common diamagnetic materials. Thus, graphite may have a bulk magnetic susceptibility of at least about −0.16×10 -4In the markers of the present disclosure, the graphite in the presence of one or more ferromagnetic elements may have a volume (negative) magnetic susceptibility of about 0.9×10 -4 Super, for example, about 1 × 10 -4 Ultra, for example, about 1.2 x 10 -4 In some embodiments, the graphite may have an apparent volume (negative) magnetic susceptibility of about 1×10 -4 ~Approx. 3×10 -4 The graphite can be advantageously manufactured to have a volume (negative) magnetic susceptibility in the above range.

[0023] Thus, at least one diamagnetic element has a volume susceptibility large enough to generate a magnetic moment of sufficient amplitude in an MRI magnetic field, and can substantially reduce the size of MRI artifacts caused by magnetization of one or more ferromagnetic elements (e.g., in an MRI image in the xz plane of an MRI scanner), preferably to less than 30 mm, and more preferably to less than 20 mm.

[0024] Preferably, the graphite may be isostatically pressed graphite. Isostatically pressed graphite is graphite formed by isostatic pressing, resulting in an isotropic grain structure (with grains substantially randomly oriented). This is in contrast to other manufacturing techniques, such as extrusion and compression molding, which can result in an anisotropic grain structure. During the process, a raw material mixture is compressed into a block using a so-called cold isostatic press. This technique can produce the most isotropic form of artificial graphite. Isostatically pressed graphite has a relatively isotropic grain structure, high density, high strength, and a fine grain structure compared to other forms of graphite.

[0025] While isostatically pressed graphite is generally known, its use in magnetic markers for surgical guides is unknown. Its desirable properties have long been recognized: high thermal and chemical resistance, good thermal shock resistance, high electrical conductivity, high thermal conductivity, increasing strength with increasing temperature, good corrosion resistance, high dimensional accuracy and surface quality, and ease of processing for applications such as electrodes for electrical discharge machining, electrodes used in semiconductor and solar cell manufacturing, molds and parts for glass casting and aluminum manufacturing, and dies used in the continuous casting of various metals and alloys. Until now, isostatically pressed graphite has been used primarily for its mechanical and thermal properties. The inventors have discovered that isostatically pressed graphite possesses useful, previously unrealized magnetic properties that make it particularly suitable for use in the field of surgical magnetic markers. In particular, it has been discovered that isostatically pressed graphite provides a highly diamagnetic material.

[0026] Isostatically pressed graphite has surprisingly been found to have properties that make it particularly suitable for use as a diamagnetic material in diamagnetic elements. In particular, it has been found to have a suitably high isotropic magnetic susceptibility (equivalent magnetic susceptibility along all axes). This offers a significant advantage over other forms of graphite, such as graphite formed by extrusion or compaction, in that the anisotropic grain structure results in stronger magnetic susceptibility along the axis perpendicular to the grain orientation compared to the axis parallel to the grain direction. Because the orientation of implanted markers in clinical settings cannot be controlled, and therefore marker artifacts within the patient cannot be controlled, isotropic magnetic susceptibility is desirable when used to counteract the effects of ferromagnetic markers, for example, because it results in a reduction in marker artifact size in MRI images in the x-z or y-plane (direction of the magnetic field) of an MRI scanner. This effect exists regardless of the orientation of the implanted marker. Therefore, isostatically pressed graphite offers advantages over other anisotropic forms of graphite and other diamagnetic materials in general when used as a diamagnetic material in diamagnetic elements. Additionally, isostatically pressed graphite is easy to manufacture and machine, and can be non-toxic or biocompatible.

[0027] Isostatically pressed graphite has a viscosity of at least about -1.2 × 10 -4 Surprisingly, isostatically pressed graphite has a bulk magnetic susceptibility of about 1.2 × 10 -4 It has been found that isostatically pressed graphite has a bulk (negative) magnetic susceptibility on the order of 1 / 2 of a micrometer, provides good isotropic magnetic susceptibility, while being inexpensive, easily machineable into shapes, and has good biocompatible properties. It is believed that the particularly good isotropic magnetic susceptibility of isostatically pressed graphite can be attributed to its isotropic grain structure (graphite is made from multiple randomly oriented grains).

[0028] Preferably, the graphite should have high purity, e.g., less than 500 ppm, e.g., less than 300 ppm, e.g., less than 50 ppm of impurities. Isostatically pressed graphite can be conveniently produced in suitable grades containing less than 5 ppm of impurities. Isostatically pressed graphite can contain more than 99.9% carbon. Higher purity has been found to advantageously increase magnetic susceptibility, since it allows for a greater amount of diamagnetic material for a given volume, thus increasing the diamagnetic response. Furthermore, if the impurities have paramagnetic susceptibility, removing the impurities avoids a decrease in diamagnetic response. A further possible effect is that higher purity may allow for the formation of a better, more appropriate crystal structure.

[0029] The inventors have further realized that high-density graphite can advantageously provide a stronger diamagnetic effect in a given volume due to the increased amount of diamagnetic material present. In other words, diamagnetic elements containing high-density graphite can provide increased diamagnetic artifact size compared to low-density graphite, leading to a further reduction in overall diamagnetic artifact size. Similarly, low-porosity graphite has been found to be advantageous for similar reasons, maximizing the amount of diamagnetic material present in a given volume.

[0030] Thus, in some embodiments, the graphite has a density 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 / cm3. -3 ~Approx. 1.95g / cm -3 Densities in the range of 0.15 to 0.5% imply low porosity (7-17%). The diamagnetic effect is approximately 1.8 g / cm. -3 This can be advantageously increased for ultra-high densities, with a corresponding increase in diamagnetic artifact size (better offsetting ferromagnetic artifact size and reducing the resulting ferromagnetic artifact size).

[0031] The graphite may have a porosity of less than 20%, more preferably less than 15%.

[0032] Advantageously, the composition of the graphite can be optimized to produce a material grade that optimally reduces MRI artifacts in the magnetic marker by increasing the diamagnetic effect of the graphite contained in the diamagnetic element. For example, graphite grades with high density (e.g., 1.8 g / cm -3 The graphite may be ultra-pure graphite (containing less than 5 ppm impurities) with a high purity (greater than 10 ppm) and corresponding low porosity (e.g., less than 15%).

[0033] The isostatically pressed graphite may be heat-treated graphite. The isostatically pressed graphite may be treated at high temperatures, such as temperatures above about 2,000°C, more preferably above about 2,200°C. In particular, the temperature of the graphite may be increased during or after pressing. Heat treatment at high temperatures has been found to advantageously increase the magnetic susceptibility of graphite, thereby reducing the size of magnetic artifacts in MRI fields. It is believed that heat treatment may improve graphite grain structure (e.g., by increasing grain size) and increase purity.

[0034] Isostatically pressed graphite can have a finer grain structure, in other words, a finer grain structure than graphite produced by other methods, such as extrusion or compression molding.

[0035] Thus, isostatically pressed graphite may have a grain size of less than 20 microns, e.g., less than 15 microns, e.g., less than 10 microns. The inventors understand that a finer grain structure may result in smaller-sized magnetic artifacts in the MRI magnetic field; for example, when the main magnetic field is defined by an MRI machine oriented along the y-axis and taken in the xz plane. It is believed that the smaller grain size along with the isotropic grain structure of isostatically pressed graphite may enable good isotropic magnetic susceptibility (e.g., due, at least in part, to the low degrees of freedom of electron movement within the graphite material). For example, isostatically pressed graphite may have a magnetic anisotropy ratio of about 7 or less.

[0036] The at least one diamagnetic element may be configured and arranged to generate, in an MRI magnetic field, an artifact having a size and shape that matches to a sufficient extent the artifact size and shape of the artifact generated by the one or more ferromagnetic elements, e.g., as disclosed above; for example, reducing the maximum dimension of the artifact generated by the marker to less than about 30 mm when defined by an MRI device whose main magnetic field is oriented along the y-axis and taken in the xz-plane.

[0037] Preferably, the total volume of diamagnetic material within the marker is about 100 to about 10,000 times greater than the total volume of ferromagnetic material, such as about 900 times greater. Preferably, at least one diamagnetic element has a total volume that is about 100 to 10,000 times greater; preferably about 500 to 3,000 times greater, such as about 900 times greater, than the volume of the one or more ferromagnetic elements.

[0038] The amount of diamagnetic material can be selected to minimize the net magnetization of the marker in the MRI field without "overcompensating" for the ferromagnetic material and thereby producing unacceptably large artifacts due to the diamagnetic material. MRI devices are available in different magnetic field strengths, typically ranging from about 0.5 T to about 3 T (although magnetic fields up to about 7 T are known for clinical applications). Thus, in some embodiments of the present disclosure, a marker may contain 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 to 10 T, and preferably about 1 to 5 T; for example, about 1.5 T and about 3 T. For example, a marker may contain amounts of ferromagnetic and diamagnetic material that result in near-zero net magnetization at one MRI magnetic field strength, while having a net magnetization that produces acceptably small artifacts at another MRI magnetic field strength. Alternatively, a marker may contain 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" particularly means less than about 30 mm, preferably less than about 20 mm in an MRI image on the xz plane of an MRI device.

[0039] Preferably, in an MRI magnetic field, the opposing magnetic moments generated by the one or more ferromagnetic elements or at least one diamagnetic element, respectively, may have an amplitude that is at least 25%, preferably at least 50%, of the amplitude of the magnetic moment generated by the at least one diamagnetic element or one or more ferromagnetic elements, respectively; artifacts generated by the marker in an MRI magnetic field may be less than about 30 mm, preferably less than about 20 mm, in their longest dimension.

[0040] The one or more ferromagnetic elements and the at least one diamagnetic element may be co-located, where "co-located" means that the one or more ferromagnetic elements and the at least one diamagnetic element are constructed and arranged to occupy and extend across substantially the same space (or volume) within the marker.

