Patent Description:
Since inception in the <NUM>'s, Magnetic Resonance Imaging (MRI) has allowed research and diagnostic imaging of humans and animals. MRI involves using a combination of high strength magnetic fields and brief radio frequency pulses to image tissue, typically by imaging the dipole movement/spin of hydrogen protons. MRI has long provided two and three dimensional imaging of internal tissue, tissue structure, and can provide imaging of functioning processes of tissue called "Functional MRI" or fMRI.

Diffusion MRI (or dMRI), also referred to as diffusion tensor imaging or DTI, is an MRI method and technology which allows the mapping of the diffusion process of molecules, mainly water, in biological tissue non-invasively. Diffusion tensor imaging (DTI) is important when a tissue, such as the neural axons of white matter in the brain or muscle fibers in the heart, has an internal fibrous structure analogous to the anisotropy of some crystals. Water will then diffuse more rapidly in the direction aligned with the internal structure, and more slowly as it moves perpendicular to the preferred direction.

The work in MRI has permitted highly detailed neural pathway mapping, sometimes known tractography or fiber tracking. Tractography or fiber tracking is a 3D MRI modeling technique used to visually represent neural tracts (or other biologic tracts) using data collected by DTI. One MRI technology is known as high definition fiber tracking, or HDFT, and is used to provide extremely highly detailed images of the brain's fiber network accurately reflecting brain anatomy observed in surgical and laboratory studies. HDFT MRI scans can provide valuable insight into patient symptoms and the prospect for recovery from brain injuries, and can help surgeons plan their approaches to remove tumors and abnormal blood vessels in the brain. HDFT is an MRI imaging tool that is based on the diffusion of water through brain cells that transmit nerve impulses. Like a cables of wire, each tract is composed of many fibers and contains millions of neuronal connections. Other MR-based fiber tracking techniques, such as diffusion tensor imaging, cannot accurately follow a set of fibers when they cross another set, nor can they reveal the endpoints of the tract on the surface of the brain.

The instant application references the work discussed at the Schneider Laboratory at the LRDC (http://www. edu/schneiderlab/) for further background on the advancement, current status, and potential of anisotropic imaging and fiber tracking techniques with advanced MRI technologies, which work forms the background for the present invention. Related Publications <CIT> and <CIT>, provide a detailed background with further source citations in this field. The Schneider Laboratory works with the Neurological Surgery Department at UPMC to visualize fiber tracts within the brain in three dimensions in order to plan the most effective and least damaging pathways of tumor excision in patients suffering from various forms of brain cancer. Additionally, the Schneider Laboratory has utilized HDFT to localize the fiber breaks caused by traumatic brain injuries (TBI), which cannot reliably be seen with the then current standard computed axial tomography (CAT or CT) scans or then available MRI scans in mild traumatic brain injury (mTBI), aiding the diagnosis and prognosis of patient brain trauma.

Others have developed fiber tracking technologies using MRI based scans. Consider, the S. Mark Taper Foundation Imaging Center at Cedars-Sinai which offers diffusion tensor imaging (DTI) fiber tracking and functional (fMRI) motor mapping using magnetic resonance imaging fused with 3D anatomical image of a brain to aid in surgical planning.

Related Publications <CIT> and <CIT> discus related background patents in this field including <CIT>, now <CIT> <CIT>; <CIT> <CIT>; <CIT>; <CIT>; and <CIT>.

As advanced MRI systems and technologies are developed, tested and/or placed in operation, the accuracy of the technology must be verified or validated. Validation may be defined as process wherein the accuracy of the technology/imaging algorithms is proven or verified. Consider that without proper validation, the most advanced and most detailed fiber tracking systems would be merely devices that make really cool and expensive images without practical application. Further, the accuracy of the associated systems must also be periodically verified, i.e., MRI system periodically calibrated - also referenced as Quality Control aspects, to ensure original and ongoing accurate results and safe operation of the MRI systems.

Generally speaking, calibration and/or test measurements for an MRI system are performed using an imaging phantom or more commonly referenced as simply a phantom. A phantom is any structure that contains one or more known tissue substitutes, or known MRI signal substances, forming one or typically more test points, and often is used to simulate the human body. A tissue substitute is defined as any material that simulates a body of tissue. Thus a phantom may be defined as a specially designed object that is scanned or imaged in the field of medical imaging to evaluate, analyze, and tune the performance of various imaging devices. A phantom is more readily available and provides more consistent results than the use of a living subject or cadaver, and likewise avoids subjecting a living subject to direct risk.

