Multimodal visible polymer embolization material

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Multimodal visible polymer embolization material
5


The present invention relates to embolization material for therapeutic use, wherein said
material is visible via more than one imaging technique.
10
Embolization therapy is a common therapeutical concept to treat pathological alterations
inside the human body. Generally, vessels are blocked by an intravascular application of a
material. Various substances can be introduced into the circulation (bloodstream) to
occlude vessels, for example to arrest or prevent hemorrhaging, to devitalize a structure,
tumor, or organ by occluding its blood supply; or to reduce blood flow to an arteriovenous 15
malformation, or other vascular malformation. For this purpose different materials have
been tested which are termed embolization materials or embolization agents synonymously
in the following.
Generally, embolization material or vascular embolization agents are particles (non-
spherical or microspherical) or fluids (glues, gels, sclerosing agents and viscous emulsions) 20
that can be released into the bloodstream through a catheter or needle to mechanically
and/or biologically occlude the target vessels, either permanently or temporarily.
Commonly, these materials are available as solids, liquids or suspensions. In principle, a
selection of the embolization agent based on the size and the calibre of the target vessels
ensures that the occlusion is confined to the desired site. Basically, particles cause 25
mechanical occlusion, whereas glues and gelling solutions solidify at the target, and e.g.
acetic acid, ethanol, and various sclerosing agents modify the vessel wall and contents,
leading to the development of a clot that occludes the vessel (Loffroy et al., “Endovascular
Therapeutic Embolisation: An Overview of Occluding Agents and their Effects on
Embolised Tissues”, Current Vasc Pharmacology, 2009, 7, 1-14). 30
Common treatment of vascular defects, e.g. intracranial aneurysms, is performed using
neurosurgical clipping. A viable alternative for treatment of such conditions is
endovascular embolization with platinum coils. High numbers of patients having a
recurrence amenable to retreatment because of thrombus recanalization, aneurysm
regrowth, or embolic mass compaction led to development and clinical use of embolic 35
devices combining platinum coils with expandable hydrogels or degradable polymers to

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reduce the retreatment rate. For example a dried hydrogel is placed over a platinum coil, or
degradable polymers such as copolymers of glycolic acid and lactic acid are placed over
and/or inside a platinum coil. Besides, other materials, e.g. hydrogel filaments are currently
used as implants for endovascular embolization such as poly(ethylene), poly(ethylene
glycol) diacrylate with 2,4,6-triiodophenyl penta-4-enoate (PEG-I), poly(ethylene glycol) 5
diacrylamide with barium sulfate (PEG-B), poly(propylene glycol) diacrylate with barium
sulfate (PPG-B) (Constant et al., “Preparation, Characterization, and Evaluation of
Radiopaque Hydrogel Filaments for Endovascular Embolization”, J Biomedical Mat
Research Part B, Appl Biomaterials, 2008, 306-313). Nevertheless, currently available
embolization devices are either not visible (e.g. not radio-opaque, or magnetic) by medical 10
imaging techniques or visible only via CT but due to the metallic nature of platinum
leading to imaging artifacts.

Embolization is frequently conducted under control of medical imaging techniques
including inter alia projectional or plain radiography (X-ray based angiography), magnetic 15
resonance angiography (MRA) based on magnetic resonance imaging (MRI) and other
radiography methods. Embolization is carried out either trans-arterial via micro catheter or
via direct puncture, whereby the embolization agent (e.g. occlusion emulsion) is injected
via puncture needle into the target region. DE 102 61 694 describes injection of a liquid
embolization agent containing a protein emulsion (Zein) and ethanol. 20