[0041] Additionally, the at least one diamagnetic material may have an apparent volume susceptibility such that, in an MRI magnetic field, the one or more ferromagnetic elements and the at least one diamagnetic element generate opposing magnetic moments whose smaller amplitude is at least about 25% of the larger amplitude. As disclosed herein, a sufficient volume of diamagnetic material can be used to generate a magnetic moment having an amplitude that is within at least 75% of the amplitude of the opposing magnetic moments generated by the one or more ferromagnetic elements, i.e., the magnetic moment generated by the diamagnetic material has an amplitude that is within about 25% to about 175% of the amplitude of the opposing magnetic moments generated by the one or more ferromagnetic elements.

[0042] In some embodiments, the marker includes 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 about 50%, of the corresponding magnetic moment generated by the other. Thus, in some embodiments, the magnetic moments generated by the diamagnetic material can have amplitudes that are within about 25% to about 175%, preferably about 50% to about 150%, of the corresponding amplitudes of the opposing magnetic moments generated by one or more ferromagnetic elements under at least two different MRI magnetic fields. Therefore, preferably, the magnetic moments generated by at least one diamagnetic element under at least two different MRI magnetic fields are at least 25% or greater than the corresponding magnetic moments generated by one or more ferromagnetic elements under each of the two different MRI magnetic fields. In this way, the amounts of ferromagnetic and diamagnetic materials in the marker can 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.

[0043] As noted above, the sensing field may suitably have 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, producing a magnetic field strength of about 40 μT to about 400 μT within about 5 mm of the probe. Advantageously, this may allow markers to be detected at ranges up to about 50 mm, about 60 mm, about 70 mm, or even up to about 80 mm from the probe.

[0044] The MRI magnetic field typically has a strength of 1.5 T. Suitably, the one or more ferromagnetic elements are constructed and arranged to generate a response magnetic field of sufficient magnitude to enable the marker to be detected in tissue using a handheld probe, as disclosed herein, in a sensing 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 or more times weaker.

[0045] The one or more ferromagnetic 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 of sufficient magnitude to enable the marker to be detected in tissue using a handheld probe in a sensing field at least 1,000 times weaker than the marker.

[0046] In some embodiments, the one or more ferromagnetic elements are about 1×10 -10 m 3 less than about 5 x 10 -11 m 3 Less than 3 x 10 -11 m 3 Less than or equal to 1 x 10 -11 m 3 Less than, say 6 x 10 -12 m 3 In some embodiments, the one or more ferromagnetic elements can have a total volume of about 1×10 -12 m 3 Typically, the total volume of the at least one diamagnetic element is about 1×10 -9 m 3 ~1.5×10 -7 m 3 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 marker may have a width ranging from about 0.8 mm to about 3 mm, preferably about 1 to 1.5 mm. The marker may have a length ranging from about 2 to 10 mm, e.g., 5 mm.

[0047] The implantable marker may comprise one or more pieces of ferromagnetic material. The one or more pieces may comprise one or more wires or strips. Preferably, the wire or strip has a total length to diameter ratio, or ratio of length to square root of cross-sectional area, of at least about 50. Preferably, the wire or strip has a length in the range of 30-40 mm, e.g., about 36 mm.

[0048] In some embodiments, one or more ferromagnetic elements can have a total length to diameter (or square root of cross-sectional area) ratio of greater than 100, greater than 500, greater than 1000, or greater than 2000, such as about 2400. In some embodiments, one or more ferromagnetic elements can have a total length to diameter (or square root of cross-sectional area) ratio of greater than 3000.

[0049] It has been found that increasing the length to diameter (or root of cross-sectional area) ratio of at least one piece of ferromagnetic material improves the sensing response of the marker, thereby allowing a smaller volume of ferromagnetic material to be used for a given response field, which results in smaller MRI artifacts.

[0050] In some embodiments, the one or more pieces of ferromagnetic material are 1×10 -10 m 3 Less than 5 x 10 -11 m 3 Less than, for example, 1 x 10 -11 m 3 Less than, for example, about 5 x 10 -12 m 3 The total volume of the sintered body may be 10 ...

[0051] Preferably, the 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 the marker may be configured to achieve a ratio of magnetic flux anisotropy of less than 7, preferably less than 5. Preferably, one or more ferromagnetic elements of the markers of the present disclosure may be configured as disclosed herein, for example, as a helix or multiple helix.

[0052] Those skilled in the art will understand that to maximize the 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, at least one diamagnetic element may be advantageously configured and arranged to generate artifacts in the MRI magnetic field having a shape similar to that of the artifacts generated by the one or more ferromagnetic elements but of opposite polarity. 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 those available from COMSOL AB (Sweden) under the trademark COMSOL Multiphysics® or from ANSYS, Inc. (Canonsburg, Pennsylvania) under the trademark ANSYS®, to generate simulated contour maps of the respective artifacts generated by the one or more ferromagnetic elements and at least one diamagnetic element in the MRI magnetic field and iteratively adjust the configuration and arrangement of the elements until the contour maps substantially match. Preferably, the at least one diamagnetic element may be configured, for example, as a cylinder, as disclosed herein. One or more ferromagnetic elements may be wrapped around the outer surface of the cylinder as a spiral or multiple spirals in some implementations of the present disclosure.

[0053] The one or more ferromagnetic elements and the at least one diamagnetic element can comprise respective volumes of ferromagnetic and diamagnetic material selected such that, in a sensing 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 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 produced by the marker as disclosed herein.

[0054] 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 the sensing field.

[0055] According to a second aspect, there is provided an implantable marker comprising one or more wires or strips formed from a ferromagnetic material, the wires or strips being disposed around or extending axially through a diamagnetic core; the diamagnetic core having a magnetic field strength of at least about −1.2×10 -4 The magnetic core comprises at least one body of isostatically pressed graphite having an apparent volume magnetic susceptibility of 0.015 to 0.015. Accordingly, one or more ferromagnetic wires or strips are arranged in juxtaposition to the diamagnetic core. The one or more ferromagnetic wires or strips may be arranged to be co-located with the diamagnetic core, for example, extending along the entire length of the diamagnetic core.

[0056] Preferably, the body of isostatically pressed graphite may be substantially cylindrical.

[0057] In some embodiments, the wire or strip formed from the ferromagnetic material may be generally straight and may be disposed around the outside of the diamagnetic core.

[0058] In some embodiments, the implantable marker may comprise one or more helical coils of wire formed from a ferromagnetic material disposed around a diamagnetic core.

[0059] Preferably, the implantable marker may include a single helical coil of wire disposed around the outside of a diamagnetic core. Alternatively, the implantable marker may comprise two, three, four, or more coils of wire disposed as multiple (e.g., triple) helices around the outside of a diamagnetic core.

[0060] The diamagnetic core may have a diameter of about 1 mm, e.g., about 1.2 mm, and a length in the range of 4-9 mm, e.g., about 5 mm. The overall length of the marker may correspondingly be in the range of 4-9 mm, e.g., about 5 mm.

[0061] The wires or strips may each have a diameter of about 15 μm or less.

[0062] According to a third aspect of the present disclosure, there is provided a method of manufacturing an implantable magnetic marker for use in surgery, the method comprising: forming one or more ferromagnetic elements from at least one ferromagnetic material; forming at least one diamagnetic element, the at least one diamagnetic element comprising graphite having a substantially isotropic grain structure; and then assembling the one or more ferromagnetic elements and the at least one diamagnetic element such that the one or more ferromagnetic elements are juxtaposed to the at least one diamagnetic element; the one or more ferromagnetic elements and the at least one diamagnetic element are configured and arranged to generate mutually opposing magnetic moments in the presence of an applied magnetic field. The implantable marker may be an implantable marker according to the first or second aspect of the present disclosure.

[0063] The one or more ferromagnetic elements and at least one diamagnetic element may be assembled such that the at least one diamagnetic element is co-located with the one or more ferromagnetic elements, e.g., extending across the same length or volume of the marker.

[0064] The graphite may be isostatically pressed graphite, and the method may include performing an isostatic pressing process to produce the isostatically pressed graphite. Advantageously, such a method results in an isotropic grain structure in the graphite, i.e., the method results in the physical properties of the resulting material being isotropic. The isostatically pressed graphite thus produced advantageously has a relatively high density, high strength, and a fine grain structure.

[0065] The method can further include heat treating the graphite. Heat treating can increase the magnetic susceptibility of the isostatically pressed graphite (by aiding in the formation of a carbon-carbon structure). Heat treating can increase the density of the isostatically pressed graphite.

[0066] Heat treatment can reduce the level of impurities in isostatically pressed graphite. The heat treatment step can be performed simultaneously with or after the graphite is pressed or extruded. The heat treatment step can be performed at temperatures in excess of 2,200°C.

[0067] According to a fourth 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 magnetic moment of the marker in an MRI magnetic field, thereby minimizing the size of artifacts produced by the marker. Preferably, the present disclosure may encompass the use of graphite having a substantially isotropic grain structure in at least one diamagnetic element juxtaposed with one or more ferromagnetic elements in the implantable marker. For example, the at least one diamagnetic element may be co-located with one or more ferromagnetic elements in the implantable marker, meaning that the one or more ferromagnetic elements and the at least one diamagnetic element are constructed and arranged to occupy and extend across substantially the same space (or volume) within the marker.

[0068] The use of graphite as the diamagnetic material (typically the only or predominant diamagnetic material) in the diamagnetic element has been found to be particularly effective in counteracting the effects of strong ferromagnetic susceptibility markers, resulting in a significant reduction in marker artifact size. Graphite can be manufactured to have properties, such as density, that result in a desired relatively high magnetic susceptibility. When the graphite is isostatically pressed graphite, it advantageously has an isotropic magnetic susceptibility, resulting in better reduction of marker artifact size in any given plane.

