U.S. patent application number 09/742411 was filed with the patent office on 2001-06-21 for fiducial marker.
Invention is credited to Allen, George S., Fitzpatrick, J. Michael, Maciunas, Robert J., Maurer, Calvin R. JR., McCrory, Jennifer J., Willcott, M. Robert.
Application Number | 20010004395 09/742411 |
Document ID | / |
Family ID | 23909037 |
Filed Date | 2001-06-21 |
United States Patent
Application |
20010004395 |
Kind Code |
A1 |
McCrory, Jennifer J. ; et
al. |
June 21, 2001 |
Fiducial marker
Abstract
An implantable fiducial marker having a sealed cavity for the
introduction of an imaging agent that provides imaging capability
in several modes, including Computed Tomographic imaging (CT) and
Magnetic Resonance Imaging (MRI) is disclosed. The marker may be
permanent, or it may be temporary and readily detachable from its
anchor site. Combinations or agents imageable under CT scanning are
combined with agents imageable under MRI scanning.
Inventors: |
McCrory, Jennifer J.;
(Lincoln, RI) ; Fitzpatrick, J. Michael;
(Nashville, TN) ; Willcott, M. Robert; (Nashville,
TN) ; Maciunas, Robert J.; (Nashville, TN) ;
Maurer, Calvin R. JR.; (Nashville, TN) ; Allen,
George S.; (Nashville, TN) |
Correspondence
Address: |
KENYON & KENYON
1500 K STREET, N.W., SUITE 700
WASHINGTON
DC
20005
US
|
Family ID: |
23909037 |
Appl. No.: |
09/742411 |
Filed: |
December 22, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09742411 |
Dec 22, 2000 |
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08480709 |
Jun 7, 1995 |
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Current U.S.
Class: |
378/162 ;
378/205; 378/63 |
Current CPC
Class: |
A61K 49/0409 20130101;
A61B 90/39 20160201; A61B 2090/3995 20160201; A61B 2090/3904
20160201; A61K 49/0447 20130101; A61K 49/18 20130101; A61B 5/055
20130101 |
Class at
Publication: |
378/162 ;
378/205; 378/63 |
International
Class: |
H05G 001/28 |
Claims
What is claimed is:
1. A fiducial marker, comprising: a material imageable in at least
one imaging modality, wherein the fiducial marker is imageable in a
plurality of imaging modalities.
2. The fiducial marker of claim 1, wherein the marker is imageable
in at least two imaging modalities selected from the group
consisting of computed tomographic (CT) imaging, magnetic resonance
(MR) imaging, positron emission tomographic (PET) imaging, and
single photon emission computed tomography (SPECT) imaging.
3. The fiducial marker of claim 1, wherein the fiducial marker is
imageable in a computed tomographic (CT) image and in a magnetic
resonance (MR) image.
4. The fiducial marker of claim 3, wherein the material renders the
marker imageable in a magnetic resonance image.
5. The fiducial marker of claim 4, wherein the material renders the
marker imageable in a T1-weighted magnetic resonance image and in a
T2-weighted magnetic resonance image.
6. The marker of claim 4, wherein the material also renders the
marker imageable in a computed tomographic image.
7. The marker of claim 6, wherein the material further comprises a
high Z-value agent that renders the marker imageable in a computed
tomographic image.
8. The marker of claim 7, wherein the high Z-value agent is
selected from the group consisting of barium, iodine, titanium,
tantalum, silver, platinum and iron.
9. The marker of claim 8, wherein the material further comprises an
aqueous solution of iothalamate meglumine and gadopentate
dimeglumine-DPTA.
10. The marker of claim 9, wherein the gadopentate dimeglumine-DPTA
is present in a concentration of about 0.5 mM.
11. The marker of claim 9, wherein the iothalate meglumine is
present in a concentration of about 50 to 600 mg iodine per ml of
solution.
12. The marker of claim 8, wherein the material further comprises
an aqueous solution of silver nitrate and gadopentate
dimglumine-DPTA.
13. The marker of claim 12, wherein the gadopentate
dimeglumine-DPTA is present in a concentration of about 0.5 mM.
14. The marker of claim 12, wherein the silver nitrate is present
in a concentration of about 100 to 600 mg silver nitrate per ml of
solution.
15. The marker of claim 4, wherein the fiducial marker further
comprises a housing that contains the material, wherein the housing
renders the marker imageable in a computed tomographic image.
16. The marker of claim 15, wherein a first part of the marker
housing is doped with a substance that renders the first part of
the marker housing imageable in a computed tomographic image, and
the geometric center of the first part of the marker housing is
coincident with the geometric center of the material.
17. The marker of claim 16, wherein the substance that renders the
first part of the marker housing visible in a computed tomographic
image is a metal salt present in a concentration up to about 400
mg/ml.
18. The marker of claim 17, wherein the metal salt is selected from
the group consisting of salts of barium, salts of platinum, and
salts of gold.
19. The marker of claim 17, wherein the substance that renders the
first part of the marker housing visible in a computed tomographic
image is titanium oxide.