Common imaging techniques in radiology are angiography, X-ray computed tomography
(CT), radiography, magnetic resonance imaging (MRI), ultrasonography (US), nuclear
medical techniques such as single photon emission computed tomography (SPECT) and
positron emission tomography (PET), optical techniques, techniques enabling localization 25
via radio waves, and magnetic particle imaging technique. Embolization agents visible via
radiology techniques enable their detection, localization, control of therapy by the
aforementioned techniques, and their display whilst application regarding the human body
and pathological alterations.
30
Currently, clinical embolization materials are not visible by imaging techniques (Siskin et
al., “Embolic Agents Used for Uterine Fibroid Embolization”, American Journal of
Roentgenology, 2000, 767-773). However, it is accepted that directly visible embolization
material provides advantages over non-visible embolization materials (Mottu et al.,
“Iodine-containing cellulose mixed esters as radiopaque polymers for direct embolization 35
of cerebral aneurysms and arteriovenous malformations”, Biomaterials, 2002, 23, 121-131;

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Siskin et al., loc. cit.; Sharma et al., “Development of "imageable" beads for transcatheter
embolotherapy”, J Vasc Interv Radio, 2010, 21(6), 865-76).
An embolization material that is directly visible by an imaging modality provides
advantages to control the application of the embolization material, to verify and document
the therapy success and might provide methods to detect misplacement of embolization 5
material.

Tumor embolization is currently mostly performed under X-ray control for application
catheter placement, treatment planning as well as treatment control (Lubienski et al.,
“Update Chemoperfusion und –embolisation”, Der Radiologe, 2007, vol. 47, 1097-106). 10

It was proposed to switch to an MRI environment for embolization therapy, because this
would reduce or eliminate the necessary radiation dose, and would enable three-
dimensional therapy control. As a consequence this would widen the potential range of
therapies and therefore increase the spectrum of potential patients. Especially young 15
women with uterus fibroids could now undergo embolization treatment without potential
harm to the very radiation sensitive ovaries (Levy, “Modern management of uterine
fibroids”, Acta Obstet Gynecol Scand, 2008, 87(8), 812-23).

Various embolization materials exist being visible via one radiology technique (X-ray 20
computed tomography (CT), radiography). There are also embolization materials being
visible via other imaging techniques, see for example DE 102 61 694 (Zein-emulsion with
radiocontrast agent); DE 09414868 U1 (synthetic particle with Iodine), US 2005/0095428
(polymer with Ni-Ti-alloy), and WO 2001/66016 (gas containing embolization agents).
25
However, no embolization materials have been described which are well visible in more
than one imaging technique. Thus, there is currently a dependency on one imaging
technique for controlling the application of embolization material and for controlling
therapy. Up to now, it is not possible to combine the advantages of different imaging
techniques. 30

Projectional radiography is a currently used environment to carry out embolization.
Physicians have the most experience here. A disadvantage of this technique is that their
application is connected with ionizing radiation which may possibly cause cancer.
35

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In future, it is envisaged to increasingly conduct embolization therapy in healthy patients
having benign tumors, which otherwise have to be surgically treated. Here, it is often
important to avoid ionizing radiation. Embolization can for example be carried out under
control of MRI. Embolization materials only visible by MRI averts control via X-ray
computed tomography (CT) or projectional radiography. 5

Current embolization therapy is mainly done by projective imaging enabling assessment of
embolization success in two dimensions only. In future, rotational angiography, cone-beam
CT, dyna-CT, MRI, ultrasonography, or magnetic particle imaging will enable availability
of three-dimensional imaging. 10

Another disadvantage of currently known embolization agents lies in the control of
therapy. Control of therapy should enable visualization e.g. which regions of tumor vessels
are successfully occluded. Embolization and control of therapy is often carried out using
one imaging technique, and thus, is restricted to it. So, there is no possibility to visualize 15
embolizations and control of therapy via a second or a third imaging technique in order to
combine their advantages.

If embolization material gets into regions of the human body or vessels not destined to be
there, e.g. healthy regions, this process is called misplacement of embolization material. 20
Currently available embolization material can only be visualized via one imaging
technique, and thus, misplaced embolization material needs to be detected using this one
imaging technique. To date no combination of the advantages of different imaging
techniques is possible. CT for example requires radio-opaque embolization materials and is
the superior mode of action to visualize lung regions compared to MRI. However, MRI 25
visualization requires certain characteristics of embolization material. MRI is the superior
mode of action for visualization of soft tissues structures compared to CT. A combination
of both techniques to enable detection in the whole human body is not feasible according
to the actual prior art because embolization material is only visible either via CT or via
MRI. 30

Current embolization materials are only visible by one imaging technique at a time, and
thus, can not be imaged by more than one imaging technique. This restricts the therapy
control, application and application control of a certain embolization material.
35

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Changing of the imaging environment during intervention comes along with a loss of the
ability to track the embolization material and perform embolization treatment evaluation.
Thus, there is a need for embolization material visible via different imaging techniques.

