WO2006119645A1 - Marker device for x-ray, ultrasound and mr imaging - Google Patents

Marker device for x-ray, ultrasound and mr imaging Download PDF

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Publication number
WO2006119645A1
WO2006119645A1 PCT/CA2006/000782 CA2006000782W WO2006119645A1 WO 2006119645 A1 WO2006119645 A1 WO 2006119645A1 CA 2006000782 W CA2006000782 W CA 2006000782W WO 2006119645 A1 WO2006119645 A1 WO 2006119645A1
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Prior art keywords
marker
tissue
region
ultrasound
interest
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PCT/CA2006/000782
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French (fr)
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WO2006119645B1 (en
Inventor
Donald B. Plewes
Yangmei Li
Jian-Xiong Wang
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Sunnybrook And Women's College Health Sciences Centre
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Priority to CA002579914A priority Critical patent/CA2579914A1/en
Publication of WO2006119645A1 publication Critical patent/WO2006119645A1/en
Publication of WO2006119645B1 publication Critical patent/WO2006119645B1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/18Materials at least partially X-ray or laser opaque
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39Markers, e.g. radio-opaque or breast lesions markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0409Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A61K49/0414Particles, beads, capsules or spheres
    • A61K49/0419Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806Suspensions, emulsions, colloids, dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/225Microparticles, microcapsules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3925Markers, e.g. radio-opaque or breast lesions markers ultrasonic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3954Markers, e.g. radio-opaque or breast lesions markers magnetic, e.g. NMR or MRI
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3995Multi-modality markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/12Devices for detecting or locating foreign bodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0833Detecting organic movements or changes, e.g. tumours, cysts, swellings involving detecting or locating foreign bodies or organic structures

Definitions

  • the present inv ention relates to the field of medical imaging, in particular to imaging procedures that utilize implantable markers for localizing, identifying, and treating abnormal tissues in the human body under each of X-ray, ultrasound (US), and magnetic resonance imaging (MRI) guidance
  • the guidewire marker is intended to enable a surgeon to pre-operatively establish tumor margins or biopsy sites b> reference to the position of the marker Surgeons typically use US to localize he guidewire marker in relation to associated tissue lesions
  • Exemplary of traditional ieedle localized markers for breast biopsy and surgery procedures is U S Patent No 0, 181 ,960 (Jensen et al ) which discloses a radiographic marker comprised of a single piece of wire lolded to form the limbs and shaft of an arrow which can be directed to point to a specific site m a tissue
  • Radiol 47: 14-22 have show n that the US visibility of guidewire markers currently used in breast tumor localization is suboptimal in 4-9% of surgical cases Furthermore, transdermal placement of the guidewire has been reported to result in adverse ⁇ aso vagal reactions in 10-20% of patients (Rissanen el al supra,, Ernst el al (Ernst M F, et al , 2002 Breast 11 ; 408-13), Abrahamson el al (2003 Acad Radiol 10; 601 -6), Jackman and Marzoni (Jackman R J and Marzom F A, 1997 Radiology 204; 677-84)
  • a second adverse effect of transdermal placement of guidewire markers is that placement of the guidewire and the surgical procedure generally must be completed within the same day This necessitates significant scheduling challenges between the departments of surgery and radiology and may even compromise the health of the patient in some instances Ideally, applicants have determined that a marker used for imaging localization of tumors and other lesions should be visible with all three imaging modalities While this
  • the present invention provides a novel interstitial marker comprised of microspheres that may be composed of ceramics, metals (especially copper and aluminum or a mixtuie), plastics or glass m a gel matrix These markers show uniformly good contrast with each of magnetic resonance (MR), Ultrasound (US) and X Ray imaging, offering them the unique ability for use in indiv idual and combined methods using one, two or three of these imaging modalities
  • the marker is small and can be easily introduced into tissue through a small (e g , an 8-, 10-, 12 or 14-gauge) biopsy needle
  • the concentration and size of the microspheres determine the contrast for US imaging
  • the contrast seen on MRI resulting from induced magnetic susceptibility is determined by the number of iron-contammg aluminum microspheres added to the marker, the shape and orientation of the marker, and the echo time of the MRI pulse sequence By selecting materials of a range of atomic numbers and density higher than that of biological tissues, the x-ray attenuation coefficients of the constituent
  • the interstitial marker prov ided in this invention is reliably v isible under each one of X-ray, US and MRI (that is, the same marker will be v isible in each one of X-ray, LS and MR systems)
  • the marker exhibits MR susceptibility that can be ( ontrolled so that a signal void is produced in spin-echo or gradient echo MR imaging sequences and serv es to outline the marker m its true position
  • the interstitial marker also achieves optimal reflectiv ity for US contrast independent of its orientation and placement in the body, thereby ⁇ ielding reliable acoustic shadowing identification regardless of the relative orientation of the US probe to the marker geometry
  • the interstitial marker also achieves optimal reflectiv ity for US contrast independent of its orientation and placement in the body, thereby ⁇ ielding reliable acoustic shadowing identification regardless of the relative orientation of the US probe to the marker geometry
  • the interstitial marker also achieves optimal reflectiv ity for US contrast independent of
  • A. further alternative distinguishing feature of the technology described herein is that placement of the localization marker may be entirely interstitial This aspect of the technology allows the tumor localization procedure and surgery to be carried out in separate stages, when this is appropriate in terms of the patient ' s health status and related medical i s factors Although the marker was initially developed for tumor localization in image guided bieast surgery and biopsy procedures, it is also useful for numerous other diagnostic procedures, such as MR spectroscopy, carried out under imaging guidance in breast or other areas of the body
  • One aspect of the presently described original technology is to provide an MRI, US 0 and X-Ray imaging compatible marker for improved localization of tumois and other tissue abnormalities
  • Another aspect of the presently described original technology is to provide an implantable imaging marker with stable and reliable imaging characteristics on MRI, US, and X. ray that is useful for pre-operative and mtra-operative surgical guidance, as well as post- 5 operative monitoring
  • Yet another aspect of the presently described original technology is to provide a small I issue-compatible marker device that can be inserted through the biopsy needle at the time of biopsy, thereby providing a radiographic target for future localization m the event of surgery
  • a further aspect of the presently described original technology is to provide a method 0 wherein the composition of the imaging marker can be altered using microspheres to incorporate paramagnetic and ferromagnetic materials yielding desirable proton density, Tl relaxivity and T2 susceptibility characteristics on MRI
  • Another aspect of the presently described original technology is to provide a method wherein the composition of the imaging marker can be further altered using microspheres to achieve optimal US reflectivity
  • FIG 1 shows both (a) Schematic diagram of marker composition (b) Photograph of a marker containing 180 microspheres bound in a gel matrix
  • FIG 2 shows images of US-guided marker delivery (a) The insertion cannula containing the marker at its tip (b) A magnified view of the tip of cannula containing the marker (c) An illustiation of how the marker is inserted into the chicken breast under US guidance (d) The corresponding US image shows the insertion of cannula (arrowheads) containing the marker at the tip (arrow) mside the breast tissue
  • FIG 3 shows images in a phantom containing 3 microspheres made of different materials with the corresponding US image (a) and the US echo intensity distribution along the line joining the three microspheres (b)
  • FIG 4 shows a US image of single glass microsphere (arrow) in a chicken breast (a) and the corresponding echo intensity plot along the depth of single microsphere (b) The US image of a collection of 10 glass microspheres (arrow) in the same tissue (c) and its echo intensity plot along the depth of 10 microspheres (d)
  • FIG 5 shows US images of 1 42mm markers with 10%, 40% and 90% glass mass concentration in a phantom (a) and the normalized peak US intensity for different glass mass concentration (b)
  • FIG 6 shows US images of a chicken breast tissue containing the 2 05mm marker of 40% mass concentration in the axial orientation (a) and sagittal orientation
  • FIG 7 shows a US image of markers of different size containing 40% glass microsphere mass concentration in a chicken breast tissue
  • FIG 8 shows an axial MRI of 2 05mm markers iron content range from 0 ⁇ g to 468 ⁇ g in separate phantoms
  • FIG 10 shows MRI (a), US image (b) and X-Ray image (c) of the final marker in a chicken breast tissue
  • X-ray mammography remains the primary screening and initial detection method for breast cancer
  • benign and malignant masses are generally made by analysis of the margins, shape, density, analysis of the margins, shape, density, and size of any detected lesion
  • a benign lesion such as a cyst or fibroadenoma
  • malignant masses often exhibit speculated contours due to the infiltrative nature of breast cancer
  • mammography has significant limitations in terms of imaging sensitivity and specificity
  • MR imaging has become a viable adjunct to X-ray mammography for detecting breast lesions
  • Some reports indicate that MRI can yield 100% sensitiv ity in the detection of malignant breast lesions
  • contrast enhanced MR imaging methods malignant and benign tumors that cannot be seen with mammography are visible on MR images
  • the architectuial features w hich have been found to be most useful in characterizing MR-visible breast lesions include lesion border irregularity and non-uniform lesion enhancement
  • Morphologic assessment of breast lesions requires high spatial resolution contrast- enhanced 3D MR
  • Such high-resolution visual images can be extremely useful to the clinician in pre-operative planning Imaging localization markers, such as interstitial marker disclosed in the present description of original technology that are all of MRI, X-ray and US-v
  • X-ray opaque mate ⁇ als are disclosed in the prior art and can take the form of radio- opaque resins, or other similar compositions such as disclosed in U S Patent No 4,581 ,390 (Flynn) or barium, bismuth or other radio-dense salts, such as disclosed in U S Patent No 3,529,633 to Vdillancourt and U S Patent No 3,608,555 (Greyson)
  • X-ray markers may be formed of metal such as platinum, as disclosed in U S Patent No 4,448, 195 (LeVeen)
  • Exemplary of guidewires markers used under X-ray view ing is the invention disclosed by U S Patent No 4,922,924 (Gambale et al )
  • U S Patent No 5,375,596 discloses a method for locating tubular medical devices implanted in the human body using an integrated system of wire transmitters and receivers
  • U S Patent No 4,572, 198 (Cod ⁇ ngton) additionally prov ides for conductive elements, such as electrode wires, for systematically disturbing the magnetic field m a iefined portion of an interventional device to yield increased MR visibility of that region of ihe device
  • the presence of conductive elements in the imaging dev ice also i ntroduces increased electronic noise and the possibility of Ohmic heating, and these factors have the overall effect of degrading the quality of the MR image and raising concerns about patient safety
  • the presence of MR incompatible w ire materials in implantable medical markers disclosed in the prior art causes large imaging artifacts on MRI Lack of clinically adequate MR v isibility and/or imaging artifact contamination caused
  • the interstitial marker should also be made of ste ⁇ lizable material that is mechanically and chemically stable and of low thrombolytic and inflammatory potential when implanted in tissues Sterility of the marker can be achieved using coating procedures employing biocompatible membianes as described in the prior art
  • biocompatible materials which could be used to practice the present invention include elastin, elastome ⁇ c hydrogel, nylon, teflon, polyamide, polyethylene, polypropylene, polysulfone, ceramics, cermets steatite, carbon fiber composites, silicon nitride, and zircoma, plexiglass, and poly-ether-ether-ketone
  • the marker should exhibit high contrast in all relevant imaging methods including X-ray, US and VlRI Imaging markers used under MR guidance should also be MR-compatible in both static and time-varying magnetic fields
  • Some metallic materials, such as copper, titanium, brass, magnesium and aluminum are also generally MR-compatible, such that large masses of these materials can be accommodated within the imaging region without significant image degradation
  • the interstitial marker of the present invention can be made MR visible by doping the marker with a material which has an MR resonance based on 19 Fluo ⁇ ne 19 Fluo ⁇ ne-labelled materials have been used previously for MRI studies of tissue oxygenation (Mason RP, et al , 2003 Adv Exp Med Biol 530 19-27) and metabolism of L-DOPA (Dingman S, et al
  • soluble paramagnetic and fluorescent material Particularly preferred as a paramagnetic contrast agent is Gadolinium, which induces an increase in Tl relaxivity yielding increased signal on Tl weighted MRI
  • an optical fluorophore can be added to the gel J or optical detection
  • a non-hmitmg example of such a fluorophore is mdocyanme green, which strongly binds to protemaceous substrates and has recently been approved by the FDA for human use This fluorophore is excited by infra-red (805 urn) and generates a fluorescence in a slightly lower energy infra-red band (850 nm)
  • optical markers such as quantum dots can be added to the composition of the marker to provide bright optical emissions
  • the materials should exhibit a difference in their acoustic impedance, which is in turn related to the material density and the speed of sound through the material. Referring to water as a surrogate for tissue, this means that we would like the material to exhibit values beyond the "'hi" and "lo" values of impedance. Again, this is easily met by the non-limiting examples of candidate materials. Again, other materials such as ceramics, metals and some plastics could also be appropriate if they satisfy these constraints.