20. The fiducial marker of claim 1, wherein the fiducial marker
does not contain any solid metal.
21. The fiducial marker of claim 20, wherein the fiducial marker is
imageable in a computed tomographic image.
22. The fiducial marker of claim 1, wherein the fiducial marker is
adapted to be removably attached to a base affixed to the
anatomy.
23. The fiducial marker of claim 22, wherein the base is adapted
for rigid affixation to a bone.
24. The fiducial marker of claim 23, wherein the base is adapted
for subcutaneous implantation.
25. The fiducial marker of claim 1, wherein the fiducial marker is
adapted for implantation beneath a patient's skin.
26. The fiducial marker of claim 1, wherein the fiducial marker is
adapted for implantation into a patient's bone.
27. The fiducial marker of claim 26, wherein the marker further
comprises a housing that contains the material, wherein the housing
is constructed of a material selected from the group consisting of
polymethyl methacrylate, high density polyethylene, zirconium oxide
and aluminum oxide.
28. The fiducial marker of claim 1, wherein the fiducial marker is
adapted for use without a stereotactic frame.
29. A fiducial marker that is imageable in a plurality of imaging
modalities.
30. A fiducial marker, comprising: means for rendering the fiducial
marker imageable in a first imaging modality, and means for
rendering the fiducial marker visible in a second imaging
modality.
31. The fiducial marker of claim 30, wherein the first imaging
modality is computed tomographic imaging, and the second imaging
modality is magnetic resonance imaging.
32. A fiducial marker kit, comprising: at least three bases, each
less than about 12 mm in length, adapted to be affixed to the
anatomy; a first set of at least three fiducial markers, each
marker further comprising a first material that is imageable in a
first imaging modality, and each marker adapted to be removably
attached to one of the three bases; and a second set of at least
three fiducial markers, each marker further comprising a second
material different from the first material that is imageable in a
second imaging modality different from the first modality, and each
marker adapted to be removably attached to one of the three bases,
wherein the three bases are transparent in the first and second
imaging modalities.
33. A fiducial marker kit, comprising: a base adapted to be affixed
to the anatomy; a first fiducial marker, further comprising a first
material having a spherical configuration that is imageable in a
first imaging modality, the first marker adapted to be removably
attached to the base; a second fiducial marker, further comprising
a second material, different from the first material, that is
imageable in a second imaging modality different from the first
imaging modality, the second material having a spherical
configuration, and the second marker adapted to be removably
attached to the base; wherein, when the first marker is attached to
the base, the geometric center of the first material is located at
a first position relative to base; and wherein, when the second
marker is attached to the base, the geometric center of the second
material is located at about the first position relative to
base.
34. A method of obtaining images of the anatomy, comprising:
affixing three bases to the anatomy; attaching to the three bases a
first set of three fiducial markers imageable in a first imaging
modality; obtaining a first series of tomographic images of the
anatomy using the first imaging modality, without using a
stereotactic frame; removing the first set of three fiducial
markers from the three bases; attaching to the three bases a second
set of three fiducial markers imageable in a second imaging
modality; obtaining a second series of tomographic images of the
anatomy using the second imaging modality, without using a
stereotactic frame; removing the second set of three fiducial
markers from the three bases; using the first series of tomographic
images to construct a first three-dimensional image of the anatomy;
using the second series of tomographic images to construct a second
three-dimensional image of the anatomy; correlating the first and
second three dimensional images with each other using the images of
the first set of fiducial markers in the first three-dimensional
image, and the images of the second set of fiducial markers in the
second three-dimensional image.
Description
BACKGROUND OF THE INVENTION
[0001] Recent years have seen the development of diagnostic
techniques that allow the practicing clinician to obtain high
fidelity views of the anatomical structure of the human body.
Imaging systems such as computed tomographic (CT) x-ray imagers,
positron emission tomographic (PET) scanners, single photon
emission computed tomography (SPECT) scanners and nuclear magnetic
resonance imaging (MRI) machines have provided clinicians with the
ability to improve visualization of the anatomical structure of the
human body without surgery or other invasive techniques. In lieu of
exploratory surgery, the patient can be subjected to the scanning
modalities of such imaging systems, and the patient's anatomical
structure can be reproduced in a form for evaluation by a trained
doctor.
[0002] The doctor sufficiently experienced in these techniques can
evaluate the images of the patient's anatomy and determine if there
are any abnormalities present. An abnormality in the form of a
lesion appears on the image as a shape that has a discernable
contrast with the surrounding area. The difference in contrast is
due to the lesion having imaging properties that differ from those
of the surrounding body tissue. Moreover, the contrasting shape
that represents the lesion appears at a location on the image where
such a shape would not normally appear with regard to a similar
image of a healthy person.
[0003] Once a lesion has been identified, several methods of
treatment are utilized to remove or destroy the lesion, including
chemotherapy, radiation therapy, and surgery. When chemotherapy is
chosen, drugs are introduced into the patient's body to destroy the
lesion. During the course of treatment, imagers are commonly used
to follow the progress of treatment by subjecting the patient to
periodic scans and comparing the images taken over the course of
the treatment to ascertain any changes in the lesion
configurations.