Furthermore, currently multimodally interventional imaging systems so called hybrid 5
systems are going to be developed in interventional radiology. (Fahrig et al., “A truly
hybrid interventional MR/X-ray system: feasibility demonstration”, J Magn Reson
Imaging, 2001, 13(2), 294-300; Kee et al., “MR-guided transjugular intrahepatic
portosystemic shunt creation with use of a hybrid radiography/MR system”, J Vasc Interv
Radiol, 2005, 227-34; Wilson et al., “Experimental Renal Artery Embolization in a 10
Combined MR Imaging/Angiographic Unit”, J Vasc Interv Radiol, 2003, 14, 1169-1175).
In such systems, several partly complementary imaging techniques are integrated into one
work space (Fahrig et al., loc. cit.; Kee et al., loc. cit.). But, the currently known
embolization materials are visible only via one of those imaging techniques. Thus, the
inherent advantages of such hybrid systems, the advantages of combining several imaging 15
techniques can not be used for detection of embolization material.

Thus, one technical problem underlying the present invention is seen as the provision of
materials and methods for enabling the visualization of embolization, of the application of
the embolization therapy and of the control of therapy and treatment using more than one 20
imaging technique in order to combine the specific advantages of the respective imaging
techniques.

The problem is solved by the embodiments of the present invention described in the claims
and the specification herein below. Specifically, the problem is solved by the provision of 25
embolization material for therapeutic applications visible via more than one imaging
technique.

The present invention relates to embolization material for therapeutic use, wherein said
material is visible via more than one imaging technique. 30

In one aspect of the invention, the embolization material of the present invention comprises
at least one polymer component and at least one inorganic component, and said
embolization material is visible with high contrast via more than one imaging technique, in
particular by two different techniques, by three different techniques or more. 35

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The term “high contrast” as used in accordance with the present invention, relates to
contrast enhanced by contrast agents in one respective imaging technique in the clinical
practice. Generally, contrast is the difference in blackness, whiteness, or other colorness,
between two adjacent tones. High contrast is further characterized as an accurate portrayal
of the structures under examination in good positioning with the minimum of geometric 5
distortion, easy perception of the relevant structures in detail, and without or very little
misleading artifacts. Furthermore, “high contrast” relates to the contrast which enables
clarification of diagnostic problems via at least two different imaging techniques.
Moreover, contrast as used herein refers to the embolization material of the present
invention visible in at least two imaging techniques already in marginal density of said 10
embolization material.

In another aspect, the embolization material of the present invention is visible via the
following imaging techniques (at the same time):
15
a) X-ray computed tomography (CT)/projectional radiography and magnetic
resonance imaging (MRI),
b) X-ray computed tomography (CT)/projectional radiography and
ultrasonography (US),
c) X-ray computed tomography (CT)/projectional radiography and single 20
photon emission computed tomography (SPECT),
d) X-ray computed tomography (CT)/projectional radiography and positron
emission tomography (PET),
e) magnetic resonance imaging (MRI) and ultrasonography (US),
f) magnetic resonance imaging (MRI) and single photon emission computed 25
tomography (SPECT),
g) magnetic resonance imaging (MRI) and positron emission tomography
(PET),
h) X-ray computed tomography (CT)/projectional radioagraphy and magnetic
particle imaging, or 30
i) a combination of two or more of said imaging techniques.

In an aspect of the present invention the embolization material is visible via three imaging
techniques at the same time.
35
The term “at the same time” as used in accordance with the present invention relates to the
embolization material of the present invention being visible via one imaging technique as

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well as via another imaging technique either at the same moment or in close sequence
(often also via even more imaging techniques).