Numerous phantoms have been developed for various imaging techniques. Related Publications <CIT> and <CIT> discus related background phantom patents including <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>, and <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>. See also <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>, and <CIT>; <CIT> and <CIT>. Related Publications <CIT> and <CIT> discus related background phantom articles providing a comprehensive background on phantoms.

Physical phantoms, as described and discussed above, provide a different balance between ground truth control and realism, to that provided by computer simulations. The above identified patents and patent applications and the art firmly establish the continued need for effective MRI phantoms for anisotropic and isotropic imaging for validating and calibrating fiber tracking technologies and systems. For fiber tracking phantoms there is a need to have tracking fibers that approximate human axons, which has proved difficult in the past. Related Publications <CIT> and <CIT> disclose textile based axon simulation fibers or tracts having an outer diameter of less than <NUM> microns and an inner diameter of less than <NUM> microns, and although these are a great improvement over prior art, there remains a need for further improvement.

International Patent Publication No. <CIT> describes phantoms having reference members with microchannels and diffusion weighted imaging using the phantoms.

In an aspect of the present invention, there is provided an MRI phantom according to Claim <NUM>.

The present disclosure addresses fiber tracking phantoms, and the present application is defining certain terms to be used herein. The term "taxon" is defined within this application as a textile based axon simulation having an outer diameter of less than <NUM> microns and an inner diameter of less than <NUM> microns, generally much smaller than this range, but this range is suitable for defining the term. Thus a taxon can be considered a single tube, often filled with fluid. The phrase "taxon fiber" is defined within this application as a collection or bundle of taxons, and the taxon fiber may be formed with integral taxons that share outer walls. The phrase "taxon filament" is defined within this application as a taxon fiber with peripheral modification, such as placing a sheath around a bundle of taxons that form a taxon fiber, or trimming/shaping the edges of a taxon fiber to form a polygon taxon filament that allows for tighter packing. The phrase "taxon ribbon" is defined within this application as a bundled or attached collection of taxon fibers or taxon filaments, typically taxon filaments.

There is provided an MRI phantom for calibrated anisotropic imaging comprising a plurality of taxons, wherein each taxon has an inner diameter of less than <NUM> microns and wherein the taxons include at least one of i) are integral and share common taxon walls, and ii) are formed within an outer sheath. The MRI phantom may be provided such that the taxons form at least one taxon filament in the MRI phantom and wherein a plurality of taxon filaments are combined to form at least one taxon ribbon. The MRI phantom may be provided such that the taxons have an average inner diameter of less than <NUM> micron, specifically about <NUM> microns and wherein adjacent taxons have a minimal wall thickness of <NUM> microns. The MRI phantom may be provided such that the taxons have a packing density of about <NUM>,<NUM>,<NUM> per square millimeter.

The MRI phantom may be provided such that the taxons are formed in taxon filaments which include structural features such as an outer frame and crossing support ribs. The MRI phantom may further include a visible alignment feature that allows for verifying orientation of an individual taxon filament.

The MRI phantom is provided such that the taxons are formed as taxon fibers manufactured using a bi or tri-component textile/polymer manufacturing process.

The MRI phantom may include one phantom section formed as an anisotropic homogeneity phantom having frame members that support fiber tracks extending in mutually orthogonal directions, wherein each fiber track is formed of taxons formed in taxon filaments.

These and other aspects of the invention are set forth in the following description of the preferred embodiments taken together with the attached figures in which like reference numerals represent like elements throughout.

For fiber tracking phantoms there is a need to have tracking fibers that approximate human axons, which has proved difficult in the past. <FIG> is an image of taxon filament <NUM> according to a first embodiment of the present invention. In this embodiment each taxon <NUM>, or textile based axon simulation, has an inner diameter of less than <NUM> microns, generally less than <NUM> micron. The taxon filament <NUM> has an outer diameter of about <NUM> microns. The individual separate taxons <NUM>, which are filled with water or other desired fluid, are bundled to form a taxon fiber <NUM> and a sheath <NUM> having a thickness of about <NUM> microns surrounds the bundled taxons <NUM> to form the taxon filament <NUM>. In this embodiment, the peripheral modification to the bundled taxons <NUM> converting the taxon fiber to a taxon filament <NUM> is the addition of the outer sheath <NUM>.