[0069] According to a fifth aspect, there is provided a detection system for locating an implantable marker, the system comprising: an implantable marker according to the first or second aspect; 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 implantable 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 signals from the sense coil and detect one or more harmonics of the drive frequency in the received signals.

[0070] It will be understood that features described herein with respect to one aspect of the present disclosure may be incorporated into other aspects of the present disclosure, for example, methods of the present disclosure may incorporate features described with reference to markers of the present disclosure, and vice versa.

[0071] Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0072] [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 image slices are cut along the y-axis and indicating the orientation of the x-, y-, and z-axes [Figure 2(a)] Hysteresis curve 1 showing magnetization as a function of magnetic field H for a typical ferromagnetic material [Figure 2(b)] A hysteresis loop similar to that in Figure 2(a) showing magnetic flux B as a function of magnetic field H for an atypical ferromagnetic material. [Figure 2(c)] Schematic diagram showing the direction of the magnetic moment that occurs in a ferromagnetic material when subjected to an applied magnetic field H [Figure 3(a)] Graph showing magnetic flux B as a function of magnetic field H for a typical diamagnetic material (the diamagnetic magnetization shown is negative) [Figure 3(b)] Schematic showing the direction of the magnetic moment that occurs in a diamagnetic material when subjected to an applied magnetic field [Figure 4] 1 is a diagram illustrating a schematic representation of the change in magnetic moment due to an applied magnetic field of a marker comprising at least one ferromagnetic element and at least one diamagnetic element, according to an embodiment of the present disclosure; [Figure 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, each extending substantially parallel to the longitudinal axis of the core and in juxtaposition on the outer surface of the core; [Figure 6(a)] 1(a) and / or 1(b) are contour plots of magnetic flux density B in the xz plane of 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 of the implantable marker of FIG. 5 in the field. [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 as a result of a ferromagnetic wire of the same configuration as shown in Figure 5 being 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 the longitudinal axis of the core; [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 field B0 as a result of the presence of the implantable marker of Figure 7 in the field. [Figure 9] 1 is a schematic perspective view of an implantable marker comprising a cylindrical diamagnetic core and a ferromagnetic wire helix extending around the outer surface of the diamagnetic core, according to a third embodiment of the present disclosure; [Figure 10(a)] 1(a) and / or 1(b) are contour plots 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 MRI magnetic field B0 as a result of the presence of the implantable marker of FIG. 9 in the field. [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 as a result of a ferromagnetic wire of the same configuration as shown in Figure 9 being present in the field but without the diamagnetic core. [Figure 11] FIG. 10 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)] 1(a) and / or 1(b) are contour plots 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 MRI magnetic field B0 as a result of the presence of the implantable marker of FIG. 10 in the field. [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 as a result of a ferromagnetic wire of the same configuration as shown in Figure 10 being present in the field but without the diamagnetic core. [Figure 13] Diagram of graphite with anisotropic grain structure [Figure 14] Diagram of graphite with isotropic grain structure [Figure 15] 10 is a flowchart illustrating a method for manufacturing an implantable marker according to a fifth embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0073] definition Isotropic graphite is graphite that has a substantially isotropic grain structure.

[0074] Isostatically pressed graphite is isotropic graphite formed by isostatic pressing.

[0075] Magnetic flux density B is a vector field that measures the strength and direction of the magnetic field around a magnet or electric current.

[0076] The magnetic field strength, or magnetic field H, is a vector field that describes the magnetic influence on moving charges, currents, and magnetic materials.

[0077] Magnetization, or magnetic polarization M, is a vector field that represents the density of permanent or induced magnetic dipole moments in a magnetic material.

[0078] Saturation of induction is the state reached when an increase in the applied external magnetic field H cannot further increase the magnetization M of the material. In this state, the resulting total magnetic flux density is the saturation induction B s The magnetization is called the saturation magnetization M s is.

[0079] Magnetic susceptibility χ is a measure of how magnetized a material is in an applied magnetic field and is defined as χ=M / H.

[0080] Bulk magnetic susceptibility is a measure of the magnetic susceptibility of a material in its bulk form when placed in a magnetic field.

[0081] 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.

[0082] 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.

[0083] Relative permeability (μ r ) is the ratio of magnetic permeability to the permeability of free space (μ0), and μ r =μ / μ0. This is the formula μ r It is related to χ by =1+χ.

[0084] Initial magnetic susceptibility (χ i ) is a measure of how much an infinite material is magnetized in a small applied magnetic field. When H is small (e.g., less than 0.01 mT), χ i =M / H, or equivalently, is less than or equal to:

number

[0085] Apparent magnetic susceptibility is a measure of the magnetic susceptibility of a material with a particular shape when placed in a magnetic field.

[0086] 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 is.

[0087] Specific initial permeability (μ r、i ) is μ for small H r is the value of μ r、i It is related to the initial magnetic susceptibility by =1+χ.

[0088] Apparent relative permeability (μ app ) is the relative permeability of a material of a particular shape, i.e., μ after taking into account the demagnetization factor r is.

[0089] 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.

[0090] Paramagnetic materials have a constant magnetic permeability μ slightly greater than 1.

[0091] 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.

[0092] Coercivity is the magnetic field H required to completely demagnetize a magnetic material.

[0093] Hard magnetic materials or permanent magnets have a high coercive force.

[0094] Soft magnetic materials have low coercivity and are therefore easily magnetized and demagnetized.

[0095] The demagnetizing or stray field is the magnetic field H within a magnet created by the magnetization M. It gives rise to shape anisotropy in ferromagnetic materials with a single magnetic domain, and to magnetic domains in larger ferromagnetic materials.

[0096] The demagnetization factor is a quantity that must be used to determine the demagnetization field. Any magnetic object of any shape will have a total magnetic field that varies with position within the object, which can be complex to calculate. This makes it difficult to determine the magnetic properties of a material, such as how the magnetization of the material varies with its shape and the magnetic field.

[0097] Anisotropic materials are materials whose properties vary depending on the direction of observation: for example, material properties such as the thermal and electrical conductivity of graphene can vary significantly depending on whether they are measured parallel to the surface of the graphene plane or perpendicular to the surface of the plane.

[0098] An isotropic material is one that has the same properties regardless of the direction of observation. For example, the material properties of isotropic graphite (such as isostatically pressed graphite) are nearly the same regardless of the direction of measurement. Structurally, isotropic graphite (i.e., graphite with an isotropic grain structure) is substantially homogeneous.

[0099] Magnetic anisotropy describes the change in magnetic properties as a function of material orientation.

[0100] The magnetic anisotropy ratio is the ratio of the strongest to the weakest magnetic signal produced by the marker at a fixed distance at different orientations of the marker relative to the probe.

[0101] Magnetic moment is the magnetic strength and orientation of a magnet or other object that produces a magnetic field.

[0102] The magnetic dipole moment is a vector quantity related to the magnetic properties of a current loop.

[0103] Magnetic resonance imaging (MRI) is a noninvasive imaging technique that produces detailed three-dimensional anatomical images. A typical MRI scanner 10 is shown schematically in Figures 1(a) and 1(b). A uniform main magnetic field 11, B0, is aligned with the scanner's longitudinal y-axis 12. As shown in Figure 1(a), an RF pulse 13 B1 is applied, momentarily perturbing the net magnetization M of atomic nuclei within the tissue of a patient 14 located within the scanner. This RF excitation temporarily tilts the magnetization from the y-axis (i.e., parallel to B0, where no signal can be detected) to the transverse x-z plane (i.e., perpendicular to the y-axis), where it can be detected by an appropriate receiver coil. After the RF pulse is turned off, the atomic magnetization relaxes and exhibits precession as it returns to thermal equilibrium. The transverse component of the process magnetization induces an electromotive force in the receiver coil, making it possible to detect the magnetization. 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).

[0104] MRI metal artifacts occur at the interface between tissue and metals with different magnetic susceptibilities, causing the local magnetic field to distort the external magnetic field. This distortion alters the precession frequency within the tissue, leading to spatial mismapping of information. critis defined as a critical change in magnetic flux B in the direction of the main magnetic field generated by the MRI machine, where metal-induced artifacts occur and cause voxels to be mapped to the wrong 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 is aligned with the y-axis 16 of the slice 16. 1 , 16 2 , 16 3 , ..., 16 n are the respective xz planes orthogonal to the main y-axis 12. Therefore, artifacts in MRI images are generally artifacts in the xz plane.

[0105] Detailed Description An object of the present disclosure is to provide an implantable marker containing one or more ferromagnetic elements that, when exposed to a drive magnetic field emitted by a handheld probe, produces a detectable response magnetic field in the probe, and produces minimal artifacts when exposed to the much stronger magnetic fields in an MRI scanner, particularly in the x-z plane of the scanner. Preferably, the marker should be detectable using susceptometry.

[0106] Thus, in one embodiment, the present disclosure provides an implantable susceptometry 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 contain amounts of ferromagnetic and diamagnetic material such that in a sensing field (at the source) of less than about 0.5 mT, the one or more ferromagnetic elements are substantially more strongly magnetized than the at least one diamagnetic element, generating a response magnetic field large enough to detect the marker in tissue using a handheld probe, and in an MRI magnetic field of 0.5 T or greater, typically 1.5 T or greater, the at least one diamagnetic element has a sufficiently strong magnetization to oppose at least a significant 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 containing the same amount of ferromagnetic material but no diamagnetic material. Thus, for a given volume of ferromagnetic material, the size of the MRI artifact can be reduced to an acceptable size. As will be explained in more detail below, the one or more ferromagnetic elements advantageously have a magnetic field strength of about 1×10 -10 m 3 In some embodiments, the total volume of ferromagnetic material in one or more pieces is less than 5×10 11 m 3 In some embodiments, the total volume of the ferromagnetic material of one or more pieces is less than about 3×10 -11 m 3 Less than or about 1 x l0 -11 m 3 In some embodiments, the one or more ferromagnetic elements may be less than about 1×10 -12 ×m 3 Thus, in some embodiments, the implantable marker can have a total volume of about 1×10 -12 m 3 ~1×10 -10 m 3 The magnetic material may include a ferromagnetic material.