Generally, embolization material as used in accordance with the present invention relates
to material consisting of a mixture of different components. The embolization material 5
frequently contains at least one polymer component and at least one inorganic component
as described in more detail herein below.

In an aspect, the embolization material of present invention comprises embolization
material, wherein the at least one polymer component is selected from the group of 10
polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, acrylate polymer,
polyamide, polysiloxane, polyester, polyurethane, polyvinyl ether, polyvinyl ester,
copolymers comprising as monomers a (meth)acrylic-derivative and/or a
meth(acrylamide)-derivative carrying a cleavable iodine substituted side group, or mixtures
thereof. 15

In another aspect, of the embolization material of the present invention, the at least one
polymer component comprises a copolymer of glycidyl-methacrylate and a (meth)acrylic-
derivative carrying a cleavable iodine substituted aromatic side group.
20
In a further aspect, the embolization material of present invention comprises at least one
polymer or copolymer component selected from the group of polyacrylate,
polymethacrylate, polyacrylamide, polymethacrylamide, acrylate polymer, polyamide,
polysiloxane, polyester, polyurethane, polyvinyl ether, polyvinyl ester, copolymer of 2-
methacryloyloxyethyl (2,3,5-triiodobenzoate) and methyl-methacrylate, or mixtures 25
thereof.

In another aspect, in accordance with the present invention, the polymer is selected from
the group consisting of polyacrylate and polymethacrylate. In a further aspect of the
embolization material of the present invention, the at least one polymer component 30
comprises a copolymer of 2-methacryloyloxyethyl (2,3,5-triiodobenzoate) and methyl-
methacrylate. Also in accordance with the present invention, the polymer component can
further be selected from biodegradable polymeric spheres, or polyesters of
tetraiodophenolphthalein.
35
The term “polymer”, as used herein, includes homo-polymers and copolymers. In the case
of a co-polymer, said co-polymer can preferably be the polymerization product of two or

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more iodine substituted monomers, or alternatively, the polymerization product of at least
one iodine substituted monomer with at least one bi-functional monomer that contains, in
addition to its polymerizable functionality, a second reactive chemical group, e.g., glycidol
methacrylate.
5
The embolization material of the invention often comprises as at least one polymer
component a copolymer of (meth)acrylic and meth(acrylamide) monomers carrying
cleavable iodine substituted side groups.

According to the present invention, the polymer component can further contain monomers, 10
e.g. vinylic monomers, e.g. hydroxyethyl methacrylate (HEMA), acryloyl chloride,
methacryloyl chloride, and/or glycidyl methacrylate. Especially preferred are (meth)acrylic
and meth(acrylamide) monomers which carry cleavable radio-opaque element (e.g. iodine)
substituted side groups.
15
In an aspect, of the embolization material of the present invention, the at least one
inorganic component comprises a radio-opaque element selected from the group of
calcium, iron, iodine, xenon, barium, ytterbium, silver, gold, bismuth, cesium, thorium, or
tungsten, and a magnetic resonance imaging (MRI) visible component selected from the
group iron oxides, gadolinium, manganese, or perfluorocarbons. 20

In another aspect, further radio-opaque elements selected from Iodine with ionic or
nonionic monomers (e.g. Diatrizoate, Iohexol), dimers (e.g. Ioxaglate, Iodixanol), or
polymers, Barium, electrondense heavy metals, rare earth elements, with chelates e.g.
EDTA, DOTA are also in accordance with the present invention. 25

Moreover, further components visible via MRI selected from gadolinium based contrast
agents, e.g. gadodiamide, gadobenic acid, gadopentetic acid, gadoteridol, gadofosveset,
gadoversetamide), gadoxetic acid, gadobutrol, gadocoletic acid, gadodenterate,
gadomelitol, gadopenamide, gadoteric acid, manganese based contrast agents (e.g. Mn-30
DPDP), Ferumoxsil,·Ferristene, or diamagnetic, ferromagnetic, paramagnetic substances in
Small- or Ultra Small Super Paramagnetic Iron Oxid (SPIOs/USPIOs) with or without
chelates are also in accordance with the present invention.