  • acoustic marker materials are particulate in nature, with such reular or irregular geometric shapes such as spherical, oval, rectangular, square, polyhedral, etc. in shape. They do not have be spherical or even, but it is desirable that they are not a flat or plate-like structure, as they should be readily observable from three dimensions.
  • the idea is to make the internal reflectivity of the marker components look "rough” or bumpy with respect to the wavelength of the ultrasound we are considering. So, therefore one could use spheres, rough particles, grains, etc.
  • the characteristic review ed is having S the particles (e g , the non-hmitmg examples of spheres are discussed) of essentially neutral magnetic susceptibility
  • the majority of the spheres should be as close to tissue in terms of their magnetic susceptibility compared to tissue. Ideally the closer the better but anything within either 2 fold higher or lower would be acceptable.
  • a formulation with copper might be better as i: is very close to the susceptibility of water, and it will not create sizeable signal v oids.
  • the Tl of the gel marker can be shortened.
  • the amount of Gd-DTPA required depends on the tissues in which the marker will be placed and how bright (how significant a contrast) is desired from the marker. For example, if the goal is to use the marker in breast tissue, the Tl of the native tissue is -0.7 seconds at 1.5 Tesla. Now, it would be desired to have the marker display at least a 10% difference in the relaxation characteristics.
  • the gel would be doped so that the gel plus marker would have a Tl less than 0.7 seconds (at least in those areas of the marker that have been doped, to give a postive contrast in the final image.
  • concentration or weight amount of the marker is again dependent upon the specific results desired and the tissue to which it is applied. It is estimated that at least a 10% reduction in Tl would be desirable, but the larger the difference the better. So, it could be suggested to reduce this Tl of the tissue in this case to 0.63 seconds for at least modest visability on Tl weighted MRI at 1.5 Tesla. This can be easily calculated on the basis of the relaxivity of the contrast media using the following formula;
  • Tl 0 is the Tl of the gel matrix of the gel without any Gd-DTPA included, Rl is known as the Tl relaxivity of Gd-DTPA and [Gd] is the concentration of the Gd- DTPA in the gel solution.
  • the Tl for 1.5 Tesla is 4.5sec "1 mmor l .
  • the basis of measurements can also be determined at other MR field intensities such as 2.0Tesla, 2.5 Tesla, 3.0 Tesla and even higher, but whatever the intensity of the field, the objective is to provide a detectable signal change between the tissue and the marker that is useful to the practitioner
  • the interstitial marker is preferably comprised of small microspheres suspended in a gelatin matrix.
  • the composition of the marker exhibits a density and an average atomic number of the tissue.
  • Tissue is composed of nitrogen, carbon, oxygen, hydrogen, etc. These all have differing atomic numbers so that an average atomic number depends on their relative abundance in the particular tissue in which the marker is placed.
  • tissue can be considered as a hydrocarbon and its ' atomic number" would be somewhere near 6-7, but would be higher in bone, which would be composed of calcium as well, thus raising the avegage atomic number.
  • the marker is made out of aluminum, silicon or copper, the atomic number of the marker is much higher than those constituents for tissue. These materials would have an effective atomic number that is substantially higher than those of tissue to ensure X-Ray visibility.
  • the composition of the marker has a substantially high acoustic impedance difference from the surrounding tissue to provide good US contrast
  • the magnetic susceptibility of the marker is similar to that of tissue m order to control MRI contrast in T2* weighted images
  • Table 1 summarizes a number of desirable physical properties of glass, copper ⁇ and aluminum, as three non-hmitmg examples of mate ⁇ als that could be used to produce the interstitial marker according to the present invention
  • the magnetic susceptibilities of these materials are all reasonably close to that of tissue but additionally can include controlled doping with ferromagnetic or paramagnetic materials selected for particularly desirable Tl and T2 properties on MRI.
  • the paramagnetic mate ⁇ als selected can include transition metal ions such as gadolinium, dysprosium, chromium, nickel, copper, iron and manganese, or stable free radicals such as mtroxyls
  • concentration of the paramagnetic agents can range from the micromolar to milhmolar range
  • Non- i s paramagnetic mate ⁇ als having desirable MR relaxation characteristics may also be employed in the manner set forth above to practice the present invention
  • the bulk of the marker is comprised of glass microspheres, which are readily available, biocompatible and prov ide all required features for optimal US and X-Ray contrast
  • glass microspheres which are readily available, biocompatible and prov ide all required features for optimal US and X-Ray contrast
  • Particularly preferred are GL-0175 glass microspheres (MO-SCI Corporation, 4000 Enterprise 0 Dm e, Rolla, MO 65402, USA) in diameters ranging from 0 4-0 6mm with a density of 4 2-4 5g/cm J
  • aluminum microspheres (Salem Specialty Ball Corporation, West Simsbury, CT 06092, USA) 0 5mm in diameter with small amounts of iron (0 7% by mass) making them slightly ferromagnetic
  • adding a small number of iron doped aluminum microspheres to the marker reliably induces a small but detectable Bo inhomogeneity around the marker which presented as a signal void in T2* weighted MRI
  • pure copper microspheres it was found that adding
  • FIG 1 (b) is a photograph of he final form of the marker suitable for delivery with a 12-gauge biopsy needle that is i outinely used clinically for breast tumor localization
  • the imaging contrast of the marker for MRI visualization was controlled by adding a variable number of iron-contdining aluminium microspheres to the marker corresponding to an iron content fiom 0 ⁇ g to 468 ⁇ g
  • the US contrast was modulated by adjusting the number of glass and aluminium microspheres added to the gelatin matrix
  • the optimal mixture was determined to provide maximum US contrast while providing clear localization of the marker in MRI and mammography
  • Imaging validation studies were performed with either homogeneous agar phantoms or ex-vno tissue samples
  • the phantoms were prepared with agar (Sigma Chemical Corporation, 3050 Spruce Street, Saint Louis, MO 63103, USA) and distilled water Amorphous silica powder (Sigma Chemical Corporation, 3050 Spruce Street, Saint Louis, MO 63103, USA) was also added to provide the phantom with a background of US backscattering material to simulate tissues
  • Two kinds of homogeneous phantoms were prepared the first kind of phantom was rectangular in structure (60 x 60 x 40mm) and designed for the US contrast study, the second kind of phantom w as cylindrical in structure (40mm long and 30mm in diameter) and used for the MRI contrast study
  • All of the phantoms were composed of 4% agar mixed with 4% silica Tissue phantoms were used in the form of fresh chicken breast tissue Three samples of chicken breast were used for the US study
  • each marker was loaded into a 12- gauge blunt cannula 4 before placement
  • the marker 5 w as placed in the tissue 6 by first using an 1 1 -gauge co-axial introducer needle 7 with a trocar (MRI Devices Corporation) to form a path into the phantom
  • the tiocar needle was withdrawn and then a 12-gauge cannula 4 containing the marker was passed through the introducer needle, as shown in FIG 2(c)
  • US guidance was used before releasing the marker 5, as show n in FIG 2(d)
  • the marker 5 was left in the desired position ty first pushing it out from the cannula 4 and then removing the cannula and introducer needle 7 from the tissue Axial and
  • the US echo intensity profile through the microspheres is shown by the dashed line in FIG. 3 (a) through each microsphere. It was found that although the glass microsphere was smaller than the aluminum or copper microspheres, they demonstrated a slightly greater signal than either the aluminum or the copper microspheres. Since the glass microspheres produced clearly defined US echoes and are biocompatible, they were chosen to form the bulk of the marker content in accordance with the method of the invention.
  • the US intensity for a single glass microsphere was compared to a collection of 10 microspheres injected into the same chicken breast 6. As shown in FIG. 4 (a), the single microsphere 8 is less well resolved. The intensity distribution along the depth of the single glass microsphere, as illustrated in FIG. 4 (b), is difficult to differentiate from the surrounding breast structure. By comparison, the collection of 1 0 glass microspheres 9 appears as a hyperintense structure with acoustic shadowing, as shown in FIG. 4 (c). With reference to FIG.
  • the corresponding acoustic intensity distribution along the depth of 10 microspheres 9 shows a clear echo in the US data demonstrating a marked contrast improvement with the larger number of glass microspheres.
  • US intensity was measured in phantoms 10 with 1.42mm markers of different glass concentrations.
  • the US image of the three markers shown in FIG. 5 (a) demonstrates that a variation in the marker visibility results from different concentrations of glass microspheres. As described for the previous imaging study, the three markers were deposited in an agar phantom at the same depth for the same acoustic conditions.
  • the effect of varying the ratio of glass microsphere volume to the total marker volume was studied using 2.3%, 8.4% and 20.7% compositions, corresponding to glass mass to total marker mass of 10%, 40% and 90% or using 3, 13 and 27 glass microspheres, respectively.
  • the relative US peak echo intensity is plotted in FIG. 5 (b) as a function of glass mass concentration and shows that the optimal concentration should be greater than 40% weight by volume.
