Marking materials and formats for magnetic mark location (MML)

Abstract

A magnetic marker for marking a site in a tissue in vivo. In one embodiment, the marker comprises a magnetic metallic glass. In another embodiment, the marker is a non-spherical configuration with an anisotropy ratio of less than 9. In another embodiment, the marker is a non-spherical configuration with an anisotropy ratio of less than 6. In another embodiment, the marker is a non-spherical configuration with an anisotropy ratio of less than 3.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 170,768, filed on June 4, 2015, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates generally to the field of labels for medical detection and more particularly to medical magnetic labels. Background Art

[0004] As mammography screening programs become more and more popular, most breast cancers are detected as small, imperceptible (or recessive) lesions that are amenable to breast-sparing therapy. Accurate positioning of imperceptible breast cancers is key to allowing surgical removal of the complete tumor with sufficient margin. If the tumor is not completely removed, the patient needs to undergo another operation to remove any remaining cancerous tissue. Accurate positioning also helps avoid removing excessive breast tissue, which can lead to adverse cosmetic effects. Other cancers require accurate positioning, such as colon cancer, prostate cancer and lung cancer, as well as other conditions known to those of ordinary skill in the art.

[0005] The current gold standard for localization of subtle lesions during surgery is Wire-Guided Localization (WGL). Despite the widespread use of this technology, WGL has multiple disadvantages. First, it involves two separate processes and can present logistical and scheduling difficulties between the radiology department and the surgical suite. Second, the positioning of the guidewire may not be optimal for achieving the desired cosmetic effect in subsequent surgery. Third, the hook wire can move away from the site of the lesion or become displaced during mammography or patient movement. Fourth, the insertion of the guidewire can be painful for the patient, and finally, the risk of infection means that surgery usually needs to occur on the same day as the guidewire insertion.

[0006] To overcome these disadvantages, other localization techniques have been developed. One such technique is Radioguided Occult Lesion Localization (ROLL), which uses a radioactive tracer injected into the tumor and detected by a handheld gamma probe. Although this eliminates the logistical complexity of WGL, the technique introduces the disadvantage of using radioactive materials, which require special handling and disposal procedures.

[0007] Magnetic markers are also used, and these overcome the inconvenience and logistical challenges that arise by using radioactive substances as markers, and they also avoid the disadvantages of guidewires.However, magnetic markers are relatively complex to manufacture compared to guidewires.

[0008] All known marking devices, including guidewires and magnetic markers, are introduced through a hollow needle or cannula. In order to minimize patient discomfort, the diameter of the needle is usually narrow. The small diameter of the needle constrains the cross-section of the marker. For traditional biopsy needles, this size is usually 14 to 18 standard sizes. This means that the needle has an inner diameter of usually 0.8mm to 1.5mm, but it is possible to be as large as 1.8mm for a specific needle design. If a vacuum-assisted needle is used, the needle size is usually 11 standard sizes, with an inner diameter of 2.3mm to 2.5mm. Therefore, magnetic markers are usually constrained to a diameter of less than 1.5mm. In practice, these size constraints limit the magnetic response and thus limit the ease with which the marker can be located using a magnetic probe. Therefore, a stronger magnetic response is desired.

[0009] Another challenge for magnetic biopsy markers is that in order to achieve an effective magnetic response, the volume of the material needs to be maximized. This volume requirement results in a marker with a typical shape that is significantly longer than its diameter. Such markers are in the region of 1 mm to 12 mm, where the ratio of length to diameter is greater than 5. This aspect ratio results in an inhomogeneous magnetic response, where a much stronger signal is obtained when the marker major axis is co-linear with the probe, and a weaker signal is obtained when the marker major axis crosses the probe. A more uniform response is generally desired.

[0010] In addition, the marker is usually guided to its position and confirmed in place under ultrasound or stereotactic X-ray imaging. This means that it is desirable for the marker to be clearly visible under X-ray or ultrasound imaging (preferably under MRI), which can also be used for this purpose.

[0011] What is needed is a label that has a small amount of material without reducing the intensity of the detectable signal and that provides a more uniform response from any direction relative to the magnetic probe.

[0012] The present invention addresses this need. Summary of the invention

[0013] The present invention relates to magnetic markers for surgical use. In particular, the present invention relates to magnetic markers that, once deployed, have a more uniform magnetic response than would be expected from their geometry prior to deployment.

[0014] In one aspect, a marker is provided whose shape is selected such that it provides a more uniform magnetic response.

[0015] In another aspect, a marker is provided whose geometry changes once deployed such that it provides a more uniform magnetic response.

[0016] In another aspect, a marker is provided whose material composition is selected such that it provides a more uniform magnetic response than would be expected from its geometry prior to deployment.

[0017] In one aspect, the marker is a non-spherical configuration having a magnetic susceptibility anisotropy ratio of less than 9. In another embodiment, the marker is a non-spherical configuration having a magnetic susceptibility anisotropy ratio of less than 6. In yet another embodiment, the marker is a non-spherical configuration having a magnetic susceptibility anisotropy ratio of less than 3. In one embodiment, the shape of the non-spherical marker configuration is selected from the group consisting of a cylinder, a cable, a "dumbbell-like" form, a bead, and a ball of yarn. In another embodiment, the cylinder bends when placed in tissue. In another embodiment, the non-spherical configuration has small facets.

[0018] In one embodiment, the marker is a magnetic marker for marking a site in a body tissue, comprising: a plurality of magnetic components connected by flexible non-magnetic components that become compact when placed in the site. In another embodiment, the magnetic marker for marking a site in a body tissue comprises a magnetic component having a first shape located in a non-magnetic matrix having a second shape. In another embodiment, the magnetic marker for marking a site in a body tissue comprises a magnetic material core in a magnetic material sheath. In yet another embodiment, one of the core and the sheath is a soft magnetic material.

[0019] In one embodiment, the magnetic marker for marking a site in a tissue in vivo comprises a plurality of magnetic components that self-assemble into a magnetic marker after the marker is placed in the body. In another embodiment, the magnetic components are all wrapped in a super-hydrophobic coating. In yet another embodiment, the magnetic marker for marking a site in a tissue in vivo comprises a magnetic metallic glass. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The structure and function of the present invention can be best understood from the description herein in conjunction with the accompanying drawings. The drawings are not necessarily to scale, but emphasis is generally placed on the illustrative principles. The drawings are to be regarded in all respects as illustrative and are not intended to limit the present invention, the scope of which is defined solely by the claims.