In another aspect, the embolization material of the present invention comprises a radio-35
opaque element, and a magnetic resonance imaging (MRI) visible component, and
additionally components enabling detection via ultrasonography (US) selected from the

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group of gas aggregates or gas bubbles, microbubbles, microspheres of human albumin,
microparticles of galactose, perflenapent, microspheres of phospholipids, and/or sulfur
hexafluoride. In an aspect, said components enabling detection via ultrasonography are
coated or incorporated into the embolization material of the present invention.
5
Moreover, in accordance with the present invention, the embolization material can
comprise further microspheres. Microspheres as used herein, consist of various materials
e.g. glass, silicone, polyvinyl-alcohol-hydrogels (PVA), or micellar components, e.g.
micellar block-copolymers, or liposomes. Further, microspheres as used in accordance
with the present invention can be loaded with Lipiodol and/or gadolinium. Also 10
contemplated, in accordance with the present invention, are microspheres of human
albumin, microspheres of phospholipids, and/or sulfur hexafluoride.

Moreover, in a further aspect, the embolization material of the present invention is visible
via PET. Thus, in an aspect, the embolization material comprises positron emitters, e.g. 15
zirconium-89, iodine-124, radionuclides, e.g. technetium-99m, (99mTc), molybdenum-99,
positrons, beta-ray-emitters, e.g. fluorine-18 (F-18), carbon-11 (C-11), nitrogen-13 (N-13)
and oxygen-15 (O-15).

In even another aspect, the embolization material of the present invention is visible via 20
SPECT. Thus, in accordance with the present invention the embolization material
comprises gamma-ray emitters, e.g. technetium-99m, iodine-123, indium-111.

The term “iron oxide” as used in accordance with the present invention relates to Fe3O4,
Fe2O3, or FeO. 25

In an even further aspect, the embolization material of the present invention comprises an
X-ray visible, iodine containing core, and a MRI visible, ultra small paramagnetic iron
oxide based coating, e.g. Fe3O4, Fe2O3, and wherein said material is selected from
magnetic iron oxide/Poly((2-methacryloyloxyethyl-(2,3,5-triiodobenzoate))-(glycidyl-30
methacrylate)) particles.

In even another aspect, the embolization material of the present invention comprises a MRI
visible, ultra small paramagnetic iron oxide based core and an X-ray visible, iodine
containing coating, e.g. the aforementioned polymer component, or a mixture of both 35
materials.

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In an aspect, the embolization material of present invention exhibits different particle sizes
ranging from 30 µm to 900 µm and is detectable in a first imaging technique displaying
good localization and at the same time in a second very sensitive imaging technique. In
accordance with the present invention, said first imaging technique is selected from X-ray
computed tomography (CT)/projectional radiography, or magnetic resonance imaging 5
(MRI). Further, in accordance with the present invention, said second imaging technique is
selected from ultrasonography (US) and nuclear medical imaging techniques. In an even
further aspect, the embolization material of present invention exhibits particle sizes ranging
from 40 µm to 200 µm.
10
Moreover, the present invention relates to a kit of at least two parts for the preparation of
embolization material of the invention, the kit comprising as one part at least one polymer
component and as second part at least one inorganic component.

Furthermore, the present invention also relates to a method for the preparation of the 15
embolization material of the invention comprising the steps of:

a) synthesizing the at least one polymer component,
b) synthesizing the at least one inorganic component, and
c) optionally synthesizing a component detectable via ultrasonography, and 20
d) combining the at least one polymer component of step a with the at least one
inorganic component of step b, and optionally with the component of step c,
and thus, obtaining the embolization material of any one of claims 1 to 13.