  • a marker of 40% mass concentration occupied only 8 4% of the marker volume, thus providing a large gel volume to ensure solid binding of the spheres in the final marker
  • a generally cylindrical shape for example, one dimension such as length, being at least 1 -%, at least 20%, at least 30% or at least 40% greater than each of the other two dimensions such as width and depth, and with the other two dimensions such as width and depth generally differing from each other by less than 50%, less than 40%, or less than 30% compared to the smallest dimension, and the cross-section may be circular, oval, triangular, rectangular, or other regular or irregular shapes
  • a spherical, square, polyhedral or other geometric or irregular marker which may have a similar appearance from multiple imaging angles This is illustrated in FIG 6, where two orthogonal US view s demonstrate how the cylindrical geometry of the marker aids in its unique identification
  • rianostructured surfaces of particles or spheres or other shapes may be used to enhance Ultrasound reflectivity (as described in Published U S Patent Application No 20050038498, Dubrow et al , which is incorporated herein by reference)
  • MR studies were performed on a 1 5-Tesla MRI system (Signa, GE Medical System) w ith a 5-inch surface coil and employing a standard 2D spoiled gradient recalled sequence (SPGR) clinical breast MRI protocol
  • the width of the signal void was estimated between the peaks of the greatest absolute gradient of the signal surrounding the marker This corresponded to the points of steepest descent on the artifact profile
  • the mean and standaid deviation of the size of the signal void from the four directions was used to characterize the size of the signal void and its ⁇ a ⁇ ability
  • the size of the signal void and its standard deviation
  • the axial 9 (a) and sagittal 9 (b) MR images showed that the marker appeared circular and rectangular when parallel to Bo-
  • the sagittal image was somewhat irregular because of the local magnetic field inhomogeneity caused by iron.
  • the marker appears as a clear signal void on MRI 10 (a), while the US image of the marker shows a clear hyperintense structure with acoustic shadowing 10 (b).
  • the X-Ray image clearly identifies the marker as a radio-opaque structure 10 (c). It is thus evident that this construction and composition of the imaging marker of the present invention is clearly visible under standard MRI, US and X-Ray examination
  • the marker may comprise a de ⁇ ice with a surface (on or m the marker) of an artifact that has at least 10% difference in ultrasound reflectivity as compared to at least one of animal breast i issue, animal brain tissue, and animal heart tissue, a material that has at least 10% difference in relaxivity at the field strength use for MR imaging as compared to at least one of animal breast tissue, animal brain tissue and animal heart tissue, l espectiv ely, and a composition that has at least 10% difference in attenuation of X- i ays from at least one of animal breast tissue, animal brain tissue, and animal heart tissue, respectiv ely By respectively, it is assumed that the marker will be implanted into approximately a single tissue composition, and that these differences should be ev coed with i espect to that single tissue composition, and not to three different tissue compositions
  • the marker will be implanted into approximately a single tissue composition, and that these differences should be ev coed with i espect to that single tissue composition, and not to
  • the marker o may further comprise a fluorophore that emits detectible radiation when stimulated by electromagnetic radiation, current, or magnetic flux, preferably electromagnetic radiation (such as UV or IR radiation)
  • at least one particle may comprise aluminum particles comprises an iron content of >0 ⁇ g to 468 ⁇ g
  • the imaging marker may
  • the matrix or gel in said imaging marker may provide a substrate into which an MRI contrast agent can be added
  • the imaging marker appears as a clear hype ⁇ ntense s ⁇ uctuie with acoustic shadowing on US images, and also appears as a radio-opaque structure on X- Ray images
  • These particles may be used in a method of performing a medical procedure comprising identifying a region of treatment interest, implanting the markei described herein into tissue in that region of interest, subsequently v iewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and performing a medical procedure on the region of mteiest identified by
  • Non-limiting examples of body regions where implantation of the marker may be pro ⁇ ided include at least body regions of a patient selected from the group consisting ⁇ of cardiovascular region, gastiomtestmal region, inti apentoneal region, organs, k idneys, retina, urethra, genitourinary tract, brain, spine, pulmonai y region, and soft tissues Surgical or treatment procedures such as invasive treatments or non-inavsive treatments may be used in combination with observation of the markers.
  • Such treatments may be with surgical probe, catheter, or biopsy implements used to implants or position the marker, as well as pre-operative and intra-operative surgical guidance; localizing breast tumors under MRI, US and X-ray; excisional biopsy of the breast under MRI, US and X-ray; pre-operative localization procedures and surgery carried out on separate days; and any other local or target specific procedures.
  • paramagnetic ions aere selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III) and Dy(III), and a superparamagnetic agent may comprise a metal oxide or metal sulfide, particularly where the metal of the ion is iron.
  • Other superparamagnetic materials may include ferritin, iron, magnetic iron oxide, manganese ferrite, cobalt ferrite and nickel ferrite.
  • the implantable imaging marker may be made of material that is mechanically stable and tissue compatible, non-limiting examples being elastin, elastomeric hydrogel, nylon, teflon, polyamide, polyethylene, polypropylene, polysulfone, ceramics, cermets steatite, carbon fiber composites, silicon nitride, zirconia, plexiglass, natural or synthetic tissue, natural or synthetic gums or resins, sols and poly-ether-ether-ketonc.
  • the implantable imaging marker may be secured at its interstitial insertion site using a mechanical or chemical anchoring device.
  • a chemical device would be an adhesive such as a fibrogen-based adhesive or an autologous fibrin.
  • the implantable imaging marker may be made of sterilizable material that is of low thrombolytic/thrombogenic and low inflammatory potential when implanted in tissues.
  • the materials may be coated for these or other effects at the site of implantation, including coatings or or diffusible material to effect those or other results, including local temporary pain or sensitivity reduction.
  • sterility of said implantable imaging marker may be achieved using coating procedures employing biocompatible membranes.
  • the implantable imaging marker may be MR-compatible in both static and time-varying magnetic fields.
  • the novel technology described herein includes a method of performing an examination procedure in a medium that has MRI, US and/or X-ray responsive characteristics different from those of the markers
  • This method could be used in manufacturing processes or in prov iding taggants to materials that can later be examined for manufacturer origins at a later date
  • the markers could be injected into elastome ⁇ c articles such as artificial rubbers (in tires, tubing), foams, bioremedial masses, structural elements and the like
  • the process would comprise identifying a region of examination interest, implanting the marker described above into a material in that region of interest, subsequently viewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating an object or providing a second material into the region of interest identified by the marker
  • the process could also include implanting the marker into mate ⁇ al in that region of interest, and after

Abstract

An imaging marker comprised of glass and iron-containing aluminum microspheres in a gel matrix which shows uniformly good contrast with MR, US and X-Ray imaging The maiker is small and can be easily introduced into tissue through a 12-gauge biopsy needle The concentration of glass microspheres and the size dictate the contrast for US imaging The contrast seen m MRI resulting from susceptibility losses is dictated by the number of iron-containmg aluminum microspheres, while the artifact of the marker also depends on its shape, orientation and echo time By optimizing the size, iron concentration and gel binding, an implantable tissue marker is created which is clearly visible with all three imaging modalities.

Description

M4RKER DEVICE FOR X-RAY, ULTRASOUND AND MR IMAGING
BACKGROUND OF THE INVENTION
1 Field of the Invention The present inv ention relates to the field of medical imaging, in particular to imaging procedures that utilize implantable markers for localizing, identifying, and treating abnormal tissues in the human body under each of X-ray, ultrasound (US), and magnetic resonance imaging (MRI) guidance
2 Background of the Art Breast tissue conserving surgical methods are increasingly being used for tumor resection in part because of significant improvements in imaging detection of small node-negative breast tumors Accurate localization and identification of the spatial extent of a tumor is highly desirable in pie-operative surgical planning to minimize damage to normal tissues while at the same time ensuring that the tumor is entirely removed Guidewire markers are the most commonly used device for preoperative localization of breast lesions performed under X-ray mammography and US imaging, and more recently undei MRI, as reported in the medical literature by Makoske et al (Makoske T, et al , 2000 Am Surg 66: 1 104-8), Staren and O'Neill (Staren E D and O'Neill T P 1999 Surgery 126: 629-34), Bedrosian et al (Bedrosian I, et al , 2003 Cancel 98; 468-73
Bedrosian I, et al , 2002 Ann Surg Oncol 9; 457-61), and Warner et al (Warner E, et dl , 2001 J Clin Oncol 19: 3524-31) Once positioned, the guidewire marker is intended to enable a surgeon to pre-operatively establish tumor margins or biopsy sites b> reference to the position of the marker Surgeons typically use US to localize he guidewire marker in relation to associated tissue lesions Exemplary of traditional ieedle localized markers for breast biopsy and surgery procedures is U S Patent No 0, 181 ,960 (Jensen et al ) which discloses a radiographic marker comprised of a single piece of wire lolded to form the limbs and shaft of an arrow which can be directed to point to a specific site m a tissue Published studies, for example, Rissanen et al (Rissanen T J, et al , 1993 Clin
Radiol 47: 14-22), have show n that the US visibility of guidewire markers currently used in breast tumor localization is suboptimal in 4-9% of surgical cases Furthermore, transdermal placement of the guidewire has been reported to result in adverse \ aso vagal reactions in 10-20% of patients (Rissanen el al supra,, Ernst el al (Ernst M F, et al , 2002 Breast 11 ; 408-13), Abrahamson el al (2003 Acad Radiol 10; 601 -6), Jackman and Marzoni (Jackman R J and Marzom F A, 1997 Radiology 204; 677-84) A second adverse effect of transdermal placement of guidewire markers is that placement of the guidewire and the surgical procedure generally must be completed within the same day This necessitates significant scheduling challenges between the departments of surgery and radiology and may even compromise the health of the patient in some instances Ideally, applicants have determined that a marker used for imaging localization of tumors and other lesions should be visible with all three imaging modalities While this is not a problem for mammography, currently used guidewire markers can obscure the visibility of tissue lesions due to large and uncontrolled magnetic susceptibility artifacts arising from the material of fabrication Magnetic susceptibility is a quantitative measure of a material's tendency to interact with and distort an applied magnetic field This effect makes verification of accurate localization difficult and can degrade the quality of the diagnostic information obtained from the image Localization markers used m MRI should therefore be MR- c ompatible in both static and time-varying magnetic fields Although the mechanical effects of the magnetic field on ferromagnetic materials present the greatest danger to patients because of possible unintended movement of the guidewire, it is also possible that tissue and device heating may result from radio-frequency power deposition in electrically conductive material present within the imaging volume Any material that i s added to the structure of a marker to improve its MR visibility must not contribute significantly to its overall magnetic susceptibility, or imaging artifacts could be introduced during the MR process Image distortion may generally include local or regional signal loss, signal enhancement, or altered background noise Applicants have found that markers used in tumor localization should also be made of material that is temporally stable so as to ensure reliable contrast, mechanically stable to ensure mechanical integrity, and tissue compatible