[0021] FIG. 1(A) and FIG. 1(B) are magnetization curves for soft magnetic materials and hard magnetic materials, respectively;

[0022] FIG2(A) is a graph showing the effect of the marker bend angle on the magnetic susceptibility anisotropy of the marker;

[0023] FIG2(B) is a diagram of an embodiment of a test arrangement for measuring magnetic anisotropy of a marker;

[0024] FIG2(C) is a signal at a constant distance from a 5 mm iron (99.5%) mark with various angles, where 180 degrees is a straight cylinder and 0 degrees is a U-shape;

[0025] FIG2(D) is a graph of a signal at a constant distance from a 7 mm multi-strand stainless steel marker having various angles, where 180 degrees is a straight cylinder and 0 degrees is a U-shape;

[0026] FIG. 3(A) is a diagram of an embodiment of the present invention having a "diamond" or "bead" form;

[0027] Figures 3(B) and 3(C) are cross-sections of magnetic beads having shaped ends;

[0028] Figure 4(A) to Figure 4(D) A diagram of an embodiment of the present invention in the form of a "dumbbell" shape;

[0029] 5(A) and 5(B) are cross-sectional views of an embodiment of the present invention in the form of a cable;

[0030] 6(A) and 6(B) are diagrams of an embodiment of the present invention having a "yarn ball" shape;

[0031] Figure 7 A diagram of an embodiment of the present invention having a "Chinese lantern" shape;

[0032] Figure 8(A) to Figure 8(G) A diagram of an embodiment of the present invention having an articulated link;

[0033] Fig. 9 A collection of drawings of cross-sections of labeled embodiments of the invention with increasing numbers of faces;

[0034] Fig.10 is a cross-sectional view of an embodiment of the present invention in the form of a core and a sheath;

[0035] Fig.11 is a drawing of an embodiment of the present invention having a sheath and multiple cores;

[0036] 12(A) and 12(B) are diagrams showing an embodiment of the present invention as a segmentation mark;

[0037] 13(A), 13(B) and 13(C) are diagrams of an embodiment of the present invention, wherein the shape of the magnetic material is different from the outer shape of the marker;

[0038] Figure 14(A) to Figure 14(E) Figures of embodiments of the present invention in the form of shaped markings of hinges made of various materials;

[0039] Fig.15A diagram of an embodiment of the present invention constructed by self-assembly;

[0040] Fig.16 A diagram of an embodiment of the present invention constructed by hydrophobic self-assembly;

[0041] 17(A) and 17(B) are diagrams of other embodiments of the present invention constructed by self-assembly;

[0042] Fig.18 A diagram of an embodiment of two interlocking U-shaped markers. DETAILED DESCRIPTION

[0043] A method for making magnetic markers such as permanent magnets is described in U.S. Patent No. 6,173, 715. Permanent magnet implants have the disadvantage that they will attract any magnetic material in the surrounding area and can therefore interact with other implants unexpectedly or move in tissue, for example, when surgical tools made of magnetic materials are nearby.

[0044] A method for making a marker formed of superparamagnetic iron oxide (SPIO) nanoparticles in a bioresorbable form is described in U.S. Publication No. 2014 / 0314679. SPIO particles avoid concerns about permanent magnet markers because such materials have no residual magnetism and are nonmagnetic themselves, but only become magnetized in the presence of a magnetic field. Detection and localization of these SPIO magnetic markers can be performed using a sensitive magnetometer (or susceptibility meter) that generates an alternating magnetic field to magnetically excite the marker and detects the magnetic field signal generated by the marker, as disclosed in U.S. Publication No. 2011 / 0133730.

[0045] Another challenge for magnetic biopsy markers is to achieve effective magnetic response, the volume of the material needs to be maximized. These requirements result in typical markers with a length significantly greater than the diameter, because the marker must be delivered by a needle and a smaller needle gauge (diameter) is less painful for the patient. Such markers are in the region of 1 mm to 12 mm, with a length to diameter ratio greater than 5. In practice, these size constraints limit the magnetic response and thus the ease with which the marker can be located using a magnetic probe. Therefore, a stronger response is desired.

[0046] In addition, the marker is usually guided to its position and confirmed in place under ultrasound or stereotactic X-ray imaging. This means that it is desirable for the marker to be clearly visible under X-ray or ultrasound imaging (preferably under MRI), and MRI can also be used for this purpose. SPIO particles have limited visibility under X-ray imaging, but can be made ultrasonically visible by combining these SPIO particles in a matrix of echogenic material (e.g., polymer). Although magnetic markers overcome the shortcomings of guidewires and radioactive methods, there is still a need for such magnetic markers: they can be introduced by narrow needles, provide strong magnetic response, be visible under X-ray and ultrasound imaging, and can be simply manufactured.

[0047] The need for the marker to be magnetically localizable requires a specific magnetic response from the implanted material, and for that response to be measurable at a certain distance away from the material. This response is related to the magnetic susceptibility parameter. In SI units, magnetic susceptibility is a dimensionless proportionality constant that represents the degree of magnetization induced in a material in response to an applied magnetic field and is defined as follows:

[0048] M=χH

[0049] Where M is the magnetization of the material measured in amperes per meter (magnetic dipole moment per unit volume), H is the magnetic field strength also measured in amperes per meter, and χ is a dimensionless constant of proportionality, i.e., the magnetic susceptibility. Strictly speaking, χ is a constant only for paramagnetic or diamagnetic materials, however, in soft or superparamagnetic materials where the hysteresis effect is small, and for an applied field H much smaller than that required to magnetically saturate the material, the linear relationship M = χH is a good approximation.

[0050] The magnetic susceptibility can be measured by a range of known methods, including Faraday magnetic balance, Gouy magnetic balance, magnetic resonance method, and induction method using SQUID magnetometer. The magnetic susceptibility can also be calculated using a computer-based finite element magnetic modeling package such as ANSYS Maxwell (ANSYS Inc., Canonsburg, PA) by modeling a marker in a homogeneous magnetic field and measuring the distortion caused by the marker corresponding to the magnetic susceptibility. See, for example, the method described in "Magnetic Susceptibility Modelling Using ANSYS" by K. Bartusek et al., published in the journal "Progress In Electromagnetics Research Symposium Proceedings" on March 20-23, 2011, Marrakech, Morocco.

[0051] For a given material, a mass magnetic susceptibility can be defined, which is the induced magnetic response of the material per unit mass. Mass magnetic susceptibility, χρ = k / ρ, where ρ is the density of the material and χ ρ The units of are m3 / kg. This is the normalized magnetic susceptibility and allows the relative magnetic susceptibility of different materials to be compared. For example, the mass magnetic susceptibility of 316 stainless steel (a standard material used for biopsy marking) has a value of approximately 3.80×10 -7 to 1.27×10 -6 range, permanent neodymium magnets have a range of approximately 6.67×10 -6 The value of superparamagnetic iron oxide (SPIO)-based labeling has a value of approximately 2.5 × 10 -5 to 1.0×10 -3 , while NiZn-ferrite has a value of about 3×10 -3 to 1.22×10 -1 Therefore, NiZn-Ferrite requires less material to detect than SPIO, and SPIO requires less material than permanent neodymium magnetic material or 316 stainless steel.

[0052] For a soft magnetic marker of volume V experiencing a field H in the linear susceptibility region, the total induced torque on the marker will be m=MV=χVH. This torque will induce its own magnetic field H marker , the magnetic field H marker At a certain distance away from the marker, it can be approximated as the magnetic field due to the equivalent point dipole moment, that is:

[0053]

[0054] Where r is a unit vector. The induced field H marker is measurable and enables the localization of magnetic markers.