According to the present invention embolization material can be used for different 25
therapeutic applications, e.g. for occlusion of vessels inside the human or animal body.
Specifically, the embolization material of the present invention can be used for occlusion,
e.g. occlusion of specific vessels, occlusion of bile ducts, or fistulae, and/or the treatment
of aneurysms. This is achieved by adjusting size, stability, structure and/or (inflammation-)
stimuli triggering features of the embolization material. Size can be variably adjusted in 30
order to directly target different vessel regions (e.g. big or small tumor vessels), or other
targets. The embolization material can exhibit different moieties, coating, charging, or
cover to target different vessels or other targets as described above.

Moreover, the embolization material of the present invention enable using special 35
characteristics of different imaging techniques, e.g. to combine partially complementary

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characteristics for quantification, sensible detection, shunt prevention, assessment of
particle distribution, and/or real-time imaging.

Also contemplated by the present invention is the use of the embolization material of
present invention together with chemotherapeutics, internal radiation sources, targeted 5
moieties, and/or activateable probes.

The present invention also relates to the use of embolization material of the present
invention detectable via ultrasonography to trace real-time shunting, and/or enable sensible
detection of the particles within tumor or shunting vessels. Moreover, the characteristics of 10
embolization material containing US detectable components can be changed by destroying
of gas aggregates or gas bubbles, thus even broadening the spectrum of their uses.

Further, and also according to the present invention, the embolization material can
additionally contain active ingredients and/or excipients. Active ingredients could for 15
example be anti-thrombolytic agents such as heparin, derivatives of heparin, or urokinase.
Also anti-proliferating agents such as enoxaparin, angiopeptin, hirudin or acetylsalicylic
acid, and anti-inflammatory agents such as dexamethasone, corticosteroids, budesonide,
sulfasalazine or mesalamine can be used. Typical oncologic active ingredients such as
cisplatin, paclitaxel, vinblastine, angiostatin, or fluorouracil can also be used in the 20
composition. The embolization material can contain as additional component an anesthetic
agent such as lidocaine, bupivacaine, or ropivacaine. Common anticoagulants can also be
contained.

The term “multimodality embolization material” as used in the present invention refers to 25
embolization material visible via more than one, in particular via two, three, or more
imaging techniques.

The embolization material due to its composition is visible via more than one medical
imaging technique. Thus, control of therapy while application and thereafter can be carried 30
out via more than one imaging technique. Because medical imaging techniques differ from
one another and are partly complementary, a combination of several imaging techniques
can unite the advantages of each technique.

The present invention relates to the application of embolization materials that can be 35
visualized via several imaging techniques. Thus, the advantages of the imaging techniques
can be combined. Long-term control of therapy can also be carried out using several

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imaging techniques. For example, definite embolized regions of tumors can be
distinguished from non-embolized regions. This can be carried out using different imaging
techniques. For instance benign tumors, such as uterine myoma can be embolized in an X-
ray environment (projectional radiography), but therapy control can be done in a low
radiation environment via MRI. Furthermore, several imaging techniques can be combined 5
for detection of misplaced embolization material. For example, MRI-particles tagged with
iron oxide particles such as “Ultra Small Super Paramagnetic Iron Oxid” (USPIO)
(Weissleder et al., “Ultrasmall Superparamagnetic Iron Oxide: Characterization of a New
Class of Contrast Agents for MR-Imaging”, Radiology, 1990, 175, 489-493) can easily be
detected in soft tissues, whereas particles in the lung can be detected with good results via 10
CT, since MRI is limited regarding good imaging quality in the lung. Moreover,
considering that imaging techniques can differ in their sensitivities for different regions of
the body, (e.g. MRI can be more sensitive than CT) a combination of several imaging
techniques can increase overall sensitivity. Highest sensitivities for visualization can be
achieved by using nuclear medical imaging technique. A combination of radio-opaque 15
embolization material with nuclear medical tracer enables for example optimal control for
application and optimal detection of misplaced embolization material. So, already smallest
amounts of misplaced embolization material can be detected. This can possibly be relevant
for selective internal radio-therapy (SIRT) a form of radiation therapy used to treat cancer.
It is generally for selected patients with unresectable cancers, those which cannot be 20
treated surgically, especially hepatic cell carcinoma or metastasis to the liver. The
treatment involves injecting tiny microspheres of radioactive material into the arteries that
supply the tumor.