[0107] To maximize magnetization in the sensing field, one or more ferromagnetic elements may have a length-to-diameter (or the square root of their cross-sectional area) ratio of at least about 50, as disclosed in GB 2115827.4, the contents of which are incorporated herein by reference. Thus, in some embodiments, the length-to-diameter (or the square root of their 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, or at least about 500. In some embodiments, the length-to-diameter (or the square root of their cross-sectional area) ratio of one or more pieces of ferromagnetic material may be greater than 1000, greater than 2000, or greater than 3000.

[0108] By way of example, the one or more pieces of ferromagnetic material can have a total length of about 36 mm and a diameter of about 15 μm. In such an example, the total length to diameter ratio of the one or more pieces of ferromagnetic material can be about 2400. The volume can be about 6×10 -12 m 3 may be

[0109] 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, about 30 μm, about 15 μm, or about 10 μm or less. The marker may comprise a wire or strip of ferromagnetic material having a 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 segments as described herein.

[0110] Preferably, the ferromagnetic material may have a relative initial permeability of at least about 1,000. In some embodiments, the ferromagnetic material may have a relative initial permeability of at least about 10,000, 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.

[0111] Furthermore, as described below, the ferromagnetic material may have a saturation induction less than a 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; and more preferably less than about 0.7 T. s may have:

[0112] The at least one diamagnetic element may suitably comprise a total volume of diamagnetic material that is about 100 to 10,000 times greater than the total volume of ferromagnetic material of the one or more ferromagnetic elements; preferably about 500 to 3,000 times greater; for example, about 950 to 1050 times greater. Thus, the at least one diamagnetic element may comprise a total volume of diamagnetic material that is about 1×10 -9 m 3 ~Approx. 1.5×10 -7 m 3 The marker may have a total volume of 1000 .001 ...

[0113] The one or more ferromagnetic elements and the at least one diamagnetic element may preferably be constructed and arranged to generate mutually opposing magnetic moments in the presence of an applied magnetic field. In particular, the marker may be configured such that, when placed in an applied magnetic field H, the magnetic moment m of the one or more ferromagnetic elements ferromagnet and at least one diamagnetic element generates an opposing magnetic moment m diamagnet Therefore, the net moment of the marker is given by: m total =m ferromagnet -m diamagnet In sensing fields below about 0.5 mT (at the source), 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.

[0114] As those skilled in the art will appreciate, MRI magnetic fields may typically have strengths of 0.5T to 10T or more; particularly about 1.5T to 7T.

[0115] In the field of the present disclosure, handheld sensitive probes can be used by surgeons to detect and locate markers after implantation. Preferably, 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.

[0116] The probe may generate a sensing 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 of one or more ferromagnetic elements. sThe sensing field can be at least 1,000 times weaker than the source. Typically, the sensing field can be an oscillating magnetic field. Thus, the sensing field can 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.

[0117] In use, when the sensing probe is brought into proximity with a marker, the sensing field generates a magnetic moment in the ferromagnetic material, causing the marker to generate a detectable responsive magnetic signal. Under sensing fields of the type described, it is desirable that the marker be easily detectable. The marker desirably has a relatively strong net magnetic moment, resulting in a relatively high magnetic flux density (B) within the sensing field. The magnetic flux is preferably isotropic (in practice, a magnetic anisotropy ratio of less than 7, preferably less than 5, is sufficient), allowing the marker to be consistently detected from a reasonable distance and in any direction. As described in more detail below, under the sensing 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 markers of the present disclosure to be detected at ranges of up to about 50 mm, about 60 mm, about 70 mm, or about 80 mm from the probe.

[0118] FIG. 2(a) is a hysteresis curve 1 showing the magnetization M as a function of applied magnetic field H for a typical ferromagnetic material. Ferromagnetic materials typically produce a strong magnetization M when subjected to a small applied magnetic field H and have a high relative initial susceptibility, as indicated by the dotted line 3. FIG. 2(b) is a similar hysteresis curve 101 showing the magnetic flux density B as a function of magnetic field H for a typical ferromagnetic material. Ferromagnetic materials typically reach magnetic saturation (saturation induction B) under relatively low applied magnetic fields (H). s 2(c) reaches 105. The magnetic moment of the ferromagnetic material 7 is in the same direction as the applied magnetic field 9, as shown in FIG. 2(c).

[0119] the magnetic moment m of one or more ferromagnetic elements in the sensing field ferromagnet is mferromagnet =χ app,ferromagnet H.V. ferromagnet The magnetic flux density (B) or magnetic field generated by all ferromagnetic material in the marker is approximately given by the following equation:

number

[0120] 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 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 smaller than the magnetic flux in free space because the induced magnetization opposes the magnetic field H, as shown by the dashed line 203 shown for reference. As shown in FIG. 3(b), when the diamagnetic material is subjected to an applied magnetic field, a magnetization or magnetic moment 207 is induced that opposes the direction of the applied magnetic field 209. As described herein, at least one diamagnetic element of the present disclosure exhibits a magnetization of less than 1×10 when subjected to a magnetic field less than 0.01 mT. -3 less than, typically about 3 x 10 -4 The magnetic moment m of at least one diamagnetic element in the sensing field may be less thandiamagnet is m diamagnet =χ app,diamagnet H.V. diamagnet The magnetic flux density (B) generated by a diamagnetic element is given by the following formula:

number

[0121] In the sensing field, the magnetic moment of one or more ferromagnetic elements is higher than the opposing magnetic moment of at least one diamagnetic element. The magnetic moment of one or more ferromagnetic elements may be at least 1,000 to 1,000,000 times greater than the opposing magnetic moment of at least one diamagnetic element.

[0122] 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 being 1.5 T or 3 T at the time of this writing. 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.

[0123] 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 therefore may be saturated when exposed to an 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 is ferromagnet is:

number

[0124] When exposed to an MRI magnetic field, the induced magnetic moment of the at least one diamagnetic element may also be significant, given the upper limit on the magnetization of the one or more ferromagnetic elements due to saturation and the substantial volume of diamagnetic material used in the at least one diamagnetic element. While 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 significant volume of diamagnetic material relative to the volume of ferromagnetic material can 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 diamagnet is:

number

[0125] As an example, the total magnetic moment of at least one diamagnetic element under a 1.5 T MRI field is approximately -1 × 10 -6 Am 2where the negative sign indicates that the magnetic moment is in the opposite direction to the MRI field.

[0126] The magnetic moment from the at least one diamagnetic element opposes the magnetic moment of the one or more ferromagnetic elements, so that the magnetic moment from the at least one diamagnetic element reduces the net magnetic moment of the entire marker when subjected to an MRI magnetic field. Thus, preferably, the marker has a net magnetic moment of about 1×10 when subjected to an MRI magnetic field. -6 Am 2 In particular, the marker can have a net magnetic moment of less than about 1×10 when subjected 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 1000 .mu.m.

[0127] 4 illustrates a schematic representation of the change in magnetic moment with an applied magnetic field H for 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 of the marker 305. At intermediate magnetic field strengths below that of a typical MRI field but above that of the sensing field, the one or more ferromagnetic elements reach 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 much smaller than the magnetic moment of the one or more ferromagnetic elements under the sensing field, but increases linearly with the applied magnetic field. At such intermediate fields, the magnetic moment of the one or more ferromagnetic elements still accounts for the total magnetic moment m marker 305, but at larger magnetic field strengths of the kind used in MRI scanners, the opposing (smaller) magnetic moment of at least one diamagnetic element may represent a significant proportion of the magnetic moment of one or more ferromagnetic elements, e.g., at least 25%, preferably at least 50%.

[0128] 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 one or more ferromagnetic elements, and thus the total or net magnetic moment of the marker may be zero or near 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.

[0129] Given the constraints on size and shape for the markers of the present disclosure and the magnetic properties of available materials, it will be understood that the need to co-locate the magnetic dipoles induced in the one or more ferromagnetic elements and at least one diamagnetic element so that they at least partially match each other and the strength of the MRI field to cancel each other out will in practice mean that the magnetic moments of the one or more ferromagnetic elements and at least one diamagnetic element may not completely cancel each other out. However, as long as the magnetic moments of the one or more ferromagnetic elements and at least one diamagnetic element cancel each other out 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 will be met.

[0130] Thus, in an MRI magnetic field, the opposing magnetic moment generated by the smaller of the one or more ferromagnetic elements, or respectively the at least one diamagnetic element, can have an amplitude that is at least 25%, preferably at least 50%, of the amplitude of the larger of the magnetic moments generated by the at least one diamagnetic element, or respectively the one or more ferromagnetic elements. In some embodiments, the smaller magnetic moment generated by the at least one diamagnetic element in an MRI magnetic field can have an amplitude that is at least 27%, preferably at least 50%, of the amplitude of the magnetic moment generated by the one or more ferromagnetic elements.

[0131] When subjected to an MRI magnetic field, one or more ferromagnetic elements produce artifacts on the MRI image, as the elements cause localized changes in the magnetic field within the MRI machine. The artifacts are generated by the 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 It is mainly caused by the component of 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 appear in the correct slice reconstructed by the MRI machine. y |≧B crit The point at does not appear in the expected slice, B crit is the magnitude of the y-component of the magnetic flux density B at which the voxel is mapped to different slices, and its value depends on the MRI scanning parameters.