[0055] However, there are factors that can affect the ease with which a given marker can be located, or in other words, affect the induced field H at a given r. marker One of these factors is called 'demagnetization'. This is a phenomenon that occurs in objects of finite size, where the induced field due to magnetization in one part of the body acts to demagnetize another part of the same body. Predicting this effect in other than the simplest geometries is very complex, so it is most often described, as here, for the special case of an object that is a spheroid of revolution (e.g., a sphere, cylinder, or disk). In such cases, the induced magnetization is uniform within the object, and the local magnetic field is usually written as:

[0056] H local =HH demag =H-NM

[0057] Among them, H demagis the 'demagnetization field' and N is the 'demagnetization factor', but more precisely, H should be divided along the x, y, z principal axes of the ellipsoid demag Defined as:

[0058] and

[0059] In SI units, N x +N y +N z = 1. For the case of a sphere, N x =N y =N z =1 / 3. For the case of a long z-axis cylinder, N x =N y =1 / 2 and N z = 0. For the case of a thin xy plane disk, N x =N y =0 and N z = 1. In the case of a mark made of a given single material of a given mass, the shape of the mark will affect the ease with which the mark can be located.

[0060] For example, if the token is made into a sphere, it will experience H local =H-1 / 3M, regardless of the orientation of the tag with respect to the applied field. The induced torque will therefore be:

[0061] m=χVH local =χVH-1 / 3χm or m=χVH / (1+1 / 3χ)

[0062] Induction field H marker It will therefore also be reduced by a factor of (1+1 / 3χ) at any given r, but this reduction will exist regardless of the orientation of the mark with respect to the magnetic field H.

[0063] By contrast: If the mark is made into a cylinder, then if H is oriented perpendicular to the long axis of the cylinder, then H marker will be reduced by a factor of (1+1 / 2χ), whereas if H is oriented along the major axis, then H marker In this case, the ratio ξ = (1 + 1 / 2χ) / 1 represents an anisotropic localization signal, and the cylinder will be based on the H used for its signal strength. marker The amplitude of the anisotropic positioning signal is presented to any method.

[0064] In the case of a cylinder of finite length, this ratio can be approximated by:

[0065]

[0066] Among them, N⊥ =N x =N y And N || =N z =1-2N ⊥ For example, in the case of the ferrite stainless steel sample listed in Table 2 (for which χ is approximately 140), the ξ ratio of 10.3:1 measured for a column with an aspect ratio of 7:1 corresponds to an N of approximately 0.48. ⊥ ; whereas the same material in a column with an aspect ratio of 3.7:1 exhibits an anisotropy ratio of approximately 4.7:1, which corresponds to an N of approximately 0.44 ⊥ .

[0067] Thus, for a magnetic marker, the magnetic response depends in part on the mass susceptibility of one or more of its constituent materials, and in part on the shape of the marker, and for a given shape, the response may vary with the orientation of the marker. The anisotropy of the magnetic response can be calculated using a demagnetization factor as described above. However, since demagnetization factors are very difficult to calculate for real shapes, a more practical approach is needed to define the anisotropy of the response. The change in magnetic response with orientation for a given marker can be viewed as a change in the "effective susceptibility" of the marker. The base susceptibility of the marker material does not change, but the change in magnetic response due to the combination of material, shape and orientation can be defined as if the susceptibility were changing.

[0068] Thus, for any given marker, a ratio of the maximum (effective) susceptibility to the minimum (effective) susceptibility can be defined. This ratio can be called the susceptibility anisotropy and gives an indication of the uniformity of the susceptibility response along different axes or from different directions of the marker.

[0069] Magnetic susceptibility anisotropy = maximum magnetic susceptibility / minimum magnetic susceptibility

[0070] Since the magnetic susceptibility is dimensionless, the magnetic susceptibility anisotropy, which is the ratio of two dimensionless quantities, is also dimensionless. If the anisotropy is 1, the magnetic susceptibility is the same from any direction. If the anisotropy is high, the magnetic susceptibility is very inhomogeneous with respect to the orientation of the mark.

[0071] The concept of magnetic susceptibility anisotropy is described in the art and can be measured by a variety of methods. For example, in "Understanding an Orogenic Belt" published by AK Dubey in the journal Springer Geology, two types of directional magnetic susceptibility meters are described: an equal impedance bridge in which the specimen can be inserted into a coil; and a balanced transformer system in which the specimen is placed inside a ferrite ring. Another method of a magnetic susceptibility meter called a three-dimensional magnetic anisotropy is described in U.S. Patent No. 3,492,566. In each case, a consistent magnetic field is applied to the sample, and the change in the induced magnetic response is measured as the sample orientation changes. Another such method is shown in FIG. 2 (C), in which a magnetic susceptibility measurement probe is used to measure the induced magnetic response. Using a magnetic susceptibility meter system similar to that described in U.S. Publication No. 2011 / 0133730, markers produced by various materials and in various forms have maximum and minimum signals measured at a fixed distance. The results are shown in Table 3.

[0072] Measuring magnetic susceptibility anisotropy using a susceptibility probe or susceptometer is an ideal method to define the uniformity of the magnetic response of a marker. However, there are alternative methods to determine the level of magnetic susceptibility anisotropy. For example, the projected area of ​​the marker in any direction can be measured and the maximum and minimum projected areas determined. For a given volume of marker material, a lower projected area indicates a greater focusing effect of the field, and vice versa. Since this focusing effect is inversely proportional to the projected area, the uniformity of the response can be defined by the ratio of the minimum projected area to the maximum projected area of ​​the marker from all available viewpoints or directions. This is the projected area anisotropy ratio of the magnetic marker and provides a useful approximation of the magnetic susceptibility anisotropy. A spherical marker will have a ratio of minimum projected area to maximum projected area equal to 1. A rod-shaped marker with a diameter d=0.75 and a length l=7.5 will have d×1 / (pi×d 2 / 4)=12.7.

[0073] It can also be seen that this ratio of projected areas is approximately equal to the shape factor of the tag, which is defined as the ratio of the largest dimension of the tag to its smallest dimension, and this can also be used as an approximation for the magnetic susceptibility anisotropy. Neither of these two geometric approaches takes into account variations in magnetic properties within the tag.

[0074] Where the term 'magnetic susceptibility anisotropy' or magnetic anisotropy is used throughout, the term 'projected area anisotropy' or 'ratio of largest dimension to smallest dimension' is understood as an alternative interchangeable measure of the uniformity of the magnetic response.

[0075] The magnetic susceptibility anisotropy may be determined for the markers before deployment (when in a delivery device) and after deployment. In the event that the marker configuration changes, the magnetic susceptibility anisotropy may have different values ​​before deployment and after deployment.