[0004] In radiation therapy, the images of the lesion generated by
the imager are used by a radiologist to adjust the irradiating
device and to direct radiation solely at the lesion while
minimizing or eliminating adverse effects to surrounding healthy
tissue. During the course of the radiation treatment, the imaging
system is also used to follow the progress of the patient in the
same manner described above with respect to chemotherapy.
[0005] When surgery is used to remove a lesion or other
abnormality, the images of the lesion in the patient can guide the
surgeon during the operation. By reviewing the images prior to
surgery, the surgeon can decide the best strategy for reaching and
biopsying, excising, or otherwise manipulating the abnormality or
lesion, whether it is a brain tumor, arteriovenous malformation,
infection or other entity. After surgery has been performed,
further scanning is utilized to evaluate the success of the surgery
and the subsequent progress of the patient.
[0006] A problem associated with the scanning techniques mentioned
above concerns the accurate selection and comparison of views of
identical areas in images that have been obtained by imagers at
different times or by images obtained essentially at the same time
using different image modalities, e.g., CT, MRI, SPECT, and PET.
This problem has two aspects. First, in order to relate the
information in an image of the anatomy to the anatomy itself, it is
necessary to establish a one-to-one mapping between points in the
image and points on the anatomy. This is referred to as registering
image space to physical space.
[0007] The second aspect concerns the registration of one image
space to another image space. The goal of registering two
arbitrarily oriented three dimensional images is to align the
coordinate systems of the two images such that any given point in
the scanned anatomy is assigned identical addresses in both images.
The calculation of the rigid body transformation necessary to
register the two coordinate systems requires knowledge of the
coordinate vectors of at least three points in the two systems.
Such points are called "fiducial points" or "fiducials," and the
fiducials used are the geometric centers of markers, which are
called "fiducial markers". These fiducials are used to correlate
image space to physical space and to correlate one image space to
another image space. The fiducial markers provide a constant frame
of reference visible in a given imaging mode to make registration
possible. The general technique for using fiducial markers to
obtain registration of image data across time is set forth in U.S.
Pat. No. 4,991,579 to George S. Allen, the contents of which are
incorporated herein by reference.
[0008] One problem extant in the field lies in the provision of
fiducials capable of use with several imaging modalities. MRI and
X-ray CT images are digital images, in which the images are formed
point by point. These points are called picture elements, or
pixels, and are associated with an intensity of light emitted from
a cathode ray tube, or are used to form an image on film. The array
of lighted pixels enables the observer to view an image. The manner
in which the intensity of any given pixel is altered or modulated
varies with the imaging modality employed. In X-ray CT, such
modulation is a function primarily of the number of electrons per
unit volume being scanned. In MR imaging, the parameters primarily
influencing this modulation are the proton spin density and
longitudinal and transverse relaxation times T1 and T2, which are
also known as the spin-lattice and spin-spin relaxation times,
respectively. In constructing a fiducial marker, one must be aware
that an agent that can be imaged under one imaging modality will
not necessarily be imageable under another modality. And yet, the
ability to image under both CT and MRI with a given marker would be
especially useful, in that one would then be able to register
images derived from different imaging modalities. For example, the
capability to register CT and MR images would allow the integration
of information concerning bony structure provided by a CT scan with
the soft tissue anatomical information provided by an MRI scan.
There remains a need for a fiducial marker that can be used to
establish a known coordinate system under several imaging
modalities.
[0009] A further problem in the field arises from the competing
needs of accommodating patient comfort, which would tend to lead
clinicians toward the minimization of marker size, with the desire
of clinicians to use markers that are as bright and thus as large
as possible. Such brightness is desirable because it provides a
strong signal that can be distinguished from noise inherent in the
imaging process. The use of large-sized markers is also desirable
so that the image of the marker occupies as many pixels as
possible. Increasing the number of pixels occupied by the marker
increases the accuracy with which the position of the marker can be
determined. Furthermore, the general technique of using fiducial
markers requires the determination of the centroid of the marker;
it is easier to compute the centroid for a large, bright marker
than for a smaller, dimmer marker. On the other hand, the larger
the marker is, the more difficult it is for the patient to tolerate
its presence for extended periods of time. There remains a need for
a marker which can exploit the advantages presented by increased
size that would also be tolerated by the patient during the period
of its use. There is also a need for a small multi-modality marker
that can be implanted into a patient and remain there for more
extended periods of time. Such a more permanent fiducial marker
would preferably be detectable by a non-invasive technique so that
its position in physical space could be determined and its centroid
computed even as it remained hidden from visual inspection beneath
the patient's skin.
SUMMARY OF THE INVENTION
[0010] In view of the foregoing needs, the present invention
provides medical workers with fiducial markers that can be imaged
under a variety of imaging modalities, i.e., are multi-modal. The
markers can be used to register image space onto image space across
imaging modalities. The fiducial marker may also be used for the
registration of imaging space and physical space for the successful
performance of image guided craniotomies, biopsies, cyst
aspirations, radiation therapy, ventricular shunt placements, and
other similar surgeries.