Initial strategies to position and visualize implantable devices used in MRI- guided piocedures were based on passive susceptibility artifacts produced by the dev ices w hen exposed to the MR field U S Patent No 4,827,931 , Longmore) and U S Patent Nos 5, 154, 179 and 4,989,608 (Ratner) disclose the incorporation of paramagnetic material into medical de\ ices such as catheters to make the devices v isible under MR imaging U S Patent No 5,21 1 ,166 (Sepponen) similarly discloses the use of surface impregnation of various "relaxants," including paramagnetic materials and nitrogen radicals, onto surgical instruments to enable their MR identification Howev er, these inv entions do not provide for artifact-fiee MR v isibility in the presence of rapidly alternating magnetic fields, such as would be produced during high-speed MR imaging procedures The magnetic susceptibility artifact produced by the marker during MRI exams must be small enough not to obscuie surrounding anatomy, or mask low-threshold physiological events that have an MR signature, which could compromise the surgeon's ability to perform the intervention Consequently, guidewire markers and other implantable devices positioned within the VlR imager must be made of materials that have properties compatible with their use n human tissues during MR imaging procedures, including real-time MR imaging A.n improv ed method for passiv e MR v isualization of implantable medical devices is disclosed in U S Patent No 5,744,958 (Werne), wherein an ultra thin coating of ( onductive matenal is applied such that the susceptibility artifact due to the metal is negligible due to the low material mass At the same time, the eddy currents associated with the device are limited because of the ultra-thin conductor coating A similar method employ ing a nitinol wire with I eflon® coat, in combination with extremely thin wires of a stainless steel alloy included betw een the nitinol wire and Teflon® coat, has been reported in the medical literature by Frahm et al (Frahm et al , ] 997 Pi oc ISMRM 3 1931 ) Exemplary of methods for active MR v isualization of implantable medical devices are U S Patent No 5,21 1 , 165 (Dumoulin et al ), U S Patent Nos 6,026,316 and 6,061 ,587 (Kucharczyk and Moseley), U S Patent No 6,272,370 (Gillies et al ), U S Patent No 6,626,902 (Kucharczyk and Gillies) These inventions disclose MR tracking systems based on transmit/receive radiofrequency coils positioned near the end of an implantable medical device by which the position and orientation of the device can be localized using radio frequency field gradients MRI-guided procedures using activ e visualization of implantable medical devices have also been described in the medical literature, for example, by Hurst et al (Hurst et al , 1992 Mag Res Med 24 343-357), Kantor et al (Kantor et al , 1984 Circ Res 55 55-60), Kandarpa et al (Kandarpa et al , 1991 Radiology 181 99), Bornert et al ( Bornert et al , 1997 Proc ISMRM 3 1925), Coutts et al ( Coutts et al , 1997 Proc ISMRM 3 1924), Wendt et al (Wendt et al , 1997 Proc ISMRM 3 1926), Langsaeter et al (Langsaeter et dl , 1997 Proc ISMRM 3 1929), Zimmerman et al ( Zimmerman et al , 1997 Proc ISMRM 3 1930), and Ladd et al ( Ladd et al , 1997 Proc ISMRM 3 1937)
The limitations of guidevvire markers for imaging localization of breast tumors have prompted alternative approaches For example, Bargaz (Bergaz F, et al , 2002 Eur Radiol 12 471 -4) has reported the use of a 3mm stainless steel clip which is i eleased with a specialized applicator and is clearly v isible by mammography How ev ei, these clips can migrate ov er time, limiting their accuracy for excisional biopsy piocedures (Birdvvell and Jackman, 2003 Radiology 229; 541-4) Fajardo (Fajardo LL, et al , 1998 Radiology 206; 275-8) has described the use of an endovascular embolization coil which can be deployed in tissue through a biopsy needle and has good mammographic visualization and stability over a 6 month peπod Harms (Harms SE, et al , 2002 ISMRM 11 633) has demonstrated the utility of a ςmall hematoma as an MRI marker by injecting the patient's blood near the tumour mass U S Patent No 6,714,808 (Khmberg et al ) further discloses a method of hematoma-directed US guided excisional breast biopsy , wherein the hematoma is produced by an injection of the patient's own blood into a pre-selected area to taiget a lssion Unlike the present invention, howev er, none of the markers reported in the prior art are clearly visible under X-rav , U S and MRl and can be used to guide MRI, X-ray, and US-guided surgical and biopsy procedures in any region of the body 1 here is therefore a need for a single non-migiating tissue compatible imaging marker that is ieliably and conspicuously visible on X-ray, US and MRI without any degradation in the diagnostic quality of the images
SUMMARY OF THE INVENTION The present invention provides a novel interstitial marker comprised of microspheres that may be composed of ceramics, metals (especially copper and aluminum or a mixtuie), plastics or glass m a gel matrix These markers show uniformly good contrast with each of magnetic resonance (MR), Ultrasound (US) and X Ray imaging, offering them the unique ability for use in indiv idual and combined methods using one, two or three of these imaging modalities The marker is small and can be easily introduced into tissue through a small (e g , an 8-, 10-, 12 or 14-gauge) biopsy needle The concentration and size of the microspheres determine the contrast for US imaging The contrast seen on MRI resulting from induced magnetic susceptibility is determined by the number of iron-contammg aluminum microspheres added to the marker, the shape and orientation of the marker, and the echo time of the MRI pulse sequence By selecting materials of a range of atomic numbers and density higher than that of biological tissues, the x-ray attenuation coefficients of the constituent materials in the marker also piovide clear v isualization v ia x-ray imaging
By optimizing the size, iron concentration and gel binding functions supporting and separating the microspheres, a marker can be created that is clearly \ isible with all three of and any one of the imaging modalities The marker disclosed in this invention overcomes numerous limitations of currently used imaging localization devices Unlike imaging markers in the prior art, the interstitial marker prov ided in this invention is reliably v isible under each one of X-ray, US and MRI (that is, the same marker will be v isible in each one of X-ray, LS and MR systems) In MRI systems, the marker exhibits MR susceptibility that can be ( ontrolled so that a signal void is produced in spin-echo or gradient echo MR imaging sequences and serv es to outline the marker m its true position The interstitial marker also achieves optimal reflectiv ity for US contrast independent of its orientation and placement in the body, thereby \ielding reliable acoustic shadowing identification regardless of the relative orientation of the US probe to the marker geometry The interstitial marker also exhibits sufficient X-ray opacity to be v isible under X-ray images and CT scans due to its constituent c omponents The iron mav be provided to enhance the MR susceptibility of the system, and the iron may be pi esent in the glass or aluminum microspheres or as a distinct additive in the gelatin, as spheres or particles The term particles includes both solid and hollow particles, but as noted later in the discussion with respect to acoustic properties of the spheres with i espect to ultrasound, all particles should not be w ith sufficient absorption characteristics as would absorb ultrasound to a degree as to ieduce its effectiveness , Viewed from another aspect, the present invention provides a method for altering the composition of the imaging marker to enable the incorporation of a number of diverse contrast generating materials Selection of a small microsphere volume relative to the gel volume ensures that adequate gel material is available m the marker -volume to provide mechanical stability and microsphere binding In addition, the gel provides a substiate of sufficient volume to add v arious contrast generating materials, such as, for example, water soluble paramagnetic species and fluorescent material In a preferred embodiment, an optical s fluoiophore can be added to the gel for optical detection A non-limiting example of such a fluorophore is mdocvanme green, w hich strongly binds to protemaceous substrates and has recently been approved by the FDA for human use In another preferred embodiment, optical markers such as quantum dots can be added to the composition of the marker to pro\ ide bright optical emissions, as previously reported in the medical literature by West ( West J L , 10 2003 Ann Rev Biomed Eng 5 285-93)
A. further alternative distinguishing feature of the technology described herein is that placement of the localization marker may be entirely interstitial This aspect of the technology allows the tumor localization procedure and surgery to be carried out in separate stages, when this is appropriate in terms of the patient's health status and related medical i s factors Although the marker was initially developed for tumor localization in image guided bieast surgery and biopsy procedures, it is also useful for numerous other diagnostic procedures, such as MR spectroscopy, carried out under imaging guidance in breast or other areas of the body
One aspect of the presently described original technology is to provide an MRI, US 0 and X-Ray imaging compatible marker for improved localization of tumois and other tissue abnormalities
Another aspect of the presently described original technology is to provide an implantable imaging marker with stable and reliable imaging characteristics on MRI, US, and X. ray that is useful for pre-operative and mtra-operative surgical guidance, as well as post- 5 operative monitoring
Yet another aspect of the presently described original technology is to provide a small I issue-compatible marker device that can be inserted through the biopsy needle at the time of biopsy, thereby providing a radiographic target for future localization m the event of surgery A further aspect of the presently described original technology is to provide a method 0 wherein the composition of the imaging marker can be altered using microspheres to incorporate paramagnetic and ferromagnetic materials yielding desirable proton density, Tl relaxivity and T2 susceptibility characteristics on MRI Another aspect of the presently described original technology is to provide a method wherein the composition of the imaging marker can be further altered using microspheres to achieve optimal US reflectivity
Yet another aspect of the presently described original technology is to provide a method wherein the composition of the imaging marker can be altered by adding an optical fluorphor in order to generate optical contrast for intia-operative visibility to a relativ ely shallow depth under infra-red excitation
These and other features, aspects, and advantages of the present invention will be apparent upon consideration of the figures and the following detailed description of the presently described original technology
BRIEF DESCRIPTION OF THE FIGURES
FIG 1 shows both (a) Schematic diagram of marker composition (b) Photograph of a marker containing 180 microspheres bound in a gel matrix FIG 2 shows images of US-guided marker delivery (a) The insertion cannula containing the marker at its tip (b) A magnified view of the tip of cannula containing the marker (c) An illustiation of how the marker is inserted into the chicken breast under US guidance (d) The corresponding US image shows the insertion of cannula (arrowheads) containing the marker at the tip (arrow) mside the breast tissue FIG 3 shows images in a phantom containing 3 microspheres made of different materials with the corresponding US image (a) and the US echo intensity distribution along the line joining the three microspheres (b)
FIG 4 shows a US image of single glass microsphere (arrow) in a chicken breast (a) and the corresponding echo intensity plot along the depth of single microsphere (b) The US image of a collection of 10 glass microspheres (arrow) in the same tissue (c) and its echo intensity plot along the depth of 10 microspheres (d)
FIG 5 shows US images of 1 42mm markers with 10%, 40% and 90% glass mass concentration in a phantom (a) and the normalized peak US intensity for different glass mass concentration (b) FIG 6 shows US images of a chicken breast tissue containing the 2 05mm marker of 40% mass concentration in the axial orientation (a) and sagittal orientation
(b) FIG 7 shows a US image of markers of different size containing 40% glass microsphere mass concentration in a chicken breast tissue
FIG 8 shows an axial MRI of 2 05mm markers iron content range from 0 μg to 468 μg in separate phantoms (a) The image was acquired at 1 5T using surface coil with a 2D SPGR sequence TR/TE/FA=18 4ms/4 2ms/3O° The av erage size of the imaging void as a function of iron content for two different TE \ alues (b) is provided Imaging was performed with 2D SPGR sequence TR/FA=18 4ms/30° (o, TE 4 2ms, *, TE 7 3ms)
FIG 9 show s axial (a) and sagittal (b) MRI of the final marker which was placed parallel to B0 in phantom Axial (c) and sagittal (d) MRI of the same marker which w as placed perpendicular to Bo Imaging was done with a 2D SPGR sequence TRZTE-TA= 18 4ms/4 2ms/30°
FIG 10 shows MRI (a), US image (b) and X-Ray image (c) of the final marker in a chicken breast tissue
DETAILED DESCRIPTION OF THE INVENTION
X-ray mammography remains the primary screening and initial detection method for breast cancer The distinction between benign and malignant masses is generally made by analysis of the margins, shape, density, analysis of the margins, shape, density, and size of any detected lesion A benign lesion, such as a cyst or fibroadenoma, typically has a sharply circumscribed margin and oval or round shape, whereas malignant masses often exhibit speculated contours due to the infiltrative nature of breast cancer However, mammography has significant limitations in terms of imaging sensitivity and specificity