[0076] From a practical point of view, during the operation of detecting the marker using a magnetic probe as described in WO2014 / 013235, high anisotropy is unexpected: the magnetic signal at a constant distance will change according to the orientation of the marker relative to the probe and make the marker appear closer when approaching from some orientations and make the marker appear farther away when away from other orientations. Minimizing the anisotropy of the implanted marker improves the surgeon's ability to locate the marker by making the marker more intuitive, and improves the surgeon's ability to remove the safety margin of the tissue around the lesion. An anisotropy ratio of 1 is ideal, providing a uniform response from any direction. However, in practice, it is challenging to achieve within the geometric constraints of the delivery by a small needle as described herein. An anisotropy ratio of less than 7 (i.e., between 1 and 7), preferably less than 5 and more preferably less than 3 is expected. Because the magnetic response decreases exponentially with distance, an anisotropy ratio less than 2 is close enough to the ideal state for practical use.

[0077] An ideal magnetic marker is magnetized in the presence of a magnetic field and exhibits no permanent remanence (retained magnetization) when the magnetic field is removed, or in other words, an ideal marker is magnetically soft, i.e., is formed of a soft magnetic material or behaves as if it were magnetically soft. Soft magnetic is defined herein as having a coercive force Hc of less than or equal to 1000 Oe, or preferably less than or equal to 100 Oe, or more preferably less than or equal to 50 Oe, as expected in various embodiments. During detection, the marker is magnetized and follows the dotted line shown in FIG. 1 , returning via the solid line when the magnetic field is removed or reversed. When an alternating magnetic field is applied, the magnetizing drive field (H) pushes the material along the solid magnetization line around the ring once per cycle. The induced field in the material (called magnetization M) is detected by a magnetic susceptibility meter probe, such as the probe of U.S. Publication No. 2011 / 0133730. The ideal marker material is soft and has a magnetic field that is similar to that in Figure 1A The magnetization curve in is similar to the magnetization curve in.

[0078] It should be noted that permanent magnets are magnetically hard, have high remanence and high coercivity ( FIG. 1(B) ). Permanent magnets are generally not suitable for use as magnetic markers in the present application because they can attract or be attracted by other ferromagnetic objects (such as surgical tools) and because they generally have very low magnetic susceptibility.

[0079] The amount of material that needs to be implanted to make the magnetic label detectable depends on the magnetic susceptibility (χ v), more specifically depends on the mass magnetic susceptibility (χ ρ = x v / ρ), which can be expressed as:

[0080] χ ρ =(μ r -1) / ρ

[0081] Among them, μ r is the relative magnetic permeability, and ρ is the material density.

[0082] The materials used in magnetic markers should have a relative magnetic permeability greater than 100 and preferably greater than 500. When using specialty magnetic materials (such as high purity iron) or amorphous materials (such as metallic glass), the relative magnetic permeability is greater than 1000 and preferably greater than 5000. The marker should have a high mass magnetic susceptibility χ ρ For traditional magnetic materials such as iron, steel, and ferrite, χ ρ Should be greater than or equal to 0.05m 3 kg -1 , preferably greater than or equal to 0.1m 3 kg -1 , and more preferably greater than or equal to 1 m 3 kg -1 The use of specialized magnetic materials (such as high purity iron) or amorphous materials (such as metallic glass) allows even higher mass susceptibility, as well as χ ρ Preferably greater than 5m 3 kg -1 And more preferably greater than 10m 3 kg -1 .

[0083] If the material mass susceptibility is high enough, then a spherical marker that can be deployed from a conventional needle as described will be able to be magnetically localized and provide a fully isotropic signal. Table 1 shows the mass susceptibility of a number of magnetic materials.

[0084] Table 1

[0085]

[0086]

[0087] Mass Magnetic Susceptibility of Various Materials

[0088] Note: Negative values ​​indicate diamagnetic materials

[0089] The detection and location of these magnetic markers can be performed using a sensitive magnetometer (or susceptibility meter) that generates an alternating magnetic field to magnetically excite the marker and detects the magnetic field signal generated by the marker, as disclosed in U.S. Publication No. 2011 / 0133730. The markers can also be detected by other techniques such as MRI, magnetic particle imaging, eddy current measurement, Hall effect, or magnetic tomography.

[0090] In one aspect of the invention, the marker comprises a superparamagnetic particle. Superparamagnetic particles typically comprise an iron oxide (magnetite and / or hematite) core surrounded by a biocompatible coating (such as dextran, carboxydextran, other sugars, albumin, PEG, or a biocompatible polymer). In order to exhibit superparamagnetic behavior, the magnetic core of the particle needs to be below a critical diameter, typically in the range of 3nm-25nm depending on the material and structure.

[0091] Iron oxide is the preferred material for superparamagnetic cores due to its low toxicity, but there are other materials that can form superparamagnetic cores. The material of the core should be a material that can be magnetically ordered. It can be: a metal such as cobalt, iron or nickel; a metal alloy; a rare earth and transition metal alloy; an M-type or spinel ferrite containing aluminum, barium, bismuth, cerium, chromium, cobalt, copper, dysprosium, erbium, europium, gadolinium, holmium, iron, lanthanum, lutetium, manganese, molybdenum, neodymium, nickel, niobium, palladium, platinum, praseodymium, promethium, samarium, strontium, terbium, thulium, titanium, vanadium, ytterbium, and yttrium or a mixture thereof.

[0092] The core can also be formed by oxidizing a combination of an iron (II) salt and another metal salt. Advantageous metal salts include aluminum salts, barium salts, bismuth salts, cerium salts, chromium salts, cobalt salts, copper salts, dysprosium salts, erbium salts, europium salts, gadolinium salts, holmium salts, iron salts, lanthanum salts, lutetium salts, manganese salts, molybdenum salts, neodymium salts, nickel salts, niobium salts, palladium salts, platinum salts, praseodymium salts, promethium salts, samarium salts, strontium salts, terbium salts, thulium salts, titanium salts, vanadium salts, ytterbium salts, and yttrium salts.

[0093] In another aspect of the invention, the marker comprises a solid soft magnetic material to provide a significantly increased magnetic response when located using a susceptibility meter probe. Markings produced by soft magnetic materials can include various paramagnetic, ferromagnetic, and ferrimagnetic materials, such as: iron, nickel, cobalt and their alloys, electromagnets (including FM, high-temperature alloy electromagnets), silicon-iron (including "A", "A-FM", "B", "B-FM", "C" variations), phosphorus-containing iron, nickel-iron (e.g., HyRa alloy, HyMu alloy, Hipemom, cis alloys, super alloys, Mu-metal), Heusler alloys, Fernico alloys (alloys based on iron-nickel-cobalt), Cunife alloys (alloys based on copper-nickel-iron), Alcomax alloys (alloys based on iron-nickel-aluminum-cobalt-copper), various stainless steels from the 300 series (e.g., 302, 304, 316), 400 series (e.g., 410, 416, 420, 430, 440, 446, 470), and specialty stainless steel alloys (e.g., chromium-iron alloys such as chromium- series (Carpenter Technology Corp, Wyomissing PA), martensitic stainless steel), ferrites such as MnZn-ferrite, NiZn-ferrite, MgZn-ferrite, Ba-ferrite, MnMgZn-ferrite, and MgZnCu-ferrite.