<FIG> is a chart or histogram that illustrates the inner diameter distribution range of the taxons <NUM> of the taxon filament <NUM> of <FIG>. The chart of <FIG> also compared with reference axon distributions. The chart in <FIG> demonstrates a mode of about <NUM> micron inner diameter for the measured taxons <NUM> of the taxon filament <NUM> in this example, over a range of about <NUM> to about <NUM> microns, with the vast majority of inner diameters of taxons <NUM> being below <NUM> micron. Subsequent measured results over greater number of examples of taxons <NUM> consistently show the mode at <NUM> microns, over a range of about <NUM> to less than about <NUM> microns, again with the vast majority of inner diameters of taxons <NUM> being below <NUM> micron. This distribution of inner diameters of taxons <NUM> favorably matches with axon distributions of relevant populations as evidenced in <FIG>.

<FIG> is an image of taxon fiber <NUM> according to a second embodiment of the present invention. In this embodiment each taxon <NUM>, or textile based axon simulation, has an inner diameter of less than <NUM> microns, generally less than <NUM> micron. The taxon fiber <NUM> has an outer diameter of about <NUM> microns. In this embodiment the taxons <NUM> are integral to each other within the taxon fiber <NUM> as they share common walls. Within the meaning of this application "integral" taxons are those, such as taxons <NUM> of taxon fiber <NUM> that share common walls. The taxons <NUM> are formed in concentric annular arrays within the taxon fiber <NUM> around a circular central core <NUM> and results in much greater or tighter packing of axons within a given space. The taxon fiber <NUM> contains more than <NUM> fibers with average inside diameter (ID) of less than <NUM> nanometers, with the specific illustrated embodiment containing <NUM> taxons <NUM> with average inside diameter (ID) of <NUM> nanometers. Again, the individual integrated taxons <NUM> are filled with water or other desired fluids. A collection of taxon fibers <NUM> may be bundled into ribbons in the manner discussed below. The taxon fibers <NUM> may be processed into polygon shapes for tighter ribbon packing as detailed below, however the concentric annular arrays, also known as radial arrays, are generally preferred where the taxon fibers <NUM>, rather than taxon filaments, are used to form taxon ribbons. The use of taxon fibers <NUM> to form ribbons such as to allow interstitial spaces between the taxon fibers <NUM> in a given tract formed by the ribbon.

In some applications the phantom may desire to have higher diameter taxons <NUM> within a taxon fiber <NUM>. <FIG> shows a "large taxon" based taxon fiber <NUM> of less than <NUM> micron outer diameter, and specifically the illustrated taxon fiber <NUM> has a <NUM> micron OD containing <NUM>"large diameter" taxons <NUM> with an average ID of <NUM>,<NUM> nanometers. The taxons <NUM> have an inner diameter ranging from <NUM>-<NUM> microns in this "large taxon" based taxon fiber <NUM>. These integral taxons <NUM> extend to the upper ranges of what is considered taxons (ID less than about <NUM> microns) within this application. Similar to taxon fiber <NUM>, the taxons <NUM> are formed in an annular array within the taxon fiber <NUM>. The taxons <NUM> are formed in linear patterns around a generally rectangular core <NUM>. Again, the individual integral taxons <NUM> are filled with water or other desired fluids. A collection of taxon fibers <NUM> may be bundled into ribbons in the manner discussed in detail herein.

<FIG> illustrates the inner diameter distribution range of the taxons <NUM> of the taxon fiber <NUM> of <FIG> and of the taxons <NUM> of the taxon fiber 3B and B. The chart of <FIG> also compared with reference human axon distributions. The chart demonstrates a mode of <NUM> micron inner diameter for the taxons <NUM> of the present invention over a range of about <NUM> to <NUM> microns, with the vast majority below <NUM> micron. This distribution of taxon <NUM> inner diameters matches axon distributions of relevant populations quite favorable. The chart demonstrates a mode of about <NUM> micron inner diameter for the taxons <NUM> of the present invention over a range of about <NUM> to <NUM> microns.