[0011] A fiducial marker having features of the present invention
includes a hollow container, preferably cylindrical or spherical,
that may be made of imageable material and which is filled with
liquids suitable for various imaging modalities. In one version,
the marker is of suitably compact size and shape to be implanted
into bone for periods of prolonged duration that may be measured in
years. A cylindrical shape is preferred, as it minimizes the size
of the incision required for insertion by maximizing the available
volume of contrast agent for a given incision size. A permanently
implanted marker allows comparison of scans over time for follow-up
therapy (for example, to make lesion volume comparisons in order to
monitor growth). It also allows fractionated radiotherapy, in which
small doses of radiation are administered frequently over the
course of treatment.
[0012] One known measure for defining known set of points about the
human skull for this purpose involves the use of a stereotactic
frame (see U.S. Pat. No. 4,608,977 for a general description of
such a device). At present, a stereotactic frame cannot be used for
this therapy because the frame poses a significant risk of
infection, is too painful, or is too bulky and restrictive to be
left on for an extended time and cannot be re-attached in the same
location to tolerance of submillimetric accuracy. This problem is
resolved by the use of an implantable marker that can be well
tolerated by the patient for extended periods of time. Such an
implantable fiducial marker can also be localized in the radiation
therapy suite and thereby enable the patient's image space,
intracranial physical space, and radiation therapy device to be
registered with each other.
[0013] In another embodiment, the fiducial marker takes the form of
a relatively larger temporary marker that is removably attached to
a base that is rigidly affixed to bone. In this embodiment, the
base portion is left in place for a period of days or weeks and is
provided with means for detachably receiving an imaging marker. By
permitting the removal of the imaging marker after scanning, the
over-all height profile of the subcutaneous marker base is reduced,
adding to its overall stability during implantation. In this way,
the imaging marker, which need only be kept in place attached to
its base for the few hours required for the medical procedure, can
be made larger than could otherwise be tolerated in the case of
markers left in place for days on end. The larger imaging marker
produces a brighter image and is easier to localize in image space
than would be the case for a smaller marker.
[0014] The interchangeable nature of this marker also makes it
suitable for use with PET and/or SPECT scans. In both of these
modalities, an image marker must be radioactive. Furthermore, in
both of these modalities, it is necessary to obtain with each
imaging scan a so-called "transmission scan," in which no
radioactive substance is present. The transmission scan must be
obtained with the patient in the same position as the imaging scan,
and it is therefore not feasible for the marker bases to be
implanted between scans. Instead, it is necessary to attach a
nonradioactive marker for the transmission scan and then to replace
the nonradioactive marker with a radioactive one for the imaging
scan. The visibility of the markers in CT, MRI, PET, and SPECT
images allows one to register images obtained with any of these
modalities.
[0015] In both the temporary and the more permanent versions of the
invention, the container is charged with aqueous imaging agents to
provide imaging capability in MRI. CT imaging capability may be
provided in either of two ways: by doping the plastic housing with
agents that will render the marker housing imageable under CT, in
which case the shape of the housing so doped is such that its
volume centroid is coincident with the center of the volume
occupied by the MRI imaging agent, or by mixing the aqueous MRI
imaging agents with other aqueous agents imageable under CT.
Additionally, both ways may be employed in the same marker. The
imaging agents are selected so as to provide suitable imaging in
both modalities and, where an aqueous CT imaging agent is employed,
must be miscible. The use of a miscible liquid combination results
in the same volume being visible in different imaging modalities
with coincident centers for the purpose of locating the center of
the marker. In the embodiment for PET and/or SPECT, and external
marker is filled with the appropriate radioisotope and used in
place of the MRI/CT markers described in the previous paragraph. In
an alternative embodiment employing the temporary fiducial marker,
a kit of markers can be provided in which each marker is optimized
for one imaging modality (MRI, CT, PET, or SPECT).
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] For a more complete understanding of this invention,
reference should now be made to the embodiments illustrated in
greater detail in the accompanying drawings and described below. In
the drawings:
[0017] FIG. 1A is an exploded perspective view of a temporary
fiducial marker embodying features of the present invention, in
which the imaging marker is shown separated from the base with
respect to which it can releasably be attached;
[0018] FIG. 1B shows the marker of FIG. 1a as assembled;
[0019] FIG. 2A is an elevational view of the fiducial marker
assembly, in which the imaging marker is shown attached to the
base;
[0020] FIG. 2B illustrates in cross section the invention shown in
FIG. 2A as viewed along line A-A;
[0021] FIG. 3A is an elevational view of the base portion of the
invention;
[0022] FIG. 3B is a view of the top portion of the base;
[0023] FIG. 3C is a cross sectional view of the base taken along
line C-C showing the grooves that receive the imaging marker;
[0024] FIG. 4A is an elevational view of the cap portion of the
imaging marker;
[0025] FIG. 4B is a top plan view of the cap portion shown in FIG.