[0094] In a preferred aspect of the invention, the marker comprises a metallic glass having a very high mass magnetic susceptibility to provide a significantly improved magnetic response. Metallic glasses are also referred to as amorphous metals or bulk metallic glasses and include: Fe or Co-based materials such as those produced by Metglas, Inc. (Conway, SC) or Neomax Materials, LLC (Osaka, Japan); and magnetic carbon allotropes (e.g., fullerenes, highly oriented pyrolytic graphite, carbon nanofoam, nanoporous carbon). Examples of metallic glasses include, but are not limited to: FINEMET, NANOPERM, HITPERM (all Hitachi Metals, Tokyo, Japan), METGLAS #2605, METGLAS #2826, METGLAS #2615, METGLAS #2714A, METGLAS #2605.

[0095] To ensure biocompatibility, these materials can be coated with or contained in biocompatible or inert materials, such as bioglass, diamond-like-carbon (DLC), gold, hydroxyapatite, iron, magnesium, nitinol alloy, polyparaxylene, phosphorylcholine (PC) polymer, polymethylbutylacrylate (PMBA) and polyethylene vinyl acetate (PEVA), polyethylene, PET, polytetrafluoroethylene (PTFE), PEBAX, PEEK, PEKK, platinum, silicone, titanium, etc.

[0096] Additionally, forming materials such as spring steel or shape memory material alloys such as Nitinol and shape memory polymers such as PEO-PET block copolymers and PEEK may also provide the additional functionality of forming a specific shape upon deployment, provided that they surround or are surrounded by a soft magnetic material.

[0097] The magnetic material can also be held within a biocompatible matrix such as collagen, gelatin and other cellulosic matrices, polyvinyl alcohol (PVA), polygluconic acid esters, polyester-based materials (formed by homopolymerization or copolymerization of one or more of the following monomers: glycolide, L-lactide and its isomers, ε-caprolactone, p-dioxanone and trimethylene carbonate (TMC)). These materials may include homopolymers such as poly(L-lactide), poly(DL-lactide), poly(TMC), polycaprolactone (PCL), polyglycolide (PGA), poly(glycolide-L-lactide) (PGL), or poly(p-dioxanone) (PDS); or copolymers such as L-lactide / DL-lactide, L-lactide / glycolide, L-lactide / caprolactone, DL-lactide / glycolide, DL-lactide / caprolactone, glycolide / caprolactone, L-lactide / glycolide / caprolactone, DL-lactide / glycolide / caprolactone, poly(dioxyester-co-trimethylene carbonate-co-glycolide), Glykomer 631 (sold as ); or copolymers of these substances with PDS, hydrogel (derived from one or more monomers selected from the following: hydroxyethyl methacrylate, hydroxyethoxyethyl methacrylate, hydroxydiethoxyethyl methacrylate, methoxyethyl methacrylate, methoxyethoxyethyl methacrylate, methoxydiethoxyethyl methacrylate, ethylene glycol dimethacrylate, N-vinyl-2-pyrrolidone, N-isopropylacrylamide, vinyl acetate, acrylic acid, MAA, N-(2-hydroxypropyl)methacrylamide, ethylene glycol, PEG acrylate, PEG methacrylate, PEG diacetate, PEG dimethacrylate).

[0098] In one aspect of the invention, an implanted marker is made of a single soft magnetic material and the marker is shaped to reduce the anisotropy of the magnetic response. The anisotropy is defined as the ratio of the maximum magnetic response to the minimum magnetic response. Anisotropy occurs in shapes with an elongated aspect ratio because the soft magnetic material focuses any magnetic field lines running through them. The focusing effect depends on the amount of material in the direction of the field lines. Therefore, an elongated shape focuses many more field lines passing through the material when its long axis is aligned with the field than when its long axis is perpendicular to the field lines. The result is that the magnetic response measured by the susceptibility meter is much larger in the direction of the long axis than in the direction of the short axis.

[0099] Table 2 shows the anisotropy ratios for a large number of cylinders of magnetic material of various sizes.

[0100] Table 2

[0101]

[0102] Magnetic susceptibility anisotropy ratio for cylinders of various sizes and materials at a constant distance

[0103] Anisotropy can be changed by changing the shape to affect the focusing effect. For example, by creating a bend in the marker, the anisotropy ratio for a given pre-deployed size ratio can be significantly reduced (Table 3). A 130° angle unexpectedly reduces the anisotropy ratio from 6.7 to 4.5, and a U bend further reduces the ratio to 2.1. In another example, a 90° bend reduces the anisotropy ratio from 10.7 to 2.6, and a 60° angle further reduces the ratio to 1.28. Referring again to Table 2, using a susceptibility meter system similar to that described in U.S. Publication No. 2011 / 0133730, markers produced by various materials and in various forms have maximum and minimum signals measured at a fixed distance. The figure shows that there is an optimal angle for a uniform signal when the angle is between 0° and 90° and more preferably between 0° and 45°. Fig.18 It is shown how the signal changes with the sensed angle relative to the major axis of the mark for marks with different included angles.

[0104] Table 3

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] Anisotropy ratio for various shapes and sizes of magnetic markers at a constant distance

[0113] FIG. 2(A) is a graph of the relative change in the anisotropy ratio when the angle of the bend in the mark is reduced. The measurements were performed using the test arrangement in FIG. 2(B). The graph (FIG. 2(A)) shows that there is an optimal angle for a uniform signal when the angle is between 0° and 90° and more preferably between 0° and 45°. FIG. 2(C) is a graph showing how the signal changes with the sensing angle relative to the main axis of the mark for iron marks with different angles. FIG. 2(D) is a graph showing how the signal changes with the sensing angle relative to the main axis of the mark for iron marks with different angles.

[0114] In some cases, it may be advantageous for a marker to take on a shape only after it is deployed so that it can be more efficiently packaged in a deployment needle prior to deployment. An elastic material or a length of elastic material may be used to facilitate this.