<FIG> is a scanning microscope image of taxon filament <NUM> according to a fourth embodiment of the present invention having a rectangular array of integrated individual taxons <NUM>. The taxon filament <NUM> shows a tight tolerance in the range of taxon inner diameters with each taxon <NUM> having about a <NUM> micron inner diameter. The taxons <NUM> are integral to each other within the taxon filament <NUM> as they share common walls and the common walls have a narrow portion or minimum wall thickness of about <NUM> microns. As noted above, within the meaning of this application "integral" taxons are those, such as taxons <NUM> of taxon filament <NUM> that share common walls. The taxons <NUM> are formed in a close pact rectangular array within the taxon filament <NUM>. Also included are structural features such as outer frame <NUM> and crossing support ribs <NUM>. The outer frame <NUM> and support ribs or struts <NUM> minimize taxon <NUM> damage during manufacturing of specific phantoms. Additionally some taxons are omitted adjacent one corner of the crossing ribs <NUM> to form a visible alignment feature <NUM> that allows for verifying orientation of an individual taxon filament <NUM>. The orientation of the taxon filament <NUM> can be important both in manufacturing precise ribbons and resulting phantoms, and in the operation of the resulting phantom. The uniform inner diameters and tight tolerance of the taxons <NUM> of taxon filament <NUM> is best shown in <FIG>, and this construction results in much greater or tighter packing of taxons <NUM> within a given space, specifically up to <NUM>,<NUM>,<NUM> taxons <NUM> within a square millimeter. The individual integrated or integral taxons <NUM> are filled with water or other desired fluids. A collection of taxon filaments <NUM> may be bundled into ribbons in the manner discussed below.

<FIG> is a schematic plan view of a forming template of a taxon fiber <NUM> forming the taxon filament <NUM> of <FIG>. The taxon filaments <NUM> are manufactured using a bi or tri-component textile/polymer manufacturing process in the form shown in the template of a taxon fiber <NUM> shown in <FIG>. The bi-component/tri component manufacturing process is existing art in the textile manufacturing world and is available from manufacturers such as Hills, Inc. in Melbourne, Florida. As shown in <FIG>, the taxon fiber <NUM> is a round fiber to start and within each taxon fiber there are roughly <NUM><NUM> micron inner diameter taxons <NUM> in a single taxon fiber <NUM>.

In manufacturing the combination of solid material(s), such as nylon or similar material, and dissolvable material(s), such as PVOH or similar material, are arranged in the desired pattern. The solid material forms the walls of the taxons <NUM> and the structural features such as outer frame <NUM> and crossing support ribs <NUM> and the visible alignment feature <NUM>. In the taxon filament <NUM> only a single solid material is used, but one type may be used for the walls of the taxons <NUM> and another for the structural features and the alignment feature <NUM> to allow for differentiation within the MRI.

When dissolvable material is removed it will leave holes between continuous thin walls to form the integral taxons <NUM>. It is also used to allow sections of the round shape of the taxon fiber <NUM> to be removed to form the taxon filament <NUM>. In this instance there is a layer of dissolvable material around the solid outer nylon frame <NUM> forming a square. The process of forming the polygon taxon filament <NUM> is known as delamination and <FIG> is a scanning microscope image of a perspective view of the taxon filament of <FIG>.

The delamination process may use soaking and/or increased humidity together with tension, agitation, pressure, temperature control, exposure duration to selectively dissolve away the dissolvable polymer and leaves only solid structures to form the taxon filament <NUM>. It is optimal to delaminate to first remove the outer unwanted sections of the taxon fiber <NUM>, while preventing the delamination process from also dissolving away any polymer inside the taxons/holes, e.g., ideally these remain filled with dissolvable polymer until a later stage in the process. This staged process allows manufacturing to proceed with a solid (more durable) filament <NUM> during ribbon <NUM> assembling and routing of ribbons <NUM> into fixtures. Then at a final stage the remaining dissolvable polymer is dissolved to evacuate the taxons <NUM> and re-fill them in a control manner with a desired substance (e.g., water, D<NUM>O, an MRI contrast agent, etc.). By delaying this until a late stage, the process minimizes the chance that air gets into the holes of the taxons <NUM>, which could remain in the micron level tube and create a susceptibility artifact in an MRI image. Later stages of the processes may be performed in a nitrogen environment to further reduce the risk of an air/oxygen bubble persisting in the taxons <NUM>.