MR imaging has become a viable adjunct to X-ray mammography for detecting breast lesions Some reports indicate that MRI can yield 100% sensitiv ity in the detection of malignant breast lesions Using contrast enhanced MR imaging methods, malignant and benign tumors that cannot be seen with mammography are visible on MR images Furthermore, by incorporating a number of morphologic breast lesion characteristics, the specificity of MRI detection of breast lesions has increased significantly The architectuial features w hich have been found to be most useful in characterizing MR-visible breast lesions include lesion border irregularity and non-uniform lesion enhancement Conversely, smooth bordered or lobulated lesions or non-enhancement hav e been found to be predictive of benign lesions Morphologic assessment of breast lesions requires high spatial resolution contrast- enhanced 3D MR Such high-resolution visual images can be extremely useful to the clinician in pre-operative planning Imaging localization markers, such as interstitial marker disclosed in the present description of original technology that are all of MRI, X-ray and US-v isible, and can be dynamically monitored b> each three imaging modalities, are likely to have considerable utility in pre- and intra-operative surgical and biopsy procedures
In many cases, it is necessary for a surgeon to pre-operati\ ely localize abnormal tissues that are to be resected in a subsequent operativ e proceduie Precise localization of tissue is also required during biopsies because the biopsy site must be reproducible in the event further biopsy or surgery is required To facilitate localization of such tissue sites, markers are temporarily inserted into the tissue at the required location When a needle biopsy of a breast lesion lacks clear radiographic evidence of the extent of the tumor because of insufficient image contrast between normal and abnormal tissue or as a result of image distortion caused by imaging artifacts, pre-operative planning is difficult Furthermore, when sxcisional biopsy results suggest cancer, further localization may be carried in order to plan for further surgical resection of the tumor bed Thus, if radiographic definition of abnormal issue is unclear, subsequent localization is problematic
Most prior art methods for localizing breast lesions involve the use of a hypodermic needle placed into the breast in close anatomic proximity to the lesion The hypodermic needle is w ithdrawn over a wire and the w ire anchored until after surgery However,
( ompression of the breast during mammographic filming can cause the wire to move or be displaced with respect to the breast lesion Sev eral patents, such as U S Patent No 4,592,356 (Gutieπez), U S Patent No 5,059,197 (Uπe et al ), U S Patent No 5,127,916 (Spencer et JI ) U S Patent No 5,800,445 (Ratchff et al ) and U S Patent No 5,853,366 (Dowlatshahi) disclose the use of various straight, curv ed or helical localization devices having an anchoπng component at a distal end to firmly anchor the device into the tissue However, ςuch prior art markers cannot be left in the patient's body for future image-guided procedui es, and typically are removed within a short period after insertion
Historically, markers used in interv entional and surgical procedures have often been made of radiopaque mateπals so that their piecise location could be identified through X ray v lewing X-ray opaque mateπals are disclosed in the prior art and can take the form of radio- opaque resins, or other similar compositions such as disclosed in U S Patent No 4,581 ,390 (Flynn) or barium, bismuth or other radio-dense salts, such as disclosed in U S Patent No 3,529,633 to Vdillancourt and U S Patent No 3,608,555 (Greyson) Similarly, X-ray markers may be formed of metal such as platinum, as disclosed in U S Patent No 4,448, 195 (LeVeen) Exemplary of guidewires markers used under X-ray view ing is the invention disclosed by U S Patent No 4,922,924 (Gambale et al )
More recently, imaging markets ha\ e been developed that are visible on MRl For example, U S Patent No 5,375,596 (Twiss et al ) discloses a method for locating tubular medical devices implanted in the human body using an integrated system of wire transmitters and receivers U S Patent No 4,572, 198 (Codπngton) additionally prov ides for conductive elements, such as electrode wires, for systematically disturbing the magnetic field m a iefined portion of an interventional device to yield increased MR visibility of that region of ihe device However, the presence of conductive elements in the imaging dev ice also i ntroduces increased electronic noise and the possibility of Ohmic heating, and these factors have the overall effect of degrading the quality of the MR image and raising concerns about patient safety Thus, the presence of MR incompatible w ire materials in implantable medical markers disclosed in the prior art causes large imaging artifacts on MRI Lack of clinically adequate MR v isibility and/or imaging artifact contamination caused by the device is also a problem for most commercially av ailable catheters, microcatheters, shunts, and other probes that can be used with image-guided methods T he limitations inherent in imaging markers disclosed in the pnor art have led to exploi ations of alternativ e tumor marking techniques The ideal marker for tumor localization would be entirely interstitial to allow the patient to return home after the localization procedure without compromising the patient s outcome 1 urthermore, the marker may need to be left in a precise location in the tissue for long periods to facilitate the investigation of lesions that require serial imaging over a peπod of vv eeks or perhaps months Thus, it w ould be desirable to anchor the interstitial marker so that the device does not migrate from its insertion site in tissue A number of mechanical anchors disclosed in the prior art, for example in U S Patent No 4,592,356 (Gutierrez,) U S Patent No 5,059, 197 (Une et al ), U S Patent No 5, 127,916 (Spencer et al ), U S Patent No 5,800,445 (Ratchff et a ), U S Patent No 5,853,366 (Dow latshahi) and U S Patent No 6, 181 ,960 (Jensen et al ) could be used More preferred is the use of a fixative, such as the fibrogen-based adhesive described in multiple references in the medical literature, for example, Alam et al (Alam HB, et al , 2005 Mil Med 170 63-9), Katkhouda (Katkhouda N, 2004 Surg Technol Int 13 65-70), Kraus et al (Kraus TW, et al , 2005 J Am Coll Surg 200 418-27), Singer et al (Singer M, et al , 2005 Dis Colon Rectum ), and Uy et al (Uy HS, et al , 2005 Ophthalmology 112 667-71) Also preferred is the use of an autologous fibrin, such as described by Hirayama et al (Hirayama T, et al , 2005 Kyobu Geka 58 128-32), v\hich could be used as a 'glue' to effectiv ely 'cement' the interstitial marker at a specific tissue location
According to the original technology described herein, the interstitial marker should also be made of steπlizable material that is mechanically and chemically stable and of low thrombolytic and inflammatory potential when implanted in tissues Sterility of the marker can be achieved using coating procedures employing biocompatible membianes as described in the prior art Examples of biocompatible materials which could be used to practice the present invention include elastin, elastomeπc hydrogel, nylon, teflon, polyamide, polyethylene, polypropylene, polysulfone, ceramics, cermets steatite, carbon fiber composites, silicon nitride, and zircoma, plexiglass, and poly-ether-ether-ketone
In accordance with the original technology described herein, the marker should exhibit high contrast in all relevant imaging methods including X-ray, US and VlRI Imaging markers used under MR guidance should also be MR-compatible in both static and time-varying magnetic fields Many materials with acceptable MR- compatibihty, such as ceramics, composites and thermoplastic polymers, are electrical insulators and do not produce artifacts or safety hazards associated with applied electric fields Some metallic materials, such as copper, titanium, brass, magnesium and aluminum are also generally MR-compatible, such that large masses of these materials can be accommodated within the imaging region without significant image degradation In one preferred embodiment, the interstitial marker of the present invention can be made MR visible by doping the marker with a material which has an MR resonance based on 19Fluoπne 19Fluoπne-labelled materials have been used previously for MRI studies of tissue oxygenation (Mason RP, et al , 2003 Adv Exp Med Biol 530 19-27) and metabolism of L-DOPA (Dingman S, et al , 2004, J Immunoassay Immunochem 25 359-70), as well as to track uptake of 5-Fluorouracil (Klomp DW, et al , 2003 Magn Reson Med 50 303-8) In a particularly preferred embodiment of the presently disclosed original technology, the interstitial marker can be clearly visualized on the basis of the Fluorine resonance in a clinical 1 5 Tesla MRI scanner by employing dual tuned transmit / receive coils set at 60 08 MHz for Fluorine and 64 85 MHz for protons, and using sequential or interleaved imaging of both resonances By simply overlaying the resulting Fluorine and proton-based images, the location of the marker can be precisely determined in relation to contiguous tissues
According to a method according to the original technology disclosed herein, providing a large gel volume in the marker allows a number of different contrast generating materials to be incorporated in the composition of the marker, including as iwo non-hmitmg examples, soluble paramagnetic and fluorescent material Particularly preferred as a paramagnetic contrast agent is Gadolinium, which induces an increase in Tl relaxivity yielding increased signal on Tl weighted MRI In another preferred embodiment of the invention, an optical fluorophore can be added to the gel J or optical detection A non-hmitmg example of such a fluorophore is mdocyanme green, which strongly binds to protemaceous substrates and has recently been approved by the FDA for human use This fluorophore is excited by infra-red (805 urn) and generates a fluorescence in a slightly lower energy infra-red band (850 nm) In another preferred embodiment, optical markers such as quantum dots can be added to the composition of the marker to provide bright optical emissions, as previously reported in the medical literature by West (West J L , 2003 Ann Rev Biomed Eng 5 285 93)
The method of the presently disclosed technology will now be described further by wa> of a detailed description of ex vivo studies with particular reference to certain non-limiting embodiments and to the accompanying drawings in FIGS 1 to 10
It is also important to appreciate the conventional bases upon which the characteristics of image quality are usually considered within each of the three imaging technologies, ultrasound, Magnetic Resonance and X-ray
^ -ray Properties. X-rays in the diagnostic energy regime aie absorbed in materials principally on the basis of their electron density and atomic number and \ary as a function of x ray energy Biological tissues are very similar to water in their attenuation properties for X-rays The goal for an x-ray marker is that it should exhibit an attenuation coefficient sufficiently different from that of tissue to be observable in typical image capture systems (e g , CCD, photography, photohtermography, or other electronic/optical detection systems) These differences could be exhibited as either a smaller or larger attenuation to x-ray, as long as they differ sufficiently from that of water as to provide the visible or detectable \ anation in properties Tissues in general exhibit a relatn ely low attenuation coefficient, so selecting a marker of a material of high attenuation coefficient as the candidate materials could be considered as the simplest approach Referring to Table I, it is seen that the linear attenuation coefficient for tissue is 0 72 cm2/gm and 0 197 cm2/gm at 20 KeV and 60 KeV respectively These two energies have been selected as they reflect a range of photon energies which span a typical monoenergetic equivalent energy range of diagnostic x- ray spectra from a mammographic (20 KeV) to an energy used for computed tomograph} (60 Kev) The practice of the claimed inv ention is not limited to this range, as it has been selected solely for the purpose of enabling and exemplifying a generic concept of the scope of the disclosed technology The point is that the attenuation coefficient should be different, and by way of non-hmitmg examples, at least 5%, at least 10%, at least 15%, at least 20%, and at least 25% different from that of water This difference could be either higher or lower than the attenuation coefficient of w ater, although it is generallv easier to select and w ork w ith materials having higher attenuation characteristics than that of water Thus the X-ray marker maj comprise a material which falls outside this range shown as the "hi' and ' lo" \ aπants on the x-ray attenuation at each energy That is an attenuation of less than 0 648/0 177 cm2/g at 20/60 KeV or more than 0 792/0 2167 cm2 g at 20/60 KeV, i especti\ ely One can see that the materials glass, ceramics, metals (especially copper and aluminum) all meet this requirement Of course these are just the obvious, non- limiting examples, and any solid or gelled material that exhibits this attenuation property may be used, such as composited, glasses, ceramics, metals, alloys, metal oxides, polymers, loaded or filled polymers, and the like Many ceramics, other metals and plastics also meet this condition.