[0115] Such shapes include but are not limited to the following:

[0116] - a "diamond" or "bead" shape (FIG. 3(A)), which reduces anisotropy by providing more magnetic material in the transverse axis (perpendicular to the long axis of the bead). Such markers may include shaped ends that include narrower sections that focus the field in a direction away from the major axis (FIGS. 3(B) and 3(C)). For example, a finite element model of the marker of FIG. 3(C) and a probe of the type described in U.S. Publication No. 2011 / 0133730, where the marker was at a distance of 20 mm from the probe tip, provided a magnetic susceptibility anisotropy ratio of 2.5;

[0117] -like Figure 4(A) to Figure 4(D) The "dumbbell type" design shown is made of multiple sections of the same material. This design similarly provides more magnetic material along the horizontal axis. In various embodiments, the length of the marker is about 5mm-10mm and is useful in reducing opposing eddy currents. For example, a finite element model of the marker and a probe of the type described in U.S. Publication No. 2011 / 0133730 (where the marker is at a distance of 20mm from the end of the probe) provides a magnetic susceptibility anisotropy ratio of 2.6;

[0118] - The cables or multifilament strands shown in Figures 5(A) and 5(B) may be twisted. A number of strand forms are shown, but other strand forms (such as 1x4, 1x5, etc.) with 3, 4, 5, 6, 7, or more strands are equally possible; using strands reduces opposing eddy current losses and having multiple faces provides superior ultrasonic response. The filaments may also be hollow, as shown, or include void areas between the strands;

[0119] - Including acute and obtuse angles of curved wire or tube, U-shape, X-shape (Table 3);

[0120] - a single length cylindrical mark divided into two or more similarly sized flakes provides an improved anisotropy ratio of less than 5;

[0121] - Cylindrical markers with a larger diameter central section and a smaller diameter outer section also provide an improved anisotropy ratio;

[0122] - A tag consisting of two interlocking U-shaped elements ( Fig.18 ).

[0123] In one aspect of the invention, the implanted marker is made primarily of a soft magnetic material and has an elongated aspect ratio before deployment but changes configuration to a shape with low magnetic susceptibility anisotropy after deployment. Before deployment, the marker may have a length to diameter ratio or shape factor greater than 5 and a magnetic susceptibility magnetic anisotropy ratio greater than 5 or even greater than 7 or 9, such values ​​​​derive from the extended length of the marker before deployment and are beneficial to increase the volume of the marker contained in the needle, thereby maximizing the magnetic response once deployed. After deployment, the magnetic susceptibility magnetic anisotropy ratio is less than 5 and preferably less than 3, and ideally 2 or less than 2 to provide a more uniform magnetic response.

[0124] In one aspect, the marker is elastically deformable or recoverable so that the marker elastically or resiliently changes in shape and size from a packaged or pre-deployed shape and associated form factor within a needle or deployment device to a deployed shape and form factor. The elasticity or restorative force can, for example, be derived from the use of elastic or resilient materials or from elastic structures, resilient structures or deployable structures or combinations thereof. Preferably, the magnetic marker is elastically deformable or recoverable between a packaged configuration with a higher magnetic susceptibility anisotropy and a deployed / opened configuration with a lower magnetic susceptibility anisotropy. Alternatively, the magnetic marker is elastically deformable or recoverable between a packaged configuration with a higher projected area anisotropy ratio and a deployed / opened configuration with a lower projected area anisotropy ratio.

[0125] Preferably, the deployed or transported configuration of the marker has a magnetic susceptibility anisotropy of less than 5, more preferably less than 3 and ideally less than 2, thereby providing the most uniform detection signal; while before being deployed in the delivery device, the marker has a magnetic susceptibility anisotropy of greater than 5 and more preferably greater than 7 in its packaged configuration, thereby maximizing the volume of material in the marker given the constrained diameter of the delivery device. By analogy, the marker has a projected area anisotropy ratio of greater than 5 and more preferably greater than 7 in its packaged configuration; but has a projected area anisotropy ratio of less than 5, more preferably less than 3 and ideally less than 2 in the deployed / opened configuration. In order to achieve this configuration change, the marker requires a certain degree of restoring force, whereby one dimension of the marker (e.g., the diameter perpendicular to the major axis) changes from its packaged value to its deployed value by a factor of at least 1.5. Preferably, the deployed dimension is greater than 2 times the packaged dimension, and more preferably greater than 3 times the packaged dimension, thereby providing a form factor (ratio of the largest dimension to the smallest dimension) close to 1 or 2 in deployment, while still having sufficient material to be detected.

[0126] The magnetic marker in its packaged configuration is packaged in a delivery device before use. The delivery device needs to be able to deliver the marker through the skin to mark an area of ​​tissue of interest, such as a cancerous lesion. Suitable delivery devices include any needle- or cannula-based delivery system, which typically includes a needle and a component, such as a piston or stylet, for pushing the marker through the end of the needle or out of the side of the needle. The needle is preferably 14 to 18 standard sizes. This means that the needle has an inner diameter of typically 0.8mm to 1.5mm, but it is possible to be as large as 1.8mm for a specific needle design. Preferably, the diameter of the needle is between 1.0mm and 1.5mm. If a vacuum-assisted needle is used, the needle size is typically 11 standard sizes, with an inner diameter of 2.3mm to 2.5mm.

[0127] Indicia that achieve the desired change in magnetic susceptibility anisotropy between the packaged configuration and the opened configuration include, but are not limited to, the following:

[0128] A "ball of yarn" type form (FIGS. 6(A) and 6(B)) which reduces anisotropy by providing a substantially consistent amount of magnetic material on any given axis of the marker. The multiple facets also provide superior ultrasonic response. The ball of yarn is preferably formed from a material having a large magnetic response, such as a metallic glass or soft magnetic material from the above list. The ball can be formed from a filament having a diameter, for example, between 10 μm and 250 μm and a length, for example, between 5 mm and 150 mm, and bent into a spherical shape. The marker can be elastically deformable or recoverably deformable. The marker is compressed to fit inside a deployment needle or delivery device, wherein, prior to delivery, the marker can be constrained to adopt a more cylindrical shape. Upon deployment, the ball expands to near its original size and adopts a substantially spherical shape. Table 3 shows that the marker can achieve an anisotropy ratio close to the ideal value of 1.

[0129] "Chinese Lantern" form ( Figure 7 ). When deployed, the marker is arranged so that it resiliently reconfigures from a pillar to a more compressed lantern configuration, thereby increasing the uniformity of the magnetic response (reducing anisotropy) because the amount of material on the transverse axis is increased compared to the amount of material in the pillar. Multiple facets also provide superior ultrasonic response.

[0130] like Figure 8(A) to Figure 8(G) The marker shown includes multiple soft magnetic elements connected by hinges, which deform into a shape when deployed (either plastically pre-stressed or through the behavior of shape memory in the material). In this embodiment, greater lengths of the marker are possible because the shape of the marker in the deployment needle is linear but folds into another configuration after injection into the site. This reduces anisotropy by providing a substantially consistent amount of magnetic material in any given axis of the marker.

[0131] Advantageously, multiple facets also provide superior ultrasonic response. It is contemplated that there are at least three elements to obtain a uniform response, and more elements may be added, but for complexity, the number is preferably less than 20 and more preferably less than 10. Articulated and other flexible or recoverable forms may include multiple smaller magnetic units or components joined by non-magnetic flexible or recoverable links (such as plastic or shape memory materials). Combinations of these forms are also included, such as curved wires made from multiple strands of cable. As shown in Table 3, such a marker having multiple spherical elements and a pre-deployment geometric length to diameter ratio of 8 can have a post-deployment magnetic susceptibility anisotropy of less than 2.

[0132] A marker comprising multiple elements joined by foldable links between them, which, when deployed, fold together to form amorphous regions with low magnetic susceptibility anisotropy ratios. These links may be formed of rope-like materials such as sutures or other polymers. Preferably, the soft magnetic elements are links in a chain that can fold on themselves after deployment.