A polygon based structure for taxon filament <NUM> with straight edges (triangle, square, rectangle, quadrilateral, octagon/honey comb) is more optimal to assure that adjacent filaments <NUM> pack in closely, and can be purposely fused in post processing, to form a compact ribbon <NUM> that eliminates any space between filaments <NUM>. A repeatable, deterministic, and accurate calculation of the area within taxons <NUM> (holes) as well as between taxon taxons <NUM> is critical/required to create precise predictive models of diffusion within diffusion MRI. <FIG> is a scanning microscope image of a taxon ribbon <NUM> formed by a plurality of the taxon filaments <NUM> of <FIG>.

The MRI phantoms formed by ribbons <NUM> form a viable anisotropic diffusion reference measurement object matched to the human axon specification with the <NUM> micron taxons <NUM> within the ribbons <NUM> yielding a packing density of <NUM><NUM> per mm<NUM>. These ribbons <NUM> can be configured to duplicate the complexity of fasciculi scale brain connectivity and diffusion chambers. The bi or tri-component manufacturing technology is critical to produce sub-micron scale features in a precise repeatable and controlled fashion using both a dissolvable polymer such as PVOH (polyvinyl alcohol) /PVA (polyvinyl acetate) with a non-dissolvable structure as nylon in the same machine. In scalable operations a ten-foot-high machine outputs a human hair size taxon fiber <NUM> at the rate of <NUM> meters per minute.

As noted above, after taxon filaments <NUM> are created, these are combined into taxon ribbons <NUM> of desired configurations/dimensions e.g., ribbons <NUM> may be <NUM> filament high by <NUM> filaments wide (rectangular shape), 1x4, 1x6, 1x8, 1x12, 2x2, 2x4, 2x6, 2x8, 2x12.

Precisely combining individual taxon filaments <NUM> provides structure; allows for a larger size unit that is easier/more feasible to work with without specialized viewing equipment; and most importantly - allows filaments <NUM> to be bonded together for long runs to assure no space to exist between the straight edges of adjacent filaments <NUM> (which allows for precise calculation and verification of the exact amount of solid mater or fill material (water) that exists in a given dimensional space/area of a ribbon <NUM>).

Once the filaments <NUM> are in a square shape (or any polygon shape with straight edges) then the filaments <NUM> are run over machined surfaces and/or channels to prevent the filament <NUM> from twisting as they are being combined into ribbons <NUM>. Twisting of the filaments <NUM> during this process would minimize/reduce the effectiveness of a diffusion calibration device. Computer controlled stepping motors and tensioning devices may be used to pull multiple filaments <NUM> through a straightening device to eliminate twisting, then the filaments <NUM> are run through an aperture specifically designed to apply side wall forces that will join adjacent filaments <NUM> together as they move closer and closer together and through the system. The optimal shape at the junction point is a torus (minimally a ½ of a torus) of a specific dimension (which depends on the size and number of filaments <NUM> being joined at one time in a ribbon <NUM>. A staged compression approach may be used which allows ribbons <NUM> to be loose until after the filling process (e.g., to allow filling substance around individual units), then the ribbons <NUM> may be compressed after to remove space between filaments <NUM>.

The above processes may be used to make "micro phantoms" which have a low number of filaments <NUM> in a ribbon <NUM> mounted into a very small fixture, which can be scanned at high resolution (primarily for research studies) in small bore, very high field MRI scanners.

Scaling production of the ribbons <NUM> is an important aspect of the invention. <FIG> is a schematic view of an assembly line <NUM> for forming various ribbons <NUM> with taxon filaments <NUM> according to the present invention including representations of distinct density ribbons <NUM>. The line <NUM> introduces and aligns multiple filaments <NUM> and coats with adhesive in initial unit <NUM> of the line <NUM> before the line <NUM> uses precisely control placement of the filaments <NUM> into fixtures at placement unit <NUM> and which placement is arranged around a wheel <NUM>. The line <NUM> can cut the ribbons <NUM> to a desired length and may selectively add intervening films (non-taxon <NUM> containing portions) at unit <NUM> to allow for a desired variation in the taxon <NUM> density of the resulting ribbon <NUM>. Various densities of ribbons <NUM> are shown in <FIG>. In summary the line <NUM> can tightly wind the ribbons <NUM> around or through the structure (into the fixtures); secure the ribbons within each fixture; and cut the ribbons <NUM> into individual segments that can be integrated into an MRI phantom as desired. As an alternative, a modified CNC type routing machine, or on a smaller scale a modified 3D printer, may be used to automate production and also precisely place the fiber within an array of fixtures.