4A;
[0026] FIG. 4C is a bottom plan view of the cap; and
[0027] FIG. 5 is a cross sectional view of a different version of
the invention.
DETAILED DESCRIPTION
[0028] Referring now specifically to the drawings, wherein like
numerals indicate like parts throughout, a version of a temporary
fiducial marker assembly is indicated in FIGS. 1 - 4. These figures
illustrate a fiducial marker assembly comprising an imaging marker
10 and a base 30.
[0029] The base 30 has a threaded portion 32 at a first end. The
threads enable a surgeon to securely attach the base into the skull
or other desired portion of bone tissue. Other connecting structure
is provided to securely and releasably link the imaging marker with
the base. For example, in the illustrated embodiment, the end of
the base opposite the threaded portion terminates in a socket head
38 which contains a socket-like recess 36. (It is anticipated that
the base will be implanted into bone with the aid of an insertion
tool that twists the base into the bone or into a hole provided in
the bone. The recess is non-circular so as to better transmit the
torque provided by such an insertion tool.) Just beneath the socket
head 38 are a plurality (as seen in FIG. 3c, three) of grooves 34.
As shall be further explained below, the socket 38 and the grooves
34 provide for the secure and releasable attachment of the imaging
marker portion with base portion.
[0030] The imaging marker portion of the temporary fiducial marker
assembly may consist of two principal portions, a cylinder 12 and a
cap 16 (see FIGS. 4A - 4C). The cylinder 12 contains a cavity 14
for receiving a mixture of imaging agents whose composition is
determined by the imaging modalities to be employed. While in this
version, the vessel containing the imaging agents is preferably
cylindrical so as to simplify the process by which the centroid of
the corresponding volume of imaging agent is determined, other
shapes (such as a box or sphere) could be employed as well. The
cylinder 12 is closed at one end and open at the other to allow for
the introduction of the imaging agents. In one version of the
device, a cap 16 is used to seal off the open end of the cylinder
once the imaging agents have been added to the cylinder. In this
version, the cap may be cemented or welded into place. The cap may
be provided with a plug portion 24 that protrudes into and thereby
helps seal off the cavity 14 of the cylinder 12 against leakage of
the imaging agents. Other conventional filling and sealing
techniques, such as blow-molding, ultrasonic welding, or heat
sealing, may be used.
[0031] Where a cap is employed, it may be provided with a
protruding boss 20 and a plurality (here, three) of snap arms 18,
which terminate with inwardly projecting portions 22. The shape and
dimensions of the boss are in direct correspondence with the shape
and size of the socket 36 provided in the base 30 so as to properly
and securely center the imaging marker on the base. The snap arms
18 cooperate with the grooves 34 of the base 30 so as to detachably
secure the imaging marker onto the base. The cooperation of these
elements is illustrated in FIGS. 2a and 2b. While this example
shows the use of snap arms, other fastener structure may be
provided for attaching the marker to the base (e.g., screw threads,
clasps, hooks, etc.).
[0032] The dimensions of the temporary fiducial marker assembly
will be somewhat dependent on the state of the art of imaging. The
greater the sensitivity of the scanner employed, the lesser the
quantity of imaging material necessary to provide a suitable image,
which in turn makes it possible to reduce the corresponding size of
the marker that must be employed to contain the imaging material.
The Applicants have found that a base portion approximately 12 mm
in length and 2 mm-3 mm in diameter is sufficiently large to
provide for the secure placement of the base into the bone beneath
the skin. When the clinician prepares the patient for imaging, the
base portion is exposed and an imaging marker approximately 6 mm in
length is attached to the base; the marker itself may protrude from
the scalp and be exposed to air while a scan is performed on the
patient. The base and the imaging marker housing are constructed of
a bio-compatible organic polymer, such as polyether imide.
[0033] FIG. 5 illustrates a second embodiment of the fiducial
marker, which may be left implanted entirely beneath the skin for
extended periods of time. The marker comprises a cylinder 42
defining a space into which is placed one or more desired imaging
agents. As noted in the Summary, a cylindrical shape is preferred,
because this shape minimizes the size of the incision that must be
made for the marker's insertion. It is also the shape that best
corresponds to the hole that one drills in the bone to accommodate
the marker. The body of the cylinder is sealed off with a cap 46 or
is otherwise sealed. The body is preferably constructed of an
organic polymer known to be well tolerated by the body for extended
periods of time, such as polymethyl methacrylate, high density
polyethylene, or ceramics such as zirconium oxide and aluminum
oxide. The entire marker assembly is small enough for long-term
implantation into bone without causing distortion of the bone over
time. One exemplary size provides for the marker to be 4 mm in
length and 3 mm in diameter.
[0034] As shall be explained below, the judicious choice of aqueous
imaging agents allows for the construction of a marker that is
visible under both CT and MRI imaging modalities. Furthermore, by
using a marker that comprises a solid outer portion and an aqueous
inner portion, the marker can be located through the use of a
non-invasive transcutaneous detection system, such as one employing
ultrasound to detect the presence of the solid-liquid interface
between the aqueous core and the solid outer portion.