Using multimodality embolization materials enables therapy control to be performed via 25
more than one imaging technique. Since imaging techniques differ in sensitivity to image
certain organs and/or disease conditions multimodality embolization materials visible in
several imaging techniques may complement those for therapy control and evaluation.
Furthermore, imaging techniques differ regarding invasiveness and radiation harm.
Embolization materials that are visible in more than one imaging techniques provide more 30
alternatives to use the appropriate imaging technique for therapy control. The imaging
technique used for application does not necessarily have to be the most suitable for therapy
control. Moreover, synergistic effects of different imaging techniques might lead to new
therapy concepts (e.g. real-time monitoring of misplacement of embolization particles, size
testing, etc.). 35

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According to the present invention embolization particles are preferably visible via CT as
well as via MRI. Even intraprocedural switches (planned or during complications) would
not come along with a loss of the ability to image the particles for application or treatment
control. Using the embolization particles provided in an aspect of the present invention,
displacement of embolization material could be detected by both techniques in 5
combination. For treatment control, both CT and MRI can be used. Weaknesses of one
imaging technique can be complemented by the other.

In an established multimodality hybrid intervention system (Fahrig et al., loc. cit.; Kee et
al., loc. cit.) the said embolization particles are beneficial because application can be 10
monitored using the X-ray component, while therapy control as well as monitoring can be
performed using the MRI component. Furthermore, for therapy control both components
X-ray CT (lung) and MRI (all other body parts) can be used synergistic. Thus, control can
be carried out using both methods during examination. This means a change of imaging
technique is not required. 15

The term “projectional or plain (film) radiography or x-ray based angiography” as used in
the present invention, relates to the branch of medicine utilizing X-rays as imaging
technique. Radiographs (or roentgenographs) are produced by the transmission of X-rays
through a patient to a capture device then converted into an image for diagnosis. The 20
original and still common imaging produces silver impregnated films. In Film-Screen
radiography an X-ray tube generates a beam of x-rays which is aimed at the patient. The
X-rays which pass through the patient are filtered to reduce scatter and noise and then
strike an undeveloped film, held tight to a screen of light emitting phosphors in a light-tight
cassette. The film is then developed chemically and an image appears on the film. Now 25
replacing Film-Screen radiography is Digital Radiography, DR, in which X-rays strike a
plate of sensors which then converts the signals generated into digital information and an
image on computer screen. Plain radiography was the only imaging modality available
during the first 50 years of radiology. It is still the first study ordered in evaluation of the
lungs, heart and skeleton because of its wide availability, speed and relative low cost. New 30
developments include the virtual X-ray system (virtX), invented by a team of computer
scientists, trauma surgeons, and radiologists enabling trainees to make C-arm adjustments
for different surgical procedures by using a simulation-based practice environment without
X-ray exposure but with visual feedback through a digitally reconstructed radiograph (or
DRR). 35

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Interventional radiology as used in the present invention is the performance of generally
minimally invasive medical procedures with the guidance of imaging techniques. The
acquisition of medical imaging is usually carried out by the radiographer physicist or
radiologic technologist.
5
The terms “other radiography methods” and “angiography” as used in the present invention
relate to fluoroscopy and angiography as special applications of X-ray imaging, in which a
fluorescent screen and image intensifier tube or flat panel detector is connected to a closed-
circuit television system. This enables real-time imaging of structures in motion or
augmented with a radiocontrast agent. Radiocontrast agents are administered, often 10
swallowed or injected into the body of the patient, to delineate anatomy and functioning of
the blood vessels, the genitourinary system or the gastrointestinal tract. Two radiocontrasts
are presently in use. Barium (as BaSO4) may be given orally or rectally for evaluation of
the GI tract. Iodine, in multiple proprietary forms, may be given by oral, rectal, intraarterial
or intravenous routes. These radiocontrast agents strongly absorb or scatter X-ray 15
radiation, and in conjunction with the real-time imaging enable demonstration of dynamic
processes, such as peristalsis in the digestive tract or blood flow in arteries and veins.
Iodine contrast may also be concentrated in abnormal areas more or less than in normal
tissues and make abnormalities (tumors, cysts, inflammation) more conspicuous.
Additionally, in specific circumstances air can be used as a contrast agent for the 20
gastrointestinal system and carbon dioxide can be used as a contrast agent in the venous
system; in these cases, the contrast agent attenuates the X-ray radiation less than the
surrounding tissues.