<FIG> is a perspective view of an anisotropic homogeneity MRI phantom <NUM> using ribbons <NUM> formed of filaments <NUM> of the present invention. A key challenge throughout MRI is getting measurements that are quantitatively stable across space. There are added challenges in anisotropic calibration that must account for variations within the X, Y, and Z dimensions. Spatial correction is hard because coil fall offs are quadric with distance in 3D space from the coil loops. A valuable role of a reference phantom is to quantify how close repeatable and accurate the measurement is across space, tensor direction and time of scan.

The phantom <NUM>, also called a disc as it may be a modular component of a larger phantom as discussed below, shown in <FIG> is may be described as an anisotropic homogeneity phantom having frame members <NUM> coupled with fasteners <NUM> that support ribbons forming tracks <NUM>, <NUM> and <NUM> extending in mutually orthogonal directions. The tracks <NUM>, <NUM> and <NUM> are formed of ribbons <NUM> formed by filaments <NUM> as discussed above. <FIG> shows that the taxon ribbons <NUM> may form the specific X, Y and Z tracks <NUM>, <NUM> and <NUM> that are supported in the fixed frames <NUM> within the phantom <NUM>. For each direction there are preferably at least five tracts each forming at least <NUM> region of interests or test points across the phantom <NUM>. Additionally there may be variations in density of the ribbons <NUM> in each dimension to allow for checking various fiber densities in each direction. The phantom <NUM>, for example, might provide <NUM>6x6x6 mm regions of interest (ROls) or test points, wherein each ROI provides a ground truth measurement of density and angle of the taxons <NUM> of that ROI. The phantom <NUM> combines all these features allowing calibration of all three axes and three directional tensors. For simplicity the X, Y dimension tracks <NUM>, <NUM> are illustrated as non-intersecting. An alternate is that the fiber ribbons <NUM> forming tracks <NUM> and <NUM> in the X, Y dimensions are crossed at each alternating layer adding the utility of a crossing fixture. The same would also apply to the Z dimension if the frame has sufficient depth to cross in this dimension efficiently to produce a crossing of fibers in <NUM> dimensions that can be used reliably as a phantom. Adding crossing fibers would add additional features but there may be an advantage to keeping the crossing functions for a separate crossing phantom.

<FIG> is a schematic perspective view of a modular MRI phantom <NUM> including an anisotropic homogeneity MRI phantom <NUM>. The phantom <NUM> includes a readable serial number <NUM> to identify the device and a biophysics disc <NUM>, a reference fluid disc <NUM>, and an anatomical disc <NUM> in addition to the spatial homogeneity disc <NUM> discussed above. <FIG> are schematic representations of the modular MRI phantom discs <NUM>, <NUM>, <NUM> and <NUM> used with the MRI phantom <NUM> of <FIG>. The construction of the biophysics and reference fluid and anatomical phantom test points for the discs <NUM>, <NUM> and <NUM> are generally known in the art. In general the biophysics disc <NUM> will include track crossings and changes in fiber densities, the reference fluid disc <NUM> includes up to <NUM> reference fluids and the anatomical disc can demonstrate anatomical variations for testing.

Claim 1:
An MRI phantom (<NUM>, <NUM>) for calibrated anisotropic imaging comprising a plurality of textile based axon simulations (<NUM>, <NUM>), filled with water or other desired fluids,
wherein each textile based axon simulation (<NUM>, <NUM>) has an inner diameter of less than <NUM> microns and wherein the textile based axon simulations (<NUM>, <NUM>) are integral as they share common textile based axon simulation walls, and wherein the textile based axon simulations (<NUM>) are formed as textile based axon simulation fibers (<NUM>) manufactured using a bi or tri-component textile/polymer manufacturing process.