[0035] Because the fiducial marker assembly is to be used in a
variety of imaging modalities, the use of solid metal is eschewed
throughout. The presence of metal may cause unwanted artifacts and
image distortion in the image, and may impede efforts to localize
the marker (i.e., locate and identify its centroid). The properties
characteristic of solid metal, such as high electrical
conductivity, paramagnetism, and, for some metals, ferromagnetism,
are generally inappropriate for use in MRI.
[0036] Although metals have been used in the past as CT markers,
they are often generally less than optimal because the high linear
attenuation of metals may cause unwanted image artifacts, such as
starbursts. While these artifacts can be reduced somewhat by
reducing the size of the markers, this reduction in size also
reduces the accuracy with which the location of the marker can be
determined. In MRI, metals cause disturbances in the local magnetic
field (the so-called "susceptibility" artifact) which diminish the
image intensity and physically shift the position of the image.
Such physical phenomena are unsuitable in a fiducial marker. The
choice of materials selected as imaging agents is therefore driven
by the physics underlying the image modalities that are
employed.
[0037] In CT studies of human tissue, the brightest anatomical
features imaged are bone, which attenuates X-rays more strongly
than other tissue. This attenuation is characterized by the
so-called "linear attenuation coefficient," which measures the
X-ray attenuation per unit of path length. The linear attenuation
coefficient increases with increasing electron density (the number
of electrons per unit of volume). In order for an X-ray CT imager
to produce pixels brighter than bone when imaging a material (such
as that of a marker), the material being scanned must have an
electron density that is greater than that of bone. Therefore, one
approach to enhancing the absorption of X-rays is to increase the
electron density per unit volume. This can be accomplished by
adding compounds having atoms of high atomic number (Z) to the
imaged object, or by substantially increasing the density of the
material being scanned. Any high Z value atom suffices. Suitable
materials include barium, iodine, titanium, tantalum, silver, gold,
platinum, and stainless steel. These materials may be solid, or
dissolved as ions in biologically compatible fluids. However, as
noted above, the use of solid metal in a fiducial marker tends to
create artifacts that degrade the ability of the marker to be used
as a true fiducial. These artifacts are higher for markers that
have higher linear attenuation coefficients. They are also higher
for markers of larger sizes. In particular, for a given linear
attenuation coefficient, if the shape and size of the marker is
altered so that there is a longer path length through the marker,
the tendency to cause an image artifact increases. It is therefore
necessary to provide the high z value material in a diluted
form.
[0038] One approach to providing an imageable marker of appropriate
size that does not yield unwanted artifacts is to dope the marker
housing with a CT imaging agent. For example, the housing for the
marker, which is normally made of organic polymers, can have barium
added as a salt. Alternatively, titanium dioxide may be added to
the polymeric housing. Salts of gold or of platinum are also
effective materials for rendering the housing shell radio-opaque
and thus imageable under CT scanning. Concentrations of these metal
salts of up to about 400 mg/ml can be used in the markers without
causing appreciable image artifacts. It must be born in mind that
it will still be necessary to locate the geometric center of the
marker housing so doped; therefore, the geometry of the doped
housing should preferably be configured so that its center will be
coincident with the center of the volume of any other imaging agent
used to accommodate other imaging modalities.
[0039] Another approach to providing high Z value agents without
resorting to the use of solid metal is to provide them in the form
of an aqueous solution. Aqueous solutions of compounds having high
Z atoms, such as barium, iodine, titanium, tantalum, silver,
platinum, and iron can be used as imaging agents in the fiducial
marker of this invention. In particular, compounds of iodine and
silver have been found to be effective for this purpose.
[0040] For example, in certain preferred embodiments, an aqueous
solution of an iodine containing organic molecule with an effective
iodine concentration of between about 50 to about 600 mg/ml
provides an effective CT imaging agent. In another preferred
embodiment, silver nitrate dissolved in water at concentrations of
between about 100 mg/ml to about 600 mg/ml is effective. Either
solution will be effective in CT at imaging the volume defined by
the marker cavity.
[0041] By judicious choice of a high-Z aqueous solution, it is
possible to create a set of markers having absorption properties in
X-ray CT that are anywhere between those of water and 15 times
those of bone. However, the effect of these agents on MRI imaging
must also be considered, as must the additional requirements that
MRI imaging presents.
[0042] For example, the use of aqueous solutions where only CT
imaging is contemplated is optional--other carriers, such as oils,
could be used as carriers for high Z-number elements. However, this
is not the case with respect to MRI. The accurate location of MRI
markers in biological tissue must be done with an aqueous imaging
agent. Substances other than water exhibit different resonance
frequencies, or chemical shifts, and will appear in the image
displaced from their true location. Therefore, where a common
liquid carrier is to be used both for CT as well as MRI imaging
agents, it should be water. (The phenomenon of chemical shift is
further described in the literature and is well known to
practitioners in the art - see e.g., "Edge Artifacts in MR Images:
Chemical Shift Effect," Journal of Computer Assisted Tomography
9(2):252-257 (1985).)