[0132] Amount of ferromagnetic material, saturation induction B sThe size of the artifact is affected by the distance, as well as the size and shape of the ferromagnetic element(s). 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, the magnetic flux density generated by a ferromagnetic element along the axis of magnetization is given by:

number

number

[0133] Combining these two formulas,

number

[0134] If we consider the edges of MRI artifacts, then

number

number

number

number

[0135] According to the present disclosure, the size of the artifact 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 subjected to an MRI magnetic field, the size of the artifact produced can be calculated as follows:

number

number

[0136] 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 Considering typical exemplary values, B MRI =1.5T, B s = 0.6T, and χ = 5 × 10 -4In this case, 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.

[0137] Large artifacts generated during MRI imaging are problematic and can lead to mismapping of spatial information. Therefore, it is important to minimize the size of artifacts generated by markers in the MRI field while still allowing the markers to be sensed in the sensing field.

[0138] For a marker to be sensed in a sensing field, the magnetic moment of one or more ferromagnetic elements must dominate the net magnetic moment when the marker is exposed to the sensing field.

[0139] The magnetic moment of the at least one diamagnetic element should at least partially cancel the magnetic moment of the one or more ferromagnetic elements so that the net magnetic moment of the marker is as small as possible, so that the artifacts produced by the marker in a typical MRI magnetic field are relatively small. Furthermore, the size and shape of the artifacts produced by the one or more ferromagnetic elements alone should at least approximate the size and shape of the artifacts produced by the at least one diamagnetic element alone, so that when closely combined with each other in the marker, as described herein, they overlap and therefore cancel each other out at least to some extent.

[0140] The size of the artifacts produced by the markers of the present disclosure when subjected 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 a large amount of ferromagnetic material can result in undesirably large artifacts. Increasing the volume of diamagnetic material can lead to smaller artifacts.

[0141] 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 marker 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 marker artifact for a given MRI magnetic field strength.

[0142] The size of the artifacts produced in the MRI 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:

[0143] 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 stronger magnetic fields. MRI scanners are available with different MRI magnetic field strengths, meaning 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 one MRI magnetic field strength but not equal under a different MRI magnetic field strength. Preferably, the respective volumes of ferromagnetic and diamagnetic material in the markers of the present disclosure are capable of producing MRI artifacts of acceptable size over a range of MRI magnetic fields; for example, 0.5-10 T, preferably 1-7 T, and more preferably 1.5-3 T.

[0144] In some embodiments, the respective volumes of ferromagnetic and diamagnetic material within 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, while still producing artifacts of acceptably small size under a second MRI magnetic field that is weaker than the first MRI magnetic field, e.g., 1.5 T.

[0145] In some embodiments, the respective volumes of ferromagnetic and diamagnetic material within a 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 acceptable. As disclosed herein, a marker may include relative amounts of ferromagnetic and diamagnetic material 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, individually. 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, individually, under at least two different MRI magnetic fields. In this sense, the respective amounts of ferromagnetic and diamagnetic material in the marker can 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. The shape and dimensions of the or each ferromagnetic element and at least one diamagnetic element can also affect the size and shape of the artifact and the ease with which the marker can be sensed.

[0146] As disclosed in UK Patent Application No. 2115827.4, for a given volume of ferromagnetic material, a ferromagnetic element with a large aspect ratio may be more easily detectable in a sensing field. By increasing the aspect ratio (e.g., L / D, where L is the length of the element and D is the diameter or width for elements with non-circular cross-sections) of a magnetic element, sensing performance in the direction of its long axis may be increased. As the ratio L / D increases, the apparent permeability μ of the element app This phenomenon is due to the demagnetization effect.

[0147] Preferably, 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.

[0148] 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.

[0149] One or more ferromagnetic elements of the markers of the present disclosure may suitably have a length-to-diameter (or the square root of its cross-sectional area) ratio (L / D) of at least 50.

[0150] The ferromagnetic element or elements preferably have a magnetic field of 1×10 -10 m 3 less than about 1 x 10 -11 m 3 The total volume may be less than 1000 .mu.m.

[0151] Unless otherwise specified, the term "length" as used herein in the context of an individual magnetic element refers to the length of the element as if the element were extending 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 phrase "total length" is used herein, unless otherwise specified, to refer to the length of one or more magnetic elements in the configuration in which they are formed within 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. Meanwhile, "total diameter" or "total width" refer to the diameter or width, respectively, of an assembly of one or more magnetic elements in a direction transverse to the longest dimension.

[0152] Ferromagnetic elements with high aspect ratios and low volumes attempt to balance useful sensing response with acceptably small MRI artifacts: reducing the volume of ferromagnetic material can reduce the MRI artifacts produced by the ferromagnetic elements, while 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.

[0153] 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 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.

[0154] Increasing the aspect ratio of the ferromagnetic element's material can dramatically increase its sensing performance in the direction of its longest dimension. As the aspect ratio increases, the apparent magnetic permeability μ appalso increases, thereby increasing the distance at which the marker can be sensed as a result of the demagnetizing effect.

[0155] A straight ferromagnetic wire has a high aspect ratio and generates a strong magnetic flux density along its longitudinal axis. This can potentially provide practical sensing performance in a sensing field parallel to this axis. However, such elements may be less easily detected perpendicular to the longitudinal axis, i.e., they may have an anisotropic sensing response, and there may be wide variations in the element's magnetic response depending on its orientation relative to the sensing field, making 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 provide good sensing performance using a relatively small volume of ferromagnetic material, which has the advantage of producing fewer artifacts in MRI images.

[0156] The sensing response and MRI artifact size of a ferromagnetic element under a sensing field may depend on different variables. Under a sensing field such as that produced by a Sentimag™ probe, sensing performance depends almost exclusively on the aspect ratio and volume of the ferromagnetic material, as well as the specific initial permeability μ r,j It is recognized that the magnitude of the magnetic field produced by a ferromagnetic element when subjected to an MRI field, and therefore the MRI artifact size, is not significantly dependent on the initial slope of the B-μH curve. In contrast, the magnitude of the magnetic field produced by a ferromagnetic element when subjected to an MRI field, and therefore the MRI artifact size, is dependent on the saturation-induced B s and the volume of ferromagnetic material. This means that it is possible to limit the size of MRI artifacts by using very thin pieces of low saturation induction ferromagnetic material that can still be sensed at a satisfactory distance.

[0157] It has been found that coiled ferromagnetic wire can have a more isotropic response in the sensing field than straight wire while still having a low volume and a high aspect ratio. Thus, coiled ferromagnetic wire can be detected in the sensing field from an improved range of directions, with less change in magnetic response due to orientation relative to the sensing field, while still producing acceptably small artifacts in the MRI field.

[0158] 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 linear rods extending through the coils or rings. In some implementations, at least one ferromagnetic element may comprise a helical wire coil.

[0159] 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.

[0160] In some embodiments, two or more ferromagnetic elements can be configured as multiple helices, for example, double helices, triple helices, or quadruple helices.

[0161] 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.

[0162] When a marker includes multiple ferromagnetic elements, the individual ferromagnetic elements can be positioned so that they do not contact one another 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 helix arrangement, for example, each individual helical ferromagnetic element can be positioned within a helical gap defined by the turns of one or more other helical ferromagnetic elements.

[0163] It has been found that the shape and size of MRI artifacts produced by coiled magnetic wires can depend on the coil pitch and / or coil diameter of the wire: larger pitches typically produce longer, thinner artifacts, while shorter, wider coils typically produce thicker, shorter artifacts.

[0164] Suitably, the wire may have a diameter of less than about 100 μm, 50 μm, 30 μm, 15 μm, or 10 μm; preferably, the wire may have a diameter of about 15 μm.

[0165] 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 1.0 mm to 1.5 mm, more preferably about 1.15 mm to 1.30 mm, e.g., 1.2 mm. It has been found that a larger coil diameter can produce a stronger transverse sensing response in the sensing field.

[0166] Suitably, the helical ferromagnetic element may have a pitch of about 0.5 mm to 3 mm, preferably about 1.4 to 1.8 mm, for example about 1.6 mm. A larger pitch may improve the sensing response of the helix in the axial direction. This is believed to be due to the greater axial extension of the helical coil.

[0167] 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 to 1.5 times the diameter of the helix. This may help maximize the lateral response of the helix in the sensing field.

[0168] 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. This may 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 reduce the MRI artifact size of the marker. It has been found that there may be an optimal pitch for producing isotropic sensing performance for each type of multi-helix marker. For triple helices, a pitch of approximately 1.6 mm for each individual helix may be optimal for a marker with a diameter of approximately 1.6 mm using a metal wire with a diameter of approximately 15 μm.

[0169] 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 4 mm to 8 mm, for example about 5 mm. It has been found that a longer helix increases the aspect ratio of the marker, which can result in an improved sensing response. Preferably, 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.

[0170] As described above, the at least one diamagnetic element may be configured and arranged to minimize the net magnetic moment of the marker in an 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.

[0171] In order for at least one diamagnetic element to most effectively cancel the magnetic field from one or more ferromagnetic elements, and thus 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.

[0172] The above objective (i) can be achieved in accordance with the present disclosure by using respective volumes of ferromagnetic and diamagnetic material as disclosed herein so that the two induced magnetic 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.

[0173] The volume of the at least one diamagnetic element may be about 100 to 10,000 times greater than the total volume of the one or more ferromagnetic elements, preferably about 500 to 3,000 times, e.g., about 900 times, greater than the total volume of the one or more ferromagnetic elements. The total volume of the ferromagnetic material forming the one or more ferromagnetic elements is preferably about 5×10 -11 m3 Less than 3 x 10 -11 m 3 Less than or equal to 1 x 10 -11 m 3 Less than, say 6 x 10 -12 m 3 Typically, the volume of the at least one diamagnetic element is about 1×10 -9 m 3 ~1.5×10 -7 m 3 , e.g. 6×10 -9 m 3 It could be.