[0133] Markers comprising elastic or recoverable wire or cylindrical shapes prior to deployment, which form a structure or wireframe when deployed. Such structures may include cylindrical coils, helices, conical coils, spherical coils, random "balls of yarn", or polyhedrons (such as tetrahedrons) or portions thereof.

[0134] Indicia of a spring comprising a resiliently deformable annular or shaped helical spring that is compressed prior to deployment and expands to a shape having a low magnetic susceptibility anisotropy ratio upon deployment. For example, a helical spring shaped as a ring provides a surprisingly low magnetic susceptibility anisotropy ratio (Table 3). Preferably, the ratio of the ring diameter to the spring coil diameter is less than 5, thereby maintaining a more uniform magnetic response.

[0135] Includes a marker of two or more elements connected by a link formed by an elastic or recoverable or resilient material, so that these elements once deployed elastically change to a new configuration that provides low magnetic susceptibility anisotropy. Table 4 shows one such embodiment, which includes two short cylindrical elements formed by soft magnetic materials joined by elastic filaments. In the deployment needle, the two elements are constrained to be aligned and joined axially by the filaments. The filaments are biased so that when deployed, the two elements span each other and rebound to approach a tetrahedral shape with a low magnetic susceptibility anisotropy ratio of less than 2. The elastic filaments can be formed by spring steel, shape memory materials, or other elastic or recoverable deformable materials. Preferably, the length of the cylindrical element is 2 to 5 times its diameter to provide good uniformity of response and a compact shape. In another embodiment of the concept, multiple elements on an elastic material are deployed by a needle and the elastic material is biased so that these elements form a structure when deployed. Exemplary structures may include cylindrical coils, spirals, conical coils, spherical coils, random "balls of yarn," or polyhedrons or portions thereof. In these designs, the length of the tag when in its packaged configuration may be 2 to 5 times its diameter, but may be even greater, such as up to 10 or more times the diameter, depending on the degree of structural flexibility of the material used, thus allowing more magnetic material to be deployed to maximize the detectability of the tag.

[0136] Another benefit of the stranded or faceted form of the "ball of yarn" (FIG. 6) is visibility superior to reflective imaging techniques such as ultrasound, IR, or ultra-wideband radar. These benefits can also be achieved by modifying the outer surface of the other forms mentioned, including articulated forms ( Figure 7 ) (from cylindrical forms to faceted or grooved forms) non-articulated cross-sections such as, but not limited to, triangular, pentagonal, dodecagonal, gear-shaped cross-sections ( Fig. 9 ). Similar effects can be observed in ultrasound from sintered materials such as ferrites. The right choice of soft material in any of the mentioned forms can provide visibility to X-ray imaging. Interlocked U uses a similar space as U, but with increased signal and reduced anisotropy ( Fig.18 ).

[0137] The above features can be combined to provide markings with reduced anisotropy and improved imaging.

[0138] In another aspect of the invention, the magnetic susceptibility anisotropy ratio of an implanted marker is modified by changing the magnetic properties of the soft magnetic material forming the marker along the length of the marker.

[0139] In another aspect of the invention, reduction in magnetic susceptibility anisotropy may be achieved by using a composite material such as a ferrite formed from two or more materials by sintering, wherein at least one material is a soft material distributed to provide a less anisotropic response. Similar forms may be formed, as described above, using multiple materials within a tag. One such embodiment is a tag of a single section having a constant cross-section.

[0140] An additional benefit of this aspect of the invention is that the soft distribution or shape may be independent of the external form and cross-section, which improves imaging visibility under ultrasound or X-ray.Other examples of composite magnetic markers with reduced anisotropy include soft markers distributed on a foldable stent-like structure, in particular, those that are self-expanding.

[0141] In addition, embodiments of cables or multifilament strands (particularly when twisted) include hollow forms wherein the individual filaments are formed of different materials or are formed of composite materials, such as core and cover or sheath materials, wherein at least one or more of these materials is a soft magnetic material. A specific example is where the core or cover material is formed of Nitinol alloy or other shape memory materials (including shape memory polymers) for forming a deployed shape ( Fig.10 ). It is also possible to form a wire in which a core made of a plurality of materials, covered by a sheath material, is produced and used directly as a magnetic marker or subsequently in a cable or multi-strand form ( Fig.11). The wire or one of the sections of the multi-core wire may also be used to provide improved X-ray visibility.

[0142] Figures 12(A) and 12(B) are examples of segmented markings (note: more or fewer segments are possible). Segmentation increases losses between sections in the axial direction and manages opposing eddy current effects, reducing anisotropy.

[0143] Figures 13(A) and 13(B) show examples of soft materials (dark grey) that can be molded into shapes that are independent of the shape of the marker (note: more than two materials can be used within the construction). Anisotropy is improved by providing more magnetic material on the horizontal axis and reducing opposing eddy currents through the combination of selected materials. In one embodiment shown in Figure 13(C), the soft magnetic core is formed of a material with a very high magnetic response (such as metallic glass) so that sufficient magnetic response can be obtained from only a very small spherical surface of the material. The core is wrapped in a protective layer that includes a biocompatible coating or capsule, such as a titanium shell or a biocompatible polymer coating. Because the core is spherical, the magnetic susceptibility anisotropy ratio is close to 1.

[0144] exist Figure 14(A) to Figure 14(E) Formed markers with plastic / prestressed / shape memory hinges using multiple materials with different magnetic properties are shown in . These configurations improve the customization of the response, thereby reducing anisotropy by providing a substantially uniform response in any given axis of the marker. Multiple facets also provide superior ultrasonic response.

[0145] In another aspect of the invention, an elongated marker is divided into multiple smaller markers. Multiple markers packaged together prior to deployment have the same overall size and material and can be used to reduce anisotropy relative to the overall size of the material. For example, a 3×2 mm long or 2×3 mm long or 6×1 mm long marker sheet has a reduced anisotropy than a 1×6 mm long marker of the same outer diameter. Surprisingly, this reduction in anisotropy occurs even when multiple segments are aligned one after another in the same shape as the individual markers of the combined size. (Table 5) For example, a single marker of 5 mm in size using ferrite stainless steel provides an anisotropy ratio of 6.7. Two markers of 3 mm in size using the same material provide an anisotropy ratio between 3.2 and 4.6 depending on the relative orientation.

[0146] Table 5

[0147]

[0148]

[0149] In another specific example, a group of markers or magnetic particles produced from soft magnetic materials can retain a small amount of magnetism. Once deployed in a patient, these magnetic particles can self-assemble into associated magnetic markers that have a lower magnetic susceptibility anisotropy. Multiple soft magnetic markers with small remanent magnetization will self-assemble into associated magnetic markers that have a substantially consistent amount of material in each direction, thereby minimizing anisotropy ( Fig.15 ). This small remanence can be overcome by magnetic excitation of the excitation field of a magnetometer (or magnetic susceptibility meter) as described above. Table 6 shows the parameters of particles assembled with two types of magnetic compositions.