[0043] The physics of MRI scanning must further be considered. Pure
water is characterized in proton nuclear magnetic resonance by a
high spin density and long T1 and T2 values. The relaxation times
are in the range of two to four seconds. MRI images are partly
based on spin density as well as T1 and T2. The effect of spin
density on image brightness is linear; reducing the spin density by
one half reduces the brightness by one half. The effects of T1 and
T2 are exponential; for example, altering these by one half results
in a change of 86% in the brightness in the image. These factors
may be summarized mathematically as follows:
I=NC(e.sup.-(TE/T2)) (1-e.sup.-(TR/T1))
[0044] where I=signal intensity, N=spin density, the parameters TR
and TE are the repetition time and the echo time determined by the
radio frequency and gradient pulses employed, and C is a constant
of proportionality that depends on the scanner and the pulses
employed.
[0045] These three parameters, T1, T2, and spin density, can be
altered by the addition of chemicals selected for their physical
properties in solution. One such property is paramagnetism, in
which the added material has an unpaired electron in its electron
configuration. Such agents shorten the relaxation times T1 and T2
drastically. Another such property is viscosity. Other chemicals
may be added to the solution for their ability to alter the
viscosity of a solution, even to a point of making a gel. viscosity
is an important consideration, because it is inversely correlated
with T2. The more viscous a solution, the greater the number of
bonds that are present and the less able the hydrogen nuclei are to
react and respond to the magnetic field, which results in a dimmer
image. These viscosity enhancing agents dilute the water in the
solution, thereby reducing the spin density, and reduce the
relaxation times T1 and T2. Whatever the added material, T1 will
always be equal to or greater than T2.
[0046] Because of the small concentrations of MRI imaging agents
appropriate for MRI enhancements, these agents have no significant
effect on the CT imaging agent. However, the efficacy of an MRI
imaging agent may be obscured by the presence of a CT imaging
agent. The MR image is modulated by the cumulative effects of all
solutes added to an aqueous medium. This modulation is due to
interactions with the hydrogen atoms in water which provide the MR
signal. The general effects of three typical CT imaging agents, of
one typical MR imaging agent, and of selected combinations of these
two types of agents are presented below.
[0047] In accordance with the above discussion, it has been
determined that silver nitrate, which, as noted above, provides a
suitable image under CT scans when provided in concentrations up to
about 600 mg/ml, reduces the observed spin density (and hence
reduces the brightness of the MR image) by up to 50%. At a
preferred concentration of about 600 mg/ml, the observed T1 and T2
values are about 1 second. As the concentration of silver nitrate
decreases, the T1 and T2 values approach those of pure water. This
observed effect affords the opportunity to provide a variety of
marker compositions based on silver nitrate (as the CT agent) to
create differing contrast levels with respect to human tissue under
MRI.
[0048] A solution of iohexol (a non-ionic X-ray CT imaging agent)
in concentrations of up to about 600 mg/ml of iodine also reduces
the observed spin density by up to 50%. At a concentration of 150
mg of iodine per ml of aqueous solution, the observed T1 value is
300-400 milliseconds, and the observed T2 value is 100-120
milliseconds. The effect on these parameters is in accord with
similar effects noted from increasing the viscosity of aqueous
solutions. Over the entire range of iohexol concentrations, it has
been determined that one can alter the spin density by 50%, change
the T1 value from 4 seconds to 0.15 seconds, and the T2 value from
4 seconds to 0.04 seconds. Thus, iohexol too, may be used to
provide a variety of marker compositions to create different
contrast levels with respect to human tissue under MRI.
[0049] A solution of iothalamate meglumine (an ionic X-ray CT
imaging agent) in concentrations up to about 600 mg/ml of iodine
reduces the observed spin density by factors ranging up to 75%. At
a concentration of 175 mg of iodine per ml of aqueous solution, the
observed T1 value is 1200-1500 milliseconds, and the observed T2
value is 300-350 milliseconds. The solution is not viscous at this
concentration. Over the entire range of iothalamate meglumine
concentrations it has been determined that one can alter proton
spin by 75%, change T1 value from 4 seconds to 1 second, and the T2
value from 4 seconds to 200 milliseconds. Thus iothalamate
meglumine may be used to provide a variety of marker compositions
to create different contrast with respect to human tissue.
[0050] Within limits, one can prepare solutions of reduced spin
density in which T1 is equal to T2, and solutions providing spin
density in which T1 is greater that T2. T1 and T2 values of these
altered solutions range from 1 millisecond to 4 seconds, while the
spin density ranges from 0 molar (no water at all) to 111 molar in
hydrogen (pure water). The instant invention identifies a number of
substances suitable for use in MRI imaging in fiducial markers. One
preferred suitable MRI imaging agent is gadopentetate dimeglumine.
Another possible MRI imaging agent is gadoteridol. (Each of the
aforementioned substances has received FDA approval for use as an
injectable MRI imaging agent.) Other possible agents for use as MRI
imaging agents include Ferric Chloride (FeCl.sub.3) and Copper
Sulfate (CuSO.sub.4) in concentrations of between 0.5 mM and 5 mM.