Table I - Properties of various candidate materials for the marker
Figure imgf000015_0001
Acoustical Properties:
Now with regard to the acoustical properties of the materials measured in ultrasound imaging, it is desirable to have a number of criteria satisfied. First, the materials should exhibit a difference in their acoustic impedance, which is in turn related to the material density and the speed of sound through the material. Referring to water as a surrogate for tissue, this means that we would like the material to exhibit values beyond the "'hi" and "lo" values of impedance. Again, this is easily met by the non-limiting examples of candidate materials. Again, other materials such as ceramics, metals and some plastics could also be appropriate if they satisfy these constraints. Another set of desirable properties for the acoustic marker materials is that they be particulate in nature, with such reular or irregular geometric shapes such as spherical, oval, rectangular, square, polyhedral, etc. in shape. They do not have be spherical or even, but it is desirable that they are not a flat or plate-like structure, as they should be readily observable from three dimensions. The idea is to make the internal reflectivity of the marker components look "rough" or bumpy with respect to the wavelength of the ultrasound we are considering. So, therefore one could use spheres, rough particles, grains, etc. They do not need to be all the same, but they should have reasonable projection areas when viewed from most if not all perpsctives, which is why the sphere or other form with three relatively large dimensions (e.g., a square or equilateral polyhedron) is useful They could be random in their shape as long as they are closed (e g , not having openings that would capture soundw aves), particulate-hke, objects of approximately the same size This will prov ide them with good acoustic scattering pioperties This also suggests that the particles should be similar in size relative to the ultrasound wavelength Thus if the particle w ere not larger than 10 times the wav elength they would still function well Similarly, it is not jesirable for a given wave for the particles to be too small relative to the w avelength A reasonable relativ e size would be to keep them no less than 10% of the acoustic .vavelength Table II shows the corresponding wavelength in tissue for diagnostic 0 ultrasound systems ranging from frequency of 5- 15 MHz, which spans the current diagnostic ultrasound regime of interest Again, the examples and displayed v alues are examples of a generic concept and are not intended to limit the disclosed practice of the present technology The Table II also shows estimates of the most reasonable upper and lower bound for particle sizes based on these wavelengths in tissue
Table II Acoustic wavelength and Particle size limits
Figure imgf000016_0001
Between the material acoustic properties (impedance) and size parameters, domains 0 of values for selecting these particles have been generically characterized
Magnetic Properties
The next factoi to consider are the magnetic properties of the tissue and reference is again made to Table I In this case, the characteristic review ed is having S the particles (e g , the non-hmitmg examples of spheres are discussed) of essentially neutral magnetic susceptibility In this case, it is desired to control the susceptibility of the marker as a whole by adding a small number of spheres of controlled levels of ferromagnetic impurity. Thus the majority of the spheres should be as close to tissue in terms of their magnetic susceptibility compared to tissue. Ideally the closer the better but anything within either 2 fold higher or lower would be acceptable. Glass particles were used, but it is clear that copper might even be better when it comes to controlling the susceptibility of the particles and minimizing susceptibility artifacts. Then by adding other spheres, such as the Aluminum spheres which contained some iron, controlled introduction of amounts of ferromagnetic doping to create a susceptibility artifact in gradient recalled images can be accomplished. In the studies, a range was explored of Fe from 0 μg to 460 μg and the effect was clearly observable. Thus, it is suggested that this is at least one example of a useful range of acceptability as a marker. The materials within this range were effective in each case. Any more than 460 μg would not necessarily be more helpful.
An alternative approach to the evaluation or characterization of this property associated with MR determinations would be to use a paramagnetic contrast agent which will cause Tl shortening. A good case in point, for a specific example of the generic class of materials recognized as MR contrast or marking agents would be to add Gd-DTPA to the gel formulation as it is water soluble. This can be characterized by the relaxivity of Gd-DTPA at 1.5 Tesla which is ~ 4.5 sec^mmol"1. Thus the Gd- DTPA may be added to the volume of the gel, which is assumed to have the Tl of water. This would be the case as long as the particles do not exhibit large susceptibility changes. So, in this case, a formulation with copper might be better as i: is very close to the susceptibility of water, and it will not create sizeable signal v oids. Then by adding Gd-DTPA, the Tl of the gel marker can be shortened. The amount of Gd-DTPA required depends on the tissues in which the marker will be placed and how bright (how significant a contrast) is desired from the marker. For example, if the goal is to use the marker in breast tissue, the Tl of the native tissue is -0.7 seconds at 1.5 Tesla. Now, it would be desired to have the marker display at least a 10% difference in the relaxation characteristics. So, the gel would be doped so that the gel plus marker would have a Tl less than 0.7 seconds (at least in those areas of the marker that have been doped, to give a postive contrast in the final image. The actual concentration or weight amount of the marker is again dependent upon the specific results desired and the tissue to which it is applied. It is estimated that at least a 10% reduction in Tl would be desirable, but the larger the difference the better. So, it could be suggested to reduce this Tl of the tissue in this case to 0.63 seconds for at least modest visability on Tl weighted MRI at 1.5 Tesla. This can be easily calculated on the basis of the relaxivity of the contrast media using the following formula;
— = — + R][Gd] Tl Tl0 Were Tl0 is the Tl of the gel matrix of the gel without any Gd-DTPA included, Rl is known as the Tl relaxivity of Gd-DTPA and [Gd] is the concentration of the Gd- DTPA in the gel solution. The Tl for 1.5 Tesla is 4.5sec"1mmorl . The basis of measurements can also be determined at other MR field intensities such as 2.0Tesla, 2.5 Tesla, 3.0 Tesla and even higher, but whatever the intensity of the field, the objective is to provide a detectable signal change between the tissue and the marker that is useful to the practitioner
Marker Fabrication.
In one embodiment of the original technology disclosed herein, the interstitial marker is preferably comprised of small microspheres suspended in a gelatin matrix. By appropriate selection of materials, optimal marker visibility can be produced in a single device for all of and each of MRI, US and X-Ray applications. In another preferred embodiment, the composition of the marker exhibits a density and an average atomic number of the tissue. Tissue is composed of nitrogen, carbon, oxygen, hydrogen, etc. These all have differing atomic numbers so that an average atomic number depends on their relative abundance in the particular tissue in which the marker is placed. Very roughly, tissue can be considered as a hydrocarbon and its ' atomic number" would be somewhere near 6-7, but would be higher in bone, which would be composed of calcium as well, thus raising the avegage atomic number. If the marker is made out of aluminum, silicon or copper, the atomic number of the marker is much higher than those constituents for tissue. These materials would have an effective atomic number that is substantially higher than those of tissue to ensure X-Ray visibility. In a further preferred embodiment of the technology disclosed herein, the composition of the marker has a substantially high acoustic impedance difference from the surrounding tissue to provide good US contrast In yet another preferred embodiment of this inv ention, the magnetic susceptibility of the marker is similar to that of tissue m order to control MRI contrast in T2* weighted images
Table 1 summarizes a number of desirable physical properties of glass, copper ^ and aluminum, as three non-hmitmg examples of mateπals that could be used to produce the interstitial marker according to the present invention The magnetic susceptibilities of these materials are all reasonably close to that of tissue but additionally can include controlled doping with ferromagnetic or paramagnetic materials selected for particularly desirable Tl and T2 properties on MRI The
10 ferromagnetic and paramagnetic agents can be incorporated as aqueous solutions or suspensions By w ay of example, the paramagnetic mateπals selected can include transition metal ions such as gadolinium, dysprosium, chromium, nickel, copper, iron and manganese, or stable free radicals such as mtroxyls The concentration of the paramagnetic agents can range from the micromolar to milhmolar range Non- i s paramagnetic mateπals having desirable MR relaxation characteristics may also be employed in the manner set forth above to practice the present invention
With regard to the X-ray properties of the selected glass, copper and aluminum materials, it was found that the materials exhibit a 3 2-46 fold increase in total X-ray absorption coefficient compared to water at an energy equivalent to a 0 mammographic exposure (~20 KeV) (Plechaty EF, et al , 1978 Lanrence Livermore National Laboratory Report UCRL-5400) Similarly, the density and speed of sound in these materials was found to result in an 1 1 -24 fold increase m acoustic impedance compared to that of water (Krautkramer J and Krautkramer H, 1990 Ultrasonic Testing of Materials, Springer Verlag, ISBN 0387512314), thus ensuimg good US 5 l eflectivity
In accoi dance with a preferred embodiment of the invention, the bulk of the marker is comprised of glass microspheres, which are readily available, biocompatible and prov ide all required features for optimal US and X-Ray contrast Particularly preferred are GL-0175 glass microspheres (MO-SCI Corporation, 4000 Enterprise 0 Dm e, Rolla, MO 65402, USA) in diameters ranging from 0 4-0 6mm with a density of 4 2-4 5g/cmJ Also preferred are aluminum microspheres (Salem Specialty Ball Corporation, West Simsbury, CT 06092, USA) 0 5mm in diameter with small amounts of iron (0 7% by mass) making them slightly ferromagnetic In a furthei preferred embodiment of the invention, it was found that adding a small number of iron doped aluminum microspheres to the marker reliably induces a small but detectable Bo inhomogeneity around the marker which presented as a signal void in T2* weighted MRI As an alternative non-limiting embodiment, it was also found that pure copper microspheres of 0 8 mm in diameter (Salem Specialty Ball Corporation, West Simsbury, CT 06092, USA) could be used instead of glass microspheres
In a further non-limiting embodiment of the original methods of this idsclosure, the aluminum and glass microspheres were suspended in a 10% gelatin solution (Sigma Chemical Corporation, 3050 Spruce Street, Saint Louis, MO 63103, USA) (Figure l(a)) The gelatin mixture was prepared by mixing with distilled water at 85-95 degrees Celsius The glass and aluminum microspheres were then added in the correct numbers to achieve significant Ultrasound response and the mixture was cast in a 12-gauge needle The mixture was allowed to cool at room temperature for 2 hours and then refrigerated at 40C for another 24 hours With reference to FIG 1, upon completion of cooling, the marker was semi-rigid and could be lemoved from the needle mold in the form of a cylindrical structure 1, 7mm long with 2 05mm diameter containing the microspheres 2 and gelatin 3 FIG 1 (b) is a photograph of he final form of the marker suitable for delivery with a 12-gauge biopsy needle that is i outinely used clinically for breast tumor localization
In accordance with the original method disclosed herein, the imaging contrast of the marker for MRI visualization was controlled by adding a variable number of iron-contdining aluminium microspheres to the marker corresponding to an iron content fiom 0 μg to 468 μg The US contrast was modulated by adjusting the number of glass and aluminium microspheres added to the gelatin matrix The optimal mixture was determined to provide maximum US contrast while providing clear localization of the marker in MRI and mammography
Imaging validation studies were performed with either homogeneous agar phantoms or ex-vno tissue samples The phantoms were prepared with agar (Sigma Chemical Corporation, 3050 Spruce Street, Saint Louis, MO 63103, USA) and distilled water Amorphous silica powder (Sigma Chemical Corporation, 3050 Spruce Street, Saint Louis, MO 63103, USA) was also added to provide the phantom with a background of US backscattering material to simulate tissues Two kinds of homogeneous phantoms were prepared the first kind of phantom was rectangular in structure (60 x 60 x 40mm) and designed for the US contrast study, the second kind of phantom w as cylindrical in structure (40mm long and 30mm in diameter) and used for the MRI contrast study All of the phantoms were composed of 4% agar mixed with 4% silica Tissue phantoms were used in the form of fresh chicken breast tissue Three samples of chicken breast were used for the US study, while a piece of chicken breast containing a small segment of bone (12 6mm long) was used for a comparative study of the marker with each imaging modality
Ultrasound Imaging Studies
The markers were placed in the phantoms under US guidance using a Philips \TL HDI-5000 imaging system with a Broadband linear array 5-12 MHz transducer (L12-5 50mm, Philips) With reference to FIG 2, each marker was loaded into a 12- gauge blunt cannula 4 before placement The marker 5 w as placed in the tissue 6 by first using an 1 1 -gauge co-axial introducer needle 7 with a trocar (MRI Devices Corporation) to form a path into the phantom After positioning the introducer needle, the tiocar needle was withdrawn and then a 12-gauge cannula 4 containing the marker was passed through the introducer needle, as shown in FIG 2(c) In order to confirm the correct position of the cannula tip, US guidance was used before releasing the marker 5, as show n in FIG 2(d) Finally, the marker 5 was left in the desired position ty first pushing it out from the cannula 4 and then removing the cannula and introducer needle 7 from the tissue Axial and sagittal US imaging was performed to v erify the position of the marker During US scanning, the gam and dynamic range v ere adjusted with the target placed at the focal zone to provide the best contrast In order to measure the echogenicity of the markers, the US echo intensity was used on E>-Scan images in orthogonal directions through the marker location The peak echo signals were measured foi each glass and aluminum microsphere concentration and normalized to the maximum echo signal A series of phantom and in vitro tissue experiments were used to determine the optimum marker composition The US image of a rectangular phantom injected w ith a single glass, aluminum and copper microsphere 8 is shown m FIG 3 (a) The three microspheres were deposited at the same depth to ensure that the microspheres were exposed to the same acoustic conditions. The US echo intensity profile through the microspheres is shown by the dashed line in FIG. 3 (a) through each microsphere. It was found that although the glass microsphere was smaller than the aluminum or copper microspheres, they demonstrated a slightly greater signal than either the aluminum or the copper microspheres. Since the glass microspheres produced clearly defined US echoes and are biocompatible, they were chosen to form the bulk of the marker content in accordance with the method of the invention.