[0150] Table 6

[0151]

[0152] In another example of this, soft magnetic markers or particles enclosed in hydrophobic surfaces (nanotextures with lotus effect, silica nanocoatings, EnBio CoBlast PTFE, hydroxyapatite, carbon nanotube coatings, precipitated calcium carbide and fatty acid coatings with composite latex, manganese oxide polystyrene or zinc oxide polystyrene nanocomposites) or spheres will be pulled together (self-assembled) into the patient upon deployment. To minimize surface energy, this embodiment will form a tightly packed shape, such as a sphere or ellipsoid system, which will have improved magnetic susceptibility anisotropy relative to the particles within the delivery system, which will be constrained in an elongated shape that will be elongated. Fig.16 Hydrophobically coated tags or particles are shown, which, in order to minimize surface energy, self-assemble into associated magnetic tags with a substantially uniform amount of material in each direction, minimizing anisotropy.

[0153] In another aspect of the present invention, small micro-markers or micro-particles of soft material can be suspended in a biocompatible matrix (FIG. 17(A) and FIG. 17(B)). Fig.10 Control of the magnetic particle distribution in a manner similar to that discussed in relation to Figure 12 allows for reduced magnetic susceptibility anisotropy and independence from extrinsic form. It can also be used to ensure set positions and orientations between magnetic markers.

[0154] In another example for this case, by using a gel matrix in which soft magnetic particles are suspended and by appropriately adjusting the size of these particles, the gel and particles can be deployed by a deployment needle (FIG. 17(B)). The shape of the deployed gel and particles will be constrained only by the injection site (i.e., the diseased tissue), which is smaller than the needle. The gel can also be set at the time of injection so that it is less likely to migrate from its deployment location and easier to surgically remove the gel if the tissue is being removed. If necessary, the addition of other particles (such as gold) can be performed to provide additional radiopaque response for X-ray visualization. In order to mark positioning, the anisotropy should be less than or equal to 9, preferably less than or equal to 6, and more preferably less than or equal to 3.

[0155] The present invention provides various ways to make magnetic labels with acceptable anisotropy while not affecting the ease of delivery of the particles.

[0156] In another aspect of the invention, a method for marking a soft tissue site of interest is provided, such as, for example, a site of a tumor or benign lesion in the chest, lung, intestine / colon, rectum, prostate or other cancer-affected organ, or a lymph node in the axilla or other nodular depression in the body. The method comprises the steps of (i) inserting such magnetic markers into tissue near the target lesion or site, and (ii) detecting such markers using a magnetic susceptibility meter, and optionally (iii) surgically cutting the target tissue around the marker. Preferably, the magnetic susceptibility meter detects the marker by providing a magnetic field in the region of the marker and measuring the induced magnetization in the marker.

[0157] Unless otherwise indicated, all numbers used in the specification and claims to express length, width, depth or other dimensions, etc., will be understood in all cases to indicate the exact values ​​shown and to be modified by the term "approximately". Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximate values ​​that may vary depending on the expected performance sought to be obtained. At least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be interpreted in view of the number of reported significant digits and by applying ordinary rounding techniques. Any specific value may vary by 20%.

[0158] The terms "a", "an", "the" and similar referents used in the context of describing the present invention (especially in the context of the appended claims) will be deemed to cover the singular and the plural, unless otherwise indicated in this article or clearly contradicted by the context. All methods described herein can be performed in any suitable order, unless otherwise indicated in this article or clearly contradicted by the context. The use of any example and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of any claim. None of the language in the specification should be deemed to indicate any non-requested element that is essential to the practice of the present invention.

[0159] The grouping of alternative elements or embodiments disclosed herein should not be considered as limiting. Each group member can be quoted and requested for protection individually or in any combination with other members of the group or other elements found herein. For convenience and / or patentability reasons, it is expected that one or more members of a group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, the specification is deemed to include the group as modified, so the written description of all Markush groups used in the appended claims is completed.

[0160] Specific embodiments are described herein, including the best mode known to the inventor for carrying out the spirit of the invention. Of course, after reading the above description, variations to these described embodiments will become apparent to those of ordinary skill in the art. The inventor expects the skilled person to adopt such variations as appropriate, and the inventor intends to practice the invention in other ways than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter listed in the claims as permitted by applicable law. In addition, any combination of the above elements in all possible variations is contemplated, unless otherwise indicated herein or clearly contradicted by context.

[0161] Finally, it should be understood that the embodiments described herein illustrate the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be utilized according to the teachings herein. Accordingly, the claims are not limited to the embodiments as precisely shown and described.

Claims

1. A marker for marking the deployment of a site in a tissue, the marker comprising: A segmented mark having one or more segments, each segment consisting of a magnetic coercivity less than 1000 Oe and a magnetic susceptibility greater than 0.05 m 3 kg -1 Made of soft magnetic material; wherein the magnetic susceptibility anisotropy ratio of the marker is less than 5, and the marker is configured to be detected using magnetic susceptibility; and Wherein each magnetic segment defines a shape selected from the group consisting of: a ring, a ball of yarn, a Chinese lantern, a cable, a U-shape, a chain, and a coil.

2. The marking according to claim 1, wherein: The marker has a size ratio greater than 2.7 prior to deployment.

3. The marking according to claim 1, wherein: The magnetic susceptibility anisotropy ratio of the marker is less than 3.

4. The marking according to claim 1, wherein: The magnetic segment includes a magnetic amorphous material.

5. The marking according to claim 1, wherein: The first magnetic segment is linked to the second magnetic segment by a flexible non-magnetic component.

6. The marker of claim 1 further comprising a matrix comprising a biocompatible material.

7. The marking according to claim 1, wherein: The marked section is coated with or disposed within a biocompatible material.

8. The marking according to claim 7, wherein: The biocompatible material is selected from: bioglass, Diamond-like carbon (DLC), gold, hydroxyapatite, iron, magnesium, nitinol, parylene, phosphorylcholine (PC) polymer, polymethyl butylacrylate (PMBA) and polyethylene vinyl acetate (PEVA), polyethylene, PET, polytetrafluoroethylene (PTFE), PEBAX, PEEK, PEKK, platinum, silicone, titanium.

9. The marking according to claim 1, wherein: The segment marking has a constant cross section.

10. The marking according to claim 1, wherein: The length of each segment is equal to the length of the other segments of the tag.

11. The marking according to claim 1, wherein: The cross-section of a section of the marking differs from the outer shape of the marking.

12. The marking according to claim 1, wherein: The marker is a cylindrical marker having a center section of larger diameter and an outer section of smaller diameter.

13. The marking according to claim 1, wherein: Each segment is aligned with another segment in the axial direction of the marking.

14. The marking according to claim 1, wherein: The marker can be deployed using a needle, wherein the marker has a first configuration before deployment and a second configuration after deployment, wherein the first configuration and the second configuration are different.

15. A marking according to any one of the preceding claims, wherein: The magnetic material has a coercive force less than 100 Oe.

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