For a more complete listing of contrast agents and their
properties, see chapter 14 of Magnetic Resonance Imaging, 2nd ed.,
edited by Stark and Bradley, 1992, the contents of which are herein
incorporated by reference.
[0051] A solution of gadopentetate dimeglumine-DPTA (an injectable
MR contrast agent) in concentrations up to about 0.5 mM
(millimolar) is seen to have little effect on the observed spin
density of the solution. At a concentration of 0.5 mM, the observed
T1 value is 50 to 100 milliseconds, and the observed T2 value is 8
to 15 milliseconds. Over the entire range of concentrations one
observes spin density of 111 molar in hydrogen (water). T1 varies
from 50 milliseconds to 4 seconds, and T2 varies from 8
milliseconds to 4 seconds. This is in accord with the reported
effect of the paramagnetic material. By varying the marker
compositions based on the gadopentetate compound, it is possible to
create a variety of different contrasts with respect to human
tissue.
[0052] The four solutions just discussed were based on one solute
in water. To provide a multi-modality marker, binary mixtures of CT
and MR contrast agents are considered. It has been observed that
binary combinations of gadopentetate-DPTA with any of the other
chemical compounds set forth produce a synergistic effect. The
matrix of possibilities for altering spin density, T1 and T2, by
varying the concentration of MRI and CT imaging agents, enhances
the ability to tailor solutions to give maximum contrast in all
three types of MR image parameters. For example, with respect to
the permanent marker, iothalamate meglumine at a concentration of
175 mg/ml combined with gadopentetate meglumine-DPTA at 0.5 mM
creates a solution with the following MR properties: a spin density
corresponding to 75-80 molar water, T1 value of 400-500
milliseconds, and a T2 value of 150-200 milliseconds. A variety of
other binary compositions permit one to create many different
ratios of spin density, T1 and T2 values.
[0053] Hence, as these examples suggest, it is possible to create a
set of MR markers with any combination of spin density, T1 and T2
that are smaller in magnitude than those of water. The optimum
values of these parameters as specified by the marker application
dictate the composition of the solution.
[0054] For one marker to be optimized for both MRI and CT, the
imaging agents and their concentrations must be selected such that
the solution and/or housing may be differentiated in the X-ray by
its radio-opacity and at the same time be differentiated in the MRI
by its MRI parameter set--spin density, T1, and T2. As noted above,
it is known that aqueous solutions of compounds based on high Z
number elements will provide the necessary degree of radio-opacity
for CT imaging. It is also known that such substances may reduce
the imaging efficacy of compounds selected for their use as MRI
contrast agent, such as gadopentetate dimeglumine-DPTA. In order to
combine the two agents in an effective manner, they are mixed
together in varying concentration and tested under both CT and MRI
scans until one has empirically determined a concentration of each
that provides a marker that is acceptably imageable under both
modalities.
[0055] As a result of such a course of testing, the Applicants have
identified two preferred binary mixtures that meet these
requirements when used in the permanent marker; these are
iothalamate meglumine (175 mg of iodine/ml) with gadopentetate
dimeglumine-DPTA (0.5 mM) and silver nitrate (350 mg/ml) with
gadopentetate dimeglumine-DPTA (0.5 mM). In the case of the
temporary marker, the concentrations of the CT imaging agents are
reduced to 165 mg of iodine per ml of aqueous solution of
iothalamate meglumine and 200 mg/ml of silver nitrate
respectively.
[0056] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. For example, the aqueous solutions used as the
carrier for the imaging agents could have the characteristics of a
gel. The imaging agents could be provided as mixtures of three or
more compounds selected to optimize particular imaging
characteristics.
[0057] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. For example, a flatter, more disk-like marker than
that which is shown in the figures may be employed. Increasing the
largest dimension of X-ray traversal boosts the brightness of the
image in CT. It also allows one to take CT scans with thicker
slices in which the image of the marker does not become lost in the
corresponding pixel. This is especially useful in trauma cases,
when there is not sufficient time for more refined views.
[0058] In another variant, the imaging agents discussed above can
be relied upon for one imaging mode and another technique relied on
for locating the marker in a second imaging mode. For example, one
may image a marker under a first modality (e.g., MRI) using the
imaging agents discussed above, and then locate the marker in the
image space generated by a second imaging modality (e.g., CT) by
physically locating the marker in the physical space of the second
imaging machine. For example, robotic arms such as are disclosed in
U.S. Pat. No. 5,142,930 (the contents of which are herein
incorporated by reference) or U.S. Pat. No. 4,991,579 could be used
for this purpose, since in the course of a scan the addresses of
each point in image space are generally defined with respect to the
imaging machine and hence to any arm (such as that disclosed in the
'930 patent) or other device whose location is clearly defined with
respect to that machine. One may then label the corresponding point
in image space as containing the location of marker, even where it
is not directly imageable in that imaging mode.
* * * * *