With reference to FIG. 4, in order to evaluate the effect of the number of glass microspheres on marker contrast, the US intensity for a single glass microsphere was compared to a collection of 10 microspheres injected into the same chicken breast 6. As shown in FIG. 4 (a), the single microsphere 8 is less well resolved. The intensity distribution along the depth of the single glass microsphere, as illustrated in FIG. 4 (b), is difficult to differentiate from the surrounding breast structure. By comparison, the collection of 1 0 glass microspheres 9 appears as a hyperintense structure with acoustic shadowing, as shown in FIG. 4 (c). With reference to FIG. 4 (d), the corresponding acoustic intensity distribution along the depth of 10 microspheres 9 shows a clear echo in the US data demonstrating a marked contrast improvement with the larger number of glass microspheres. With reference to FIG. 5, to evaluate the effect of glass microsphere concentration suspended in the gel matrix, US intensity was measured in phantoms 10 with 1.42mm markers of different glass concentrations. The US image of the three markers shown in FIG. 5 (a) demonstrates that a variation in the marker visibility results from different concentrations of glass microspheres. As described for the previous imaging study, the three markers were deposited in an agar phantom at the same depth for the same acoustic conditions. The effect of varying the ratio of glass microsphere volume to the total marker volume was studied using 2.3%, 8.4% and 20.7% compositions, corresponding to glass mass to total marker mass of 10%, 40% and 90% or using 3, 13 and 27 glass microspheres, respectively. The relative US peak echo intensity is plotted in FIG. 5 (b) as a function of glass mass concentration and shows that the optimal concentration should be greater than 40% weight by volume. In accordance with the method of the invention, it was found that a marker of 40% mass concentration occupied only 8 4% of the marker volume, thus providing a large gel volume to ensure solid binding of the spheres in the final marker
In accordance with the original technology disclosed herein, in order to aid in identifying the marker with US, a generally cylindrical shape (for example, one dimension such as length, being at least 1 -%, at least 20%, at least 30% or at least 40% greater than each of the other two dimensions such as width and depth, and with the other two dimensions such as width and depth generally differing from each other by less than 50%, less than 40%, or less than 30% compared to the smallest dimension, and the cross-section may be circular, oval, triangular, rectangular, or other regular or irregular shapes) is preferred because it presents a predicable change in the appearance with different US orientations Less preferred is a spherical, square, polyhedral or other geometric or irregular marker which may have a similar appearance from multiple imaging angles This is illustrated in FIG 6, where two orthogonal US view s demonstrate how the cylindrical geometry of the marker aids in its unique identification
The results with different marker sizes are shown in FIG. 7, where the US image was obtained from markers with diameters of 1.42mm, 1 78mm and 2 05mm njected into a chicken breast In this case, the glass concentration of these markers is 40% by weight All of the markers appear as bright circular structures and demonstrate that contrast increases with marker size Thus, in accordance with the method of the invention, the 2 05 mm marker appears to provide a practical compromise between minimum invasiveness and good US visibility
It has also been disclosed in the art that irregular surface particles, whether hollow or solid, can provide enhanced reflectivity of ultrasound, and such constructions are useful herein (see Burbank et al , Published U S Patent
Application No 20050063908, which is incorporated herein by reference) Similarly, rianostructured surfaces of particles or spheres or other shapes may be used to enhance Ultrasound reflectivity (as described in Published U S Patent Application No 20050038498, Dubrow et al , which is incorporated herein by reference)
MRI Studies
MR studies were performed on a 1 5-Tesla MRI system (Signa, GE Medical System) w ith a 5-inch surface coil and employing a standard 2D spoiled gradient recalled sequence (SPGR) clinical breast MRI protocol The pulse sequence parameters were TR/TE/FA = 18 4ms/4 2ms/30°, with a bandwidth of 15 6KHz and a spatial resolution of 0 39mm m-plane and 2mm slice thickness *> Fo measure the size of the MRI signal void resulting from markers with different iron content, four measurements along the horizontal, vertical and diagonal directions w ere pei formed for each marker The width of the signal void was estimated between the peaks of the greatest absolute gradient of the signal surrounding the marker This corresponded to the points of steepest descent on the artifact profile The mean and standaid deviation of the size of the signal void from the four directions was used to characterize the size of the signal void and its \ aπability The size of the signal void and its standard deviation were plotted as a function of iron content at two different TE values (4 2 and 7 3 ms)
In accordance with the original technology disclosed herein, alternative compositions of the marker were evaluated in order to find the optimal iron content that allows clear maiker definition on MRI without excessive distortion of the MR image from Bo mhomogeneities Accordingly, the effect of replacing some glass microspheres with the same number of iron-containing aluminum microspheres was tested Imaging was carried with a gradient recall sequence (SPGR) at two different ^cho times as shown in FIG 8 (a), with the direction of the axis of the marker parallel o Bo It was lound that increasing the iron content of the marker generated a larger maging void The size of the \ oid was measured and plotted as a function of iron content as shown in FIG 8 (b) The signal void was found to vary from 2 4 mm to 3 7mm in diameter for a 1 E of 4 2ms, and from 2 4mm to 9 78mm for a TE of 7 3ms \ TE of 4 2ms was chosen to comply with standard clinical breast MRI protocol The i esults indicate that the marker containing ~ 180 glass spheres and 52 μg iron produces a void artifact of 5 15mm in diameter for a TE of 4 2ms This signal artifact is comparable to prior art studies in which MRI artifacts of 8 to 18mm were produced by FDA approved stainless steel alloy clips (Meisamy et al 2004) However, it should be understood by those of ordinary skill in the art that MR contrast may be precisely ( ontrolled by adjusting the number, size, shape, and composition of the microspheies, as well as the MR imaging parameters To evaluate the effect of the shape and orientation of the marker with respect to the magnitude of its susceptibility artifact, the axis of the marker was placed at different angles to B0. With reference to FIG. 9, the axial 9 (a) and sagittal 9 (b) MR images showed that the marker appeared circular and rectangular when parallel to Bo- The sagittal image was somewhat irregular because of the local magnetic field inhomogeneity caused by iron. By comparison, when the marker was perpendicular to Bo, the axial 9 (c) and sagittal 9 (d) MR images of the indicated that the marker appeared oval and rectangular. This result demonstrated that the artifact of the marker is orientation dependent, in agreement with prior art studies (Seppenwoolde et al 2003).
X-Ray Imaging Studies
All X-Ray imaging studies were performed on a GE Senographe® 2000D full field digital mammography system using a tube voltage of 25kVp, a tube current of 87mA and a FOV of 13cm. Modest compression was applied to the agar and tissue phantoms to simulate clinical conditions. With reference to FIG. 10, the image of the marker is seen as a region of increased X-Ray attenuation that exhibits sufficient X-ray opacity to make the marker visible under high quality X-ray images and particularly high resolution CT scans.