[0174] Objective (ii) can be achieved by distributing one or more ferromagnetic elements and at least one diamagnetic element in a similar manner in space. Generally, 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. Because of this, and because perfectly co-locating the two materials may not be possible, the magnetic fields generated by the two materials typically may not completely cancel each other in the MRI magnetic field. Matching the dipole components of the two fields is most beneficial, while matching 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 an appropriate computer mathematical modeling program to generate contour maps 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 maps substantially match. The shape and size of the artifacts produced by one or more pieces of ferromagnetic or diamagnetic material in an MRI field are determined by the B crjt , 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 voxels are mapped to different slices due to the presence of one or more fragments in the field.

[0175] The one or more ferromagnetic elements and the at least one diamagnetic element may be preferably 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. The one or more ferromagnetic elements and the at least one diamagnetic element may advantageously be co-located. The one or more ferromagnetic elements and the at least one diamagnetic element may be configured and arranged such that the center, e.g., a 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., a 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.

[0176] 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.

[0177] 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. Preferably, 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 helixes, as described above. Alternatively, the at least one diamagnetic element may be juxtaposed to the single or multiple helixes 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 adjacent to the helix in the form of a hollow cylinder.

[0178] It has been found that the size of the artifacts produced by the marker can be advantageously minimized if 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 if the diameters or widths of all of the one or more ferromagnetic elements are the same as or similar to the diameters or widths of all of the at least one diamagnetic element.

[0179] Thus, preferably, the one or more ferromagnetic elements can 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 can have a total length of about 2 mm to 10 mm, preferably about 6 mm to 8 mm. In some implementations, the total length of the at least one diamagnetic element can be approximately the same as the total length of the one or more ferromagnetic elements; for example, the length of the spiral if the one or more ferromagnetic elements form a spiral. The total length of the at least one diamagnetic element can be within 25%, e.g., within 10%, e.g., within 5%, of the total length of the one or more ferromagnetic elements. The total length of the at least one diamagnetic element can be within about 2% of the total length of the one or more ferromagnetic elements.

[0180] Preferably, the marker may be sized to fit within a particular needle gauge, e.g., 12G to 18G, preferably 16G to 18G. Thus, in some embodiments, the marker may have a diameter ranging from about 0.514 mm to about 1.803 mm, preferably about 0.838 mm to about 1.194 mm. 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 housings or outer coatings for the ferromagnetic and diamagnetic elements.

[0181] Generally, 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 to 1.8 mm, more preferably about 0.80 to 1.4 mm, e.g., 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 as possible to one another can 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 is used or if the wire diameter is very thin, only a small amount of diamagnetic material may be needed to balance the ferromagnetic moment. In such cases, the overall diameter of at least one diamagnetic element may be smaller than the overall diameter of 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.

[0182] Thus, the one or more ferromagnetic elements and at least one diamagnetic element may be configured and arranged as disclosed herein so that the artifacts produced 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 produced 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 produced 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 produced 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.

[0183] For a marker according to one embodiment of the present invention, as described above, the one or more ferromagnetic elements have a low saturation induction (B s ), for example, less than 1.5 T. Furthermore, the one or more ferromagnetic elements have a high relative initial permeability; for example, greater than 1,000 for a magnetic field of 0.1 mT to 0.5 mT. In some embodiments, the one or more ferromagnetic elements may have a relative initial permeability greater than 10,000. In some embodiments, the one or more ferromagnetic elements may have a relative initial permeability greater than 50,000 or even 100,000.

[0184] The or each ferromagnetic element may preferably 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, such as those sold under the trade names Yshield MCE61™, Metglas 2705M™, and Metglas 2714A™. Suitable ferromagnetic materials also include manganese-zinc ceramic ferrites, such as those sold under the trade names Fair-Rites 31™, 76™, and 78™. Suitable ferromagnetic materials further include nickel-iron-based soft ferromagnetic alloys, such as those sold under the trade names Mu-metal, Permalloy 80, Permalloy C, Permalloy, and Supermalloy. Other suitable ferromagnetic materials include nickel-zinc ceramic ferrites, such as those sold under the trade names Fair-Rites 15™, 20™, and 43™; and preferably cobalt-based amorphous metals, such as Yshield™ and Metglas 2714A™. However, while ceramics have low saturation induction, they are less easily formed into wires or flat wires and are therefore less suitable for markers according to the present disclosure. 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.

[0185] Advantageously, at least one diamagnetic element is ferrodiamagnetic, i.e., approximately 1×10 -4 This means that the magnetic susceptibility can be as high as about −0.91×10 -5 In some embodiments, the at least one diamagnetic element has a magnetic susceptibility of about −1×10 -4 ~-3×10 -4 In some embodiments, the at least one diamagnetic element may have a bulk or apparent volume magnetic susceptibility of up to about −7×10 -4Diamagnetic elements with 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.

[0186] According to the present disclosure, at least one diamagnetic element comprises graphite having a substantially isotropic grain structure, preferably a fine grain structure. For example, isostatically pressed graphite has a suitably small grain size and may have a higher density and higher strength than graphite formed by extrusion or compaction. Furthermore, isostatically pressed graphite may advantageously have more isotropic properties than anisotropic graphite formed by, for example, extrusion or compaction. Isostatically pressed graphite is also inexpensive, easily machinable, has good biocompatibility properties, and may be manufacturable in grades with less than 5 ppm impurities. Thus, preferably, the graphite may be highly pure, containing greater than 99.9% carbon. 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 corresponds to a low porosity (e.g., less than 15%). 3 High purity, high density isostatically pressed graphite may have a density of about -1.2 x 10 in implantable markers according to the present disclosure. -4 It has been found to have an apparent volume magnetic susceptibility of

[0187] Thus, 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 embodiment, an implantable marker of the present disclosure may include one or more ferromagnetic elements and at least one diamagnetic element formed from high-purity graphite and having a substantially isotropic grain structure, for example, by isostatic pressing. As described herein, the one or more ferromagnetic elements are advantageously disposed in juxtaposition with the at least one diamagnetic element.

[0188] The purity of the graphite can be further enhanced, preferably by heat treatment, for example at a temperature of at least about 2,200° C. The heat treatment can be carried out simultaneously with or after pressing or extruding the graphite.

[0189] According to embodiments, the present disclosure provides a method for manufacturing a magnetic marker. The method may include forming one or more ferromagnetic elements and at least one diamagnetic element, the diamagnetic element including graphite having a substantially isotropic grain structure, 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 may comprise respective volumes of ferromagnetic material and diamagnetic material selected as disclosed herein, such that in a sensing 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 enable the marker to be detected in tissue using a handheld probe, while in an MRI magnetic field, the at least one diamagnetic element has a 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. The one or more ferromagnetic elements may be configured and arranged to maximize the strength and isotropy of the response magnetic field generated in response to the sensing field. The at least one diamagnetic element may be constructed and arranged to produce an artifact within the MRI magnetic field having a size and shape that matches the artifact size and shape of the artifact produced by the one or more ferromagnetic elements, at least to an extent sufficient to reduce the maximum dimension of the artifact produced by the marker to less than about 30 mm, preferably less than about 20 mm. The graphite may be high purity, high density graphite.

[0190] In embodiments of the present disclosure, the method may 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 may be negligible in a sensing 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 the probe, and may be of the same order of magnitude as the strength of the magnetic moment generated by the one or more ferromagnetic elements in an MRI magnetic field, thereby canceling or substantially balancing the magnetic moments of the at least one ferromagnetic element and thereby minimizing the size of artifacts generated by the marker on MRI images.

[0191] In some embodiments, the method further comprises performing an isostatic pressing process to provide isostatically pressed graphite.

[0192] In some embodiments, the method further comprises heat treating the graphite at a temperature greater than 2,200°C.

[0193] In some embodiments, constructing and arranging one or more ferromagnetic elements and at least one diamagnetic element can include winding one or more ferromagnetic elements around a core or mandrel formed from the at least one diamagnetic element. Accordingly, one embodiment of the present disclosure provides a method for manufacturing a marker comprising a diamagnetic core received within a coil of one or more ferromagnetic wires or strips. The core can have an initial length several times the length of a single marker. One or more ferromagnetic wires or strips can be wound around the diamagnetic core. The ends of the wires or strips can be conveniently secured to the core at the beginning and end of the winding, for example, using an adhesive. The resulting assembly can then be divided into two or more segments, each having a length corresponding to the length of the marker. The segments can be separated from one another by cutting, for example, by mechanical, pressure, or thermal means, using, for example, a blade, water jet, or laser. Alternatively, the diamagnetic core can be cut into separate segments prior to coil winding.

[0194] 5 is a schematic diagram of an implantable marker 401 according to one embodiment of the present disclosure. 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 understood that in variations of this embodiment, fewer or more ferromagnetic wires may be used. Diamagnetic core 405 has a χ=-1.66×10 -4 The cylinder comprises isostatically pressed graphite and has a diameter of approximately 1 mm and a length of approximately 8 mm. Ferromagnetic wires 403a, 403b, and 403c have an initial volume magnetic susceptibility of approximately 72,000. Each wire 403a, 403b, and 403c has a diameter of approximately 16 μm and a length of approximately 8 mm, and wires 403a, 403b, and 403c extend in a direction substantially parallel to the longitudinal axis of diamagnetic core 405 such that the length of the wire substantially matches the length of core 405.

[0195] For sensing fields below 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 of the wires. app,wire the volume of the 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 the product of app,wire。 3.V wire is approximately 4.6 x 10 -8 m 3 and the quantity χ of the diamagnetic core 405 may be calculated as app,core V core is approximately -1.0 x 10 -12 m 3 Therefore, the combined magnetic field generated by the ferromagnetic wires 403a, 403b, 403c in the sensing field is about 45,000 times larger than the magnetic moment generated by the diamagnetic core 405, which is negligible in comparison.