The term “X-ray computed tomography” (CT) as used in accordance with the present 25
invention relates to an imaging technique using X-rays in conjunction with computing
algorithms to image the body. Therefor, an X-ray generating tube opposite an X-ray
detector (or detectors) in a ring shaped apparatus rotate around a patient producing a
computer generated cross-sectional image (tomogram). CT is acquired in the axial plane,
while coronal and sagittal images can be rendered by computer reconstruction. Radio 30
contrast agents are often used with CT for enhanced delineation of anatomy. Although
radiographs provide higher spatial resolution, CT can detect more subtle variations in
attenuation of X-rays. CT exposes the patient to more ionizing radiation than a radiograph.
Spiral Multi-detector CT utilizes 8, 16, 64 or more detectors during continuous motion of
the patient through the radiation beam to obtain much finer detail images in a shorter exam 35
time. With rapid administration of contrast during the CT scan these fine detail images can
be reconstructed into three-dimensional (3D) images of carotid, cerebral and coronary

- 15 -

arteries, CTA, CT angiography. CT scanning has become the test of choice in diagnosing
some urgent and emergent conditions such as cerebral hemorrhage, pulmonary embolism
(clots in the arteries of the lungs), aortic dissection (tearing of the aortic wall), appendicitis,
diverticulitis, and obstructing kidney stones. Continuing improvements in CT technology
including faster scanning times and improved resolution have dramatically increased the 5
accuracy and usefulness of CT scanning and consequently increased utilization in medical
diagnosis.

The term “magnetic resonance angiography” (MRA) relates to a branch of medicine
utilizing magnetic resonance imaging (MRI) as imaging technique. 10

The term “magnetic resonance imaging” (MRI) as used in accordance with the present
invention relates to an imaging technique using strong magnetic fields to align atomic
nuclei (usually hydrogen protons) within body tissues, then uses a radio signal to disturb
the axis of rotation of these nuclei and observes the radio frequency signal generated as the 15
nuclei return to their baseline states plus all surrounding areas. The radio signals are
collected by small antennae, called coils, placed near the area of interest. An advantage of
MRI is its ability to produce images in axial, coronal, sagittal and multiple oblique planes
with equal ease. MRI scans give the best soft tissue contrast of all the imaging modalities.
With advances in scanning speed and spatial resolution, and improvements in computer 3D 20
algorithms and hardware, MRI has become a versatile tool in radiology especially in
musculoskeletal radiology and neuroradiology. Nevertheless, it is disadvantageous that the
patient needs not to move for long periods of time in a noisy, cramped space while the
imaging is performed. Claustrophobia severe enough to terminate the MRI exam is
reported in up to 5% of patients. Recent improvements in magnet design including stronger 25
magnetic fields (3 teslas), shortening exam times, wider, shorter magnet bores and more
open magnet designs, have brought some relief for claustrophobic patients. However, in
magnets of equal field strength there is often a trade-off between image quality and open
design. MRI has great benefit in imaging the brain, spine, and musculoskeletal system. The
modality is currently contraindicated for patients with pacemakers, cochlear implants, 30
some indwelling medication pumps, certain types of cerebral aneurysm clips, metal
fragments in the eyes and some metallic hardware due to the powerful magnetic fields and
strong fluctuating radio signals the body is exposed to. Areas of potential advancement
include functional imaging, cardiovascular MRI, as well as MR image guided therapy.
35
The term “radiography” as used in accordance with the present invention relates to the use
of X-rays to cross materials to view inside objects. A heterogeneous beam of X-rays is