Comparative MRI, US, X-ray Imaging Studies
The preceding imaging studies indicated that optimal MRI and US visibility is achieved with a marker diameter of 2.05 mm and 52 μg iron content. With reference to FIG. 10, the marker appears as a clear signal void on MRI 10 (a), while the US image of the marker shows a clear hyperintense structure with acoustic shadowing 10 (b). The X-Ray image clearly identifies the marker as a radio-opaque structure 10 (c). It is thus evident that this construction and composition of the imaging marker of the present invention is clearly visible under standard MRI, US and X-Ray examination
Although the presently disclosed original technology has been described mainly in terms of an imaging marker for localizing breast lesions, it will be understood by those of ordinary skill in the art that the availability of an interstitial marker visible on MRI, US, and X-ray, such as disclosed in this invention, would facilitate obtaining useful imaging information under all three imaging modalities in numerous surgical and interventional procedures Medical and surgical applications of the invention would include vascular surgery and interventional radiology, cardiac surgery and cardiology, thoracic surgery and radiology, gastrointestinal surgery and radiology, obstetrics, gynecology, urology, orthopedics, neurosurgery and neurointerventional radiology, head & neck surgery and radiology, ENT surgery and radiology, and oncology In addition to breast surgery and biopsy, the method of the invention applies to numerous interventional procedures that can be performed as intraluminal, intracavitary, laparoscopic, endoscopic, intravenous, and lntra-arteπal applications A variety of probes, including surgical instruments, endoscopes, catheters, and other devices that can be inserted into the body can also be used with this inv ention
Another general description of original technology described herein is pro\ ided by the following An implantable image marker is provided for enabling non-mvasiv e viewing of the marker subsequent to implantation The marker may comprise a de\ ice with a surface (on or m the marker) of an artifact that has at least 10% difference in ultrasound reflectivity as compared to at least one of animal breast i issue, animal brain tissue, and animal heart tissue, a material that has at least 10% difference in relaxivity at the field strength use for MR imaging as compared to at least one of animal breast tissue, animal brain tissue and animal heart tissue, l espectiv ely, and a composition that has at least 10% difference in attenuation of X- i ays from at least one of animal breast tissue, animal brain tissue, and animal heart tissue, respectiv ely By respectively, it is assumed that the marker will be implanted into approximately a single tissue composition, and that these differences should be ev aluated with i espect to that single tissue composition, and not to three different tissue compositions The implantable marker may have at least two distinct particles supported in a matrix arc used to provide the surface(s), the material that has at least 10% difference in relaxivity at 1 0 Tesla, and the composition that has at least 10% cifference in attenuation of X-rays The marker may be such that ultrasound reflectivity in the marker is provided at least in pait by artifacts comprising particles exhibiting ultrasound reflectivity A particularly good marker construction has ultrasound reflectivity in the marker provided at least in part by artifacts comprising particles exhibiting ultrasound reflectivity and the matrix comprises a gel The exemplary particles comprise ceramic, glass, metal or metal oxide particles, and tthe particles may comprise ceramic, glass, metal or metal oxide particles and the surface of the particles comprise surface structure enhancing ultrasound reflectivity as compared to a particle of the same size and material having a smooth surface s Another construction comprises a material that alters MR relaxπ ity is present w ithin a particle, such as a paramagnetic or superparamagnetic material selected from the gioup consisting of Cr, V, Mn, Fe, Co, Pr, Yd, Eu, Gd, Tb, Dy, Ho, Er, Tm, Tb and Ln The composition for attenuation of X-ray may comprise at least one metal One combination of particles (with similar or different shapes) may comprise a) a glass or
10 cei amic particle and b) a metal particle The marker omay further comprise a fluorophore that emits detectible radiation when stimulated by electromagnetic radiation, current, or magnetic flux, preferably electromagnetic radiation (such as UV or IR radiation) In the use of particles, at least one particle may comprise aluminum particles comprises an iron content of >0 μg to 468 μg The imaging marker may
15 ha\ e a glass mass concentration greater than 40% weight by volume The matrix or gel in said imaging marker may provide a substrate into which an MRI contrast agent can be added The imaging marker appears as a clear hypeπntense sϋ uctuie with acoustic shadowing on US images, and also appears as a radio-opaque structure on X- Ray images
20 These particles may be used in a method of performing a medical procedure comprising identifying a region of treatment interest, implanting the markei described herein into tissue in that region of interest, subsequently v iewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and performing a medical procedure on the region of mteiest identified by
2^ the marker The subsequent viewing may be immediately thereafter, or at a later time such as at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours or at least 24 hours subsequent to implantation of the maiker Non-limiting examples of body regions where implantation of the marker may be pro\ ided include at least body regions of a patient selected from the group consisting λθ of cardiovascular region, gastiomtestmal region, inti apentoneal region, organs, k idneys, retina, urethra, genitourinary tract, brain, spine, pulmonai y region, and soft tissues Surgical or treatment procedures such as invasive treatments or non-inavsive treatments may be used in combination with observation of the markers. Such treatments may be with surgical probe, catheter, or biopsy implements used to implants or position the marker, as well as pre-operative and intra-operative surgical guidance; localizing breast tumors under MRI, US and X-ray; excisional biopsy of the breast under MRI, US and X-ray; pre-operative localization procedures and surgery carried out on separate days; and any other local or target specific procedures. Examples of particular paramagnetic ions aere selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III) and Dy(III), and a superparamagnetic agent may comprise a metal oxide or metal sulfide, particularly where the metal of the ion is iron. Other superparamagnetic materials may include ferritin, iron, magnetic iron oxide, manganese ferrite, cobalt ferrite and nickel ferrite. The implantable imaging marker may be made of material that is mechanically stable and tissue compatible, non-limiting examples being elastin, elastomeric hydrogel, nylon, teflon, polyamide, polyethylene, polypropylene, polysulfone, ceramics, cermets steatite, carbon fiber composites, silicon nitride, zirconia, plexiglass, natural or synthetic tissue, natural or synthetic gums or resins, sols and poly-ether-ether-ketonc. The implantable imaging marker may be secured at its interstitial insertion site using a mechanical or chemical anchoring device. A chemical device would be an adhesive such as a fibrogen-based adhesive or an autologous fibrin. The implantable imaging marker may be made of sterilizable material that is of low thrombolytic/thrombogenic and low inflammatory potential when implanted in tissues. The materials may be coated for these or other effects at the site of implantation, including coatings or or diffusible material to effect those or other results, including local temporary pain or sensitivity reduction. To this end, sterility of said implantable imaging marker may be achieved using coating procedures employing biocompatible membranes. The implantable imaging marker may be MR-compatible in both static and time-varying magnetic fields.
In the preceding detailed description of the preferred embodiments, reference is made to the accompanying drawings which form a part hereof, and in which are shown by way of illustration specific preferred embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized and that structural, logical, physical, computational, medical, architectural, and other related changes may be made without departing from the spirit and scope of the present invention The preceding detailed description is, therefoi e, not to be taken in a limiting sense, and the scope of the present in\ ention is defined only by the appended claims and their equivalents
The novel technology described herein includes a method of performing an examination procedure in a medium that has MRI, US and/or X-ray responsive characteristics different from those of the markers This method could be used in manufacturing processes or in prov iding taggants to materials that can later be examined for manufacturer origins at a later date For example, the markers could be injected into elastomeπc articles such as artificial rubbers (in tires, tubing), foams, bioremedial masses, structural elements and the like The process would comprise identifying a region of examination interest, implanting the marker described above into a material in that region of interest, subsequently viewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating an object or providing a second material into the region of interest identified by the marker In masses that may change in composition because of motion or changes in composition over time, such as in polymerization processes, bioremediation masses and the like, the process could also include implanting the marker into mateπal in that region of interest, and after at least four hours subsequent to implantation of the marker, viewing the region of inteiest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating an object or providing a second mateπal into the region of interest identified by the marker The process would be supported by use of a system for the delivery of a marker supported m a matrix comprising a storage container containing a volume of the marker supported in the matrix, a mass transportation system for moving the marker supported in the matrix from the storage contamei along a mass transportation pathway into a delivery port, and a power source to nove the marker supported in the matrix The matrix must be flowable m the system and should be movable by pressure differences of less than 0 1 atmospheres (76mm Hg), such as 0 05 atmospheres (0 38mm Hg), as opposed to the matrix being so rigid m attempting to support the markers that it cannot flow through the delivery system

Claims

W H 4T IS CLAIMED:
1 An implantable image maiker supported in a matrix for enabling non-mvasive v iewing of the marker subsequent to implantation, the marker comprising a surface of an artifact that has at least 10% difference m ultrasound reflectivity as compared to at least one animal tissue a material that has at least 10% difference in relaxivity at a field strength used for magnetic resonance imaging as compaied to at least one of animal breast tissue, animal brain tissue, and animal heart tissue, respectively, and a composition that has at least 10% difference m attenuation of X-rays from at least one of animal breast tissue, animal bram tissue, and animal heart tissue, respectively
2 The implantable marker of claim 1 wherein at least two distinct particles supported in a matrix are used to provide the surface of an artifact that has at least 10% diffeience in ultrasound reflectiv ity as compared to at least one of animal breast tissue, animal bram tissue, and animal heart tissue, the material that has at least 10% difference in relaxiv itv at the magnetic resonance imaging field strength as compared to at least one of animal breast tissue, animal brain tissue, and animal heart tissue, respectiv ely, and the composition that has at least 10% difference in attenuation of X- rays from at least one of animal breast tissue, animal bram tissue, and animal heart tissue, respectiv ely
3 The marker of claim 1 wherein ultrasound reflectiv ity in the marker is provided at least in part by artifacts comprising particles exhibiting ultrasound reflectivity
4 The marker of claim 2 wherein ultrasound reflectiv ity in the marker is prov ided at least in part by artifacts comprising particles exhibiting ultrasound reflectivity and the matrix comprises a gel
5 The marker of claim 3 w herein the particles comprise ceramic, glass, metal or metal oxide particles
6 The marker of claim 4 wherein the particles comprise ceramic, glass, metal or metal oxide pai tides and the surface of the particles comprise surface structure enhancing ultrasound reflectiv ity as compared to a particle of the same size and material having a smooth surface
7 The marker of claim 3 wherein a marker that alters MR relaxivityis present within a particle
8 The marker of claim 7 w herein the marker that alters MR relaxivity is a paramagnetic materials selected from the group consisting of Cr, V, Mn, Fe, Co, Pr, Nd, Eu, Gd, Tb, Dy, Ho, Er, Tm, Tb and Ln
9 The marker of claim 4 wherein a marker that alters MR relaxivity is present within a particle and the marker that alters MR relaxivitv is a pai amagnetic materials selected from the group consisting of Cr, V, Mn, Fe, Co, Pr, Nd, Eu, Gd, Tb, Dy, Ho, Er, Tm, Tb and Ln
10 The marker of claim 3, 4 or 9 wherein the composition for attenuation of X-ray comprises at least one metal
1 1 The marker of claim 10 wherein ultrasound reflectiv ity in the marker is provided at least in part by artifacts compiising particles exhibiting ultrasound reflectivity and the matrix comprises a gel
12 The marker of claim 1 , 4, 10 or 1 1 comprising a) a glass or ceramic particle and b) a metal particle
13 A method of performing an examination procedure comprising identifying a region of examination interest, implanting the marker of claim 1 , 4 or 9 into a material in that region of interest, subsequently viewing the region of interest and observ ing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating and object or providing a second material into the region of interest identified by the marker 14 A method of performing an examination procedure comprising identifying a region of examination interest, implanting the marker of claim 12 into a material in that region of interest, subsequently viewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating an object or pro\idmg a second material into the region of interest identified by the marker
1 5 A method of performing an examination procedure comprising identifying a region of examination interest, implanting the marker of claim 4 into material in that region of interest, and after at least four hours subsequent to implantation of the marker, viewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X-rays, and manipulating an object or providing a second material into the region of interest identified by the marker
16 A method of performing an examination procedure comprising identifying a region of examination interest, implanting the marker of claim 13 into material in that region of interest, and after at least four hours subsequent to implantation of the market , viewing the region of interest and observing the location of the implanted marker by at least one of ultrasound, MR and X rays, and manipulating an object or providing a second material into the region of interest identified by the marker
17 The marker of claim 4 further comprising a fluorophore that emits detectible radiation when stimulated by electromagnetic radiation, current, or magnetic flux
18 The markei of claim 4 wherein at least one particle comprises aluminum particles comprises an iron content of >0 μg to 468 μg
19 A sy stem for the delivery of a marker supported in a matrix comprising a storage container containing a \ olume of the marker supported in the matrix according to claim 1 , a mass transportation system for moving the marker supported in the matrix from the storage container along a mass transportation pathway into a delivery port, and a power source to move the marker supported m the matrix
20 A system for the delivery of a marker supported m a matrix in accordance with the method of claim 13 comprising a storage container containing a volume of the marker supported in the matrix, a mass transportation system for moving the marker supported in the matrix from the storage container along a mass transportation pathw ay into a delivery port, and a power source to move the marker supported in the matrix
PCT/CA2006/000782 2005-05-12 2006-05-12 Marker device for x-ray, ultrasound and mr imaging WO2006119645A1 (en)

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