[0196] When subjected to a 1.5 T MRI magnetic field, each of the ferromagnetic wires 403a, 403b, 403c reaches induction saturation. Thus, the combined magnetic moment of the three wires 403a, 403b, 403c is given by:

number

number

[0197] Comparing the magnetic moments of the diamagnetic core 405 and the ferromagnetic wires 403a, 403b, and 403c under a 1.5 T MRI magnetic field, the magnetic moment of the diamagnetic core 405 is about 57% of the magnetic moment of the ferromagnetic wires 403a, 403b, and 403c.

[0198] Figure 6(a) shows 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 5 is a contour plot 507 showing the magnetic flux density deviation due to the presence of the marker 401 of FIG. 5 in the MRI magnetic field. The contours represent lines of constant magnetic flux density deviation in the vicinity of the marker 401. As mentioned above, B crjt is the value above which voxels are mapped to the wrong slice of the MRI image, |B-B0| y Therefore, B crjt The contours at represent 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. crjt Although values ​​of B have been found to give reasonably good agreement between theoretical predictions and experimental data, those skilled in the art will appreciate that B crjt It will be appreciated that depends on the configuration of the particular MRI system (e.g., slice thickness). Thus, Figure 6(a) shows that the artifact size is B crjt To show how it varies for different values ​​of |B-B0| y Other contours at different values ​​of .

[0199] For comparison, FIG. 6(b) shows the magnetic flux density B generated in the same MRI magnetic field B for the same configuration of ferromagnetic wires 403a, 403b, and 403c without the diamagnetic core 405. y Deviation in |B-B0| y The contour line 513 is a contour map 511 showing B crjt = 0.6 μT. The effect of the diamagnetic core in reducing the size of the artifact in the xz plane of Figure 6(a) is self-evident.

[0200] 7 is a schematic diagram of a different implantable marker 601 according to one embodiment of the present disclosure. Similar to marker 401 of FIG. 5 described above, marker 601 includes three ferromagnetic wires 603a, 603b, and 603c, although fewer or more wires may be used in variations. However, in this embodiment, ferromagnetic wires 603a, 603b, and 603c extend axially through diamagnetic core 605. Diamagnetic core 605 is substantially the same size and shape as diamagnetic core 405 of FIG. 5, and has substantially the same properties. Core 605 therefore has a χ=-1.66×10 -4 The ferromagnetic wires 603a, 603b, and 603c are substantially the same length and gauge as the wires 403a, 403b, and 403c shown in FIG. 5. Thus, the ferromagnetic wires 603a, 603b, and 603c have an initial volume magnetic susceptibility of approximately 72,000. Each wire 403a, 403b, and 403c has a diameter of approximately 16 μm and a length of approximately 8 mm, such that the length of the wire substantially matches the length of the diamagnetic core 405.

[0201] 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. y Deviation in |B-B0| y , which is due to the presence of the marker 601 of FIG. 7 in the MRI magnetic field, with the axial length of the marker 601 oriented along the y-axis. As in FIGS. 6(a) and 6(b), B crjt6(a) with that of FIG. 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.

[0202] 9 is a schematic diagram of another implantable marker 801 according to one embodiment of the present disclosure. Marker 801 comprises a substantially cylindrical diamagnetic core 805 of isostatically pressed graphite or another suitable diamagnetic material disclosed herein, having a diameter of about 1.15 mm and a length of about 8 mm. 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 803 of iron-cobalt based alloy wire. It will be understood that other ferromagnetic materials may be used, as disclosed herein. The wire 803 has a diameter of approximately 15 μm, and the helix has a length of approximately 8 mm (i.e., approximately the same length as the core 805). The helix has a pitch of approximately 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, e.g., double or triple helices. This allows the same amount of wire to be used, as disclosed herein, but with a longer pitch to increase the sensitivity of the marker.

[0203] FIG. 10(a) is a contour plot 907 similar to those of 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. y Deviation in |B-B0| y , which is due to the presence of the marker 801 of FIG. 9 in the MRI magnetic field, with the axial length of the marker 801 oriented along the y-axis. As in FIGS. 6(a), 6(b) and 8, B crjtThe contour 909 at 0.6 μT, which may correspond to 0.6 μT, therefore represents the contour of artifacts that may be produced in the xz plane of the marker 801 in the MRI magnetic field. For comparison, FIG. 10(b) is a contour plot 911 showing the magnetic flux density B produced 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 crjt = 0.6 μT. The effect of the diamagnetic core in reducing the size of the artifact in the xz plane of Figure 10(a) is self-evident.

[0204] 11 is a schematic diagram of yet another implantable marker 1001 according to one 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, and 1004c. Each ferromagnetic element 1004a, 1004b, and 1004c includes a coil of wire made of a ferromagnetic iron-cobalt-based material, the wire having a diameter of approximately 15 μm. As shown in FIG. 11 , the coils are arranged to form a triple helix 1003 in which the respective wires 1004a, 1004b, and 1004c do not contact each other. Preferably, the wires may be bonded or otherwise held in place on the outer surface 1005. Each coil of the triple helix has a pitch of approximately 1.80 mm. Each coil of the triple helix 1003 includes approximately 4.4 turns of wire, for a total of approximately 14.2 turns of triple helix 1003. The total length of the ferromagnetic wire used in the triple helix is ​​approximately 52 mm (in another exemplary embodiment, it may be less than 52 mm, for example, less than 40 mm).

[0205] In an MRI magnetic field of approximately 1.5 T, the total magnetic moment of the three ferromagnetic wires 1004a, 1004b, and 1004c is approximately 2.1×10 -6 Am 2On the other hand, the magnetic moment of the diamagnetic core 1005 is calculated to be about -1.2 × 10 -6 Am 2 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 Figure 12(a) shows the magnetic flux density B from a 3T MRI magnetic field B across the xz plane of the MRI scanner. y Deviation in |B-B0| y 11 is a contour plot 1107 showing the magnetic flux deviation due to the presence of the marker 1001 of FIG. 11 in the MRI magnetic field. The contour plot shows lines of constant magnetic flux deviation in the vicinity of the marker 1001. As mentioned above, B crjt is |B-B0| y , above which voxels will be mapped to the wrong slice of the MRI image. crjt The contours at represent contours of artifacts that may be produced in the xz plane of the marker 1001 of FIG. 11 in an MRI magnetic field, with the axial length of the marker 1001 oriented along the y-axis. crjt Although values ​​of B have been found to give reasonably good agreement between theoretical predictions and experimental data, those skilled in the art will appreciate that B crjt It will be appreciated that B depends on the configuration of the particular MRI device (e.g., slice thickness). crjt To show how the artifact size changes for different values ​​of |B-B0| y Other contours at different values ​​of .

[0206] For comparison, FIG. 12(b) shows the magnetic flux density B generated in the same MRI magnetic field B for the same configuration of ferromagnetic wires 1004a, 1004b, 1004c without the diamagnetic core 1005. y Deviation in |B-B0| y The contour line 1113 is a contour map showing the B crjt= 0.6 μT. The effect of the diamagnetic core in reducing the size of the artifact in the xz plane of Figure 12(a) is self-evident.

[0207] By using a triple helix 1003, the same amount of wire can be used within a given axial length as with a single helix, but because the helix coils have a larger directional component along the axial length of the marker, the pitch is longer to increase the axial sensitivity of the marker. A pitch of approximately 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's axial sensing distance is approximately 34 mm, and the lateral sensing distance is approximately 34 mm.

[0208] Figure 13 of the accompanying drawings shows a typical grain structure 1500 of a graphite rod 1600 having an anisotropic grain structure (e.g., formed from extruded graphite), with the grains aligned longitudinally. The magnetic susceptibility of graphite is high across the grain size and low across the grain size (i.e., longitudinal direction).

[0209] 14 of the drawings shows a typical grain structure 1700 of a graphite rod 1800 having an isotropic grain structure (e.g., formed from isostatically pressed graphite), where the grains are randomly oriented (not aligned). The magnetic susceptibility of graphite can be moderate to high in all directions.

[0210] FIG. 15 is a flowchart illustrating a method 1100 for manufacturing a marker according to one 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, where the diamagnetic element comprises graphite having a substantially isotropic grain structure. In a second step 1103, the method includes juxtaposing the one or more ferromagnetic elements and the at least one diamagnetic element so that they are co-located and configured and arranged to generate 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 relative to the strength of the magnetic moment generated by the at least one ferromagnetic element at sensing fields of less than about 0.5 mT, thereby enabling the magnetic moment generated by the at least one ferromagnetic element to be detected by the probe, and is relatively high at MRI fields of 1.5 T or greater, thereby minimizing the size of artifacts generated by the marker on MRI images by canceling out the magnetic moments of the at least one ferromagnetic element.

[0211] The ferromagnetic material configured into the required shape can then be enclosed within a cylindrical housing. The cylindrical housing is preferably injectable to allow for placement of the marker. Preferably, the housing therefore has a maximum diameter that allows it to be deployed through a small gauge needle, e.g., 18G to 12G, as disclosed above. The marker may be packaged within other materials, or a coating may be applied to the marker to ensure its biocompatibility and robustness. The marker may be enclosed within a tube made of, for example, nitinol, titanium, stainless steel, or other biocompatible alloys, the material preferably being non-magnetic and having a relatively low conductivity. Low conductivity is achieved by, for example, using a material that is non-magnetic and has a relatively low conductivity. 6It may include conductivities below Siemens. Suitable coating materials include polymer coatings such as Invar®, FEP, Parylene®, PTFE, ETFE, PE, PET, PVC or silicone, or epoxy-based encapsulants.

[0212] 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.

[0213] Where the foregoing description refers to integers or elements that have known, obvious, or foreseeable equivalents, such equivalents are incorporated herein as if individually set forth. Reference should be made to the claims to determine the true scope of the present disclosure, and the claims should be construed to encompass any such equivalents. The reader will also understand that any integers or features of the present disclosure described as advantageous, convenient, or the like are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that such optional integers or features may be advantageous in some embodiments of the present disclosure, but undesirable and therefore absent in other embodiments. Other embodiments 1. An implantable marker for use in a surgical guide, comprising one or more ferromagnetic elements formed from at least one ferromagnetic material and at least one diamagnetic element formed from at least one diamagnetic material; The at least one diamagnetic material includes graphite having a substantially isotropic grain structure, and the one or more ferromagnetic elements are juxtaposed to the at least one diamagnetic element. An implantable marker. 2. The graphite is -0.16 x 10 -4 2. The implantable marker of embodiment 1, characterized in that it has a volume magnetic susceptibility of 3. The graphite has a viscosity of -0.9 x 10 in the marker. -4 3. The implantable marker of embodiment 1 or 2, characterized in that it has an apparent volume magnetic susceptibility of greater than 1000 .mu.m. 4. An embeddable marker according to any one of embodiments 1 to 3, wherein the graphite is isostatically pressed graphite. 5. The isostatically pressed graphite has a viscosity of at least about -1.2 x 10 in the marker. -4 4. The implantable marker of embodiment 3, characterized in that it has an apparent volume magnetic susceptibility of 6. An implantable marker as described in embodiment 5, characterized in that the isostatically pressed graphite contains less than 300 ppm of impurities. 7. An implantable marker as described in embodiment 5 or 6, characterized in that the isostatically pressed graphite contains more than 99.9% carbon. 8. The isostatically pressed graphite has a viscosity of at least about 1.75 g / cm 3 8. The implantable marker according to any one of embodiments 4 to 7, having a density of: 9. The isostatically pressed graphite has a viscosity of about 1.85 g / cm3 9. The implantable marker of embodiment 8, having a density of 10. The embeddable marker according to any one of embodiments 1 to 9, wherein the graphite is heat-treated graphite. 11. An implantable marker described in any one of embodiments 1 to 10, characterized in that the at least one diamagnetic element has a total volume that is approximately 100 to 10,000 times greater than the volume of the one or more ferromagnetic elements. 12. An implantable marker described in any of embodiments 1 to 11, characterized in that the one or more ferromagnetic elements include one or more wires or strips of ferromagnetic material having a length-to-diameter (or length-to-square-root-cross-sectional area) ratio of at least 50. 13. An implantable marker comprising a plurality of wires or strips formed from a ferromagnetic material, said wires being disposed around or extending axially through at least one diamagnetic core; The diamagnetic core has a magnetic field strength of at least about −0.16×10 -4 at least one body of isostatically pressed graphite having a bulk magnetic susceptibility of An implantable marker. 14. The isostatically pressed graphite has a hardness of at least about -1.2 x 10 -4 14. The implantable marker of embodiment 13, characterized in that it has an apparent volume magnetic susceptibility of 15. An implantable marker as described in embodiment 14, characterized in that the body of isostatically pressed graphite is substantially cylindrical. 16. An implantable marker as described in embodiment 14 or 15, characterized in that it comprises one or more helical coils of wire formed from a ferromagnetic material arranged around the diamagnetic core. 17. An implantable marker as described in embodiment 16, characterized in that it comprises a single helical coil of wire formed from a ferromagnetic material disposed around the diamagnetic core. 18. An implantable marker as described in embodiment 16, characterized in that it comprises three coils of wire formed from the ferromagnetic material arranged as a triple helix around the diamagnetic core. 19. An implantable marker according to any one of embodiments 14 to 18, wherein the diamagnetic core has a diameter of about 1 mm and a length of about 8 mm. 20. An implantable marker according to any one of embodiments 14 to 19, wherein each of the wires has a diameter of about 15 μm or less. 21. A method of making an implantable magnetic marker for use in a surgical procedure, comprising: forming one or more ferromagnetic elements from at least one ferromagnetic material; forming at least one diamagnetic element comprising graphite having a substantially isotropic grain structure; and thereafter assembling the one or more ferromagnetic elements and the at least one diamagnetic element such that the one or more ferromagnetic elements are juxtaposed to the at least one diamagnetic element. Including, The one or more ferromagnetic elements and the at least one diamagnetic element are constructed and arranged to generate mutually opposing magnetic moments in the presence of an applied magnetic field. A method characterized by: 22. The method for producing an embeddable magnetic marker of claim 21, wherein the graphite is isostatically pressed graphite, and the method includes performing an isostatic pressing process to provide the isostatically pressed graphite. 23. The method for producing an implantable magnetic marker according to claim 21 or 22, further comprising the step of heat treating the graphite at a temperature above about 2,200°C. 24. Use of graphite having a substantially isotropic grain structure in an implantable marker containing one or more ferromagnetic elements to reduce the magnetic moment of the marker in an MRI magnetic field, thereby minimizing the size of artifacts produced by the marker. 25. A detection system for locating an implanted marker, comprising: An implantable marker according to any one of embodiments 1 to 20; 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 implantable marker; a magnetic field generator arranged to drive an alternating magnetic field through the at least one drive coil; and at least one detector positioned to receive a signal from the sensing coil and to detect one or more harmonics of the drive frequency in the received signal; A detection system comprising:

Claims

1. 1. An implantable marker for use in a surgical guide, comprising one or more ferromagnetic elements formed from at least one ferromagnetic material and at least one diamagnetic element formed from at least one diamagnetic material, The at least one diamagnetic material includes graphite having a substantially isotropic grain structure, and the one or more ferromagnetic elements are juxtaposed to the at least one diamagnetic element. An implantable marker.

2. The graphite is −0.16×10 －４ 2. The implantable marker of claim 1, having a volume magnetic susceptibility of .gtoreq..times ...

3. The graphite has a particle size of −0.9×10 in the marker. －４ 3. The implantable marker according to claim 1, characterized in that it has an apparent volume magnetic susceptibility of greater than 1000 .mu.m.

4. 3. The embeddable marker according to claim 1, wherein the graphite is isostatically pressed graphite.

5. The isostatically pressed graphite has a viscosity of at least about −1.2×10 in the marker. －４ 5. The implantable marker of claim 4, having an apparent volume magnetic susceptibility of 0.1 to 0.

25.

6. 5. The embeddable marker of claim 4, wherein the isostatically pressed graphite contains less than 300 ppm of impurities.

7. 5. The implantable marker of claim 4, wherein the isostatically pressed graphite contains more than 99.9% carbon.

8. The isostatically pressed graphite has a viscosity of at least about 1.75 g / cm ３ 5. The implantable marker of claim 4, having a density of:

9. The isostatically pressed graphite has a density of about 1.85 g / cm ３ 5. The implantable marker of claim 4, having a density of:

10. 3. The embeddable marker according to claim 1, wherein the graphite is heat-treated graphite.

11. 3. The implantable marker of claim 1, wherein the at least one diamagnetic element has a total volume that is approximately 100 to 10,000 times greater than the volume of the one or more ferromagnetic elements.

12. 3. The implantable marker of claim 1 or 2, wherein the one or more ferromagnetic elements comprise one or more wires or strips of ferromagnetic material having a length-to-diameter ratio of at least 50.

13. An implantable marker comprising a plurality of wires or strips formed from a ferromagnetic material, the wires or strips being disposed around or extending axially through at least one diamagnetic core; The diamagnetic core has a magnetic field strength of at least about −0.16×10 －４ at least one body of isostatically pressed graphite having a bulk magnetic susceptibility of An implantable marker.

14. The isostatically pressed graphite has a viscosity of at least about −1.2×10 －４ 14. The implantable marker of claim 13, having an apparent volume magnetic susceptibility of

15. 15. The implantable marker of claim 14, wherein the body of isostatically pressed graphite is substantially cylindrical.

16. 16. An implantable marker as claimed in claim 14 or 15, characterized in that it comprises one or more helical coils of wire formed from a ferromagnetic material disposed around the diamagnetic core.

17. 17. The implantable marker of claim 16, comprising a single helical coil of wire formed from a ferromagnetic material disposed about the diamagnetic core.

18. 17. The implantable marker of claim 16, comprising three coils of wire formed from said ferromagnetic material arranged as a triple helix around said diamagnetic core.

19. 16. An implantable marker according to claim 14 or 15, characterized in that the diamagnetic core has a diameter of about 1 mm and a length of about 8 mm.

20. 16. An implantable marker according to claim 14 or 15, wherein each of said wires has a diameter of about 15 μm or less.

21. 1. A method of manufacturing an implantable magnetic marker for use in a surgical procedure, comprising: forming one or more ferromagnetic elements from at least one ferromagnetic material; forming at least one diamagnetic element comprising graphite having a substantially isotropic grain structure; and thereafter assembling the one or more ferromagnetic elements and the at least one diamagnetic element such that the one or more ferromagnetic elements are juxtaposed to the at least one diamagnetic element. Including, The one or more ferromagnetic elements and the at least one diamagnetic element are constructed and arranged to generate mutually opposing magnetic moments in the presence of an applied magnetic field. A method characterized by:

22. 22. The method of claim 21, wherein the graphite is isostatically pressed graphite, and the method includes performing an isostatic pressing process to provide the isostatically pressed graphite.

23. 23. The method of claim 21 or 22, further comprising the step of heat treating the graphite at a temperature above about 2,200°C.

24. 1. A detection system for locating an implanted marker, comprising: An implantable marker according to any one of claims 1 to 2 and 13 to 15; 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 implantable marker; a magnetic field generator arranged to drive an alternating magnetic field through the at least one drive coil; and at least one detector positioned to receive a signal from the sensing coil and to detect one or more harmonics of the drive frequency in the received signal; A detection system comprising:

Images