Keywords
embolic material - embolization - interventional - radiology
Introduction
Embolization is a fundamental procedure for interventional radiologists with several
applications.[1]
[2]
[3]
[4] The technique has continued to evolve and find new areas of clinical use, with current
indications ranging from the treatment of benign and malignant tumors, acute trauma,
and chronic pain.[1]
[2]
[3]
[4] Given the wide variety of clinical applications, it is not surprising that there
is also a wide variety of materials available for the interventionalist to utilize
for any embolization procedure.[1] Furthermore, there has been consistent evolution of these products, which continues
at present. Knowledge of these materials as well as the strengths and weaknesses of
each is paramount to allow the treating physician to achieve favorable results. This
review examines the different classes of embolic materials, discusses strengths and
weaknesses, and reports on current and future directives.
Coils
Coils are a commonly utilized embolic material with clinical applications in several
different scenarios.[1]
[5] This likely explains why there are greater than 50 different coils commercially
available.[1] One important aspect of coils to understand is that they rely on thrombosis to completely
occlude the vessel.[5]
[6]
[7] Therefore, it is beneficial for the materials that make up coils to have thrombogenic
properties, an area of evolution over the years.[5]
[6]
[7] For instance, companies have attached nylon fibers to a platinum backbone to increase
the filling and thrombogenicity of the coil.[8]
[9] Other types of fibers or coating have been used to provoke platelet aggregation
as well, but it should be noted that some coils continue to be made of bare metal.
While there is some disagreement on the importance of the presence or absence of fibers,
it is generally accepted that cross-sectional packing represents the ideal embolization
technique. The selection of the coil softness, size, and length plays an important
role in the ability to densely pack the vessel and thus prevent recanalization.[1]
[10] Coils have many advantages including the ability to provide controlled and predictable
embolization of a target vessel. This precise knowledge of embolization location can
provide reassurance for providers and reduce complications, such as non-target ischemia,
at times.
However, as with all materials coils have weaknesses as well. One weakness of coils
is the risk of incomplete vessel occlusion or vessel recanalization. A factor that
has been shown to affect vessel occlusion and recanalization is packing density, as
mentioned above.[11]
[12] Therefore, significant research has been done on coil softness and shape formation.[10] It is important for operators to understand the differences in shape formation for
each coil as this may directly affect the technical success of any given embolization
procedure. Some coils have “memory” and will form a predictable shape (loop, sine
wave, complex 3D shape, etc.), while others are relatively amorphous but soft and
designed to fill the entirety of a vessel. Another weakness of coils is their tendency
to “run” down a target vessel and form a non-occlusive line. There are a few ways
to combat this, one is by starting the coil in a small side branch vessel and letting
it extrude into the target vessel. However, some coils have been designed with a stiff
“anchor” portion at the beginning of the coil, which then becomes softer throughout
its course, allowing anchoring and then filling of the vessel.[13] Another consideration when using a coil is deliverability. Namely, the stiffness
of a coil can result in the inability of that coil to be delivered to an area reached
by a catheter or microcatheter. In general, softer coils are more amenable to delivery
through tortuous vessels. Finally, coils can migrate, especially in high flow scenarios.
Detachable coils were developed to compensate for this weakness. A detachable coil
has a mechanism holding it to a wire, which can be released when desired by the operator.
This differs from pushable coils that are attached to nothing and cannot be “retrieved”
easily after delivery. While pushable coils are less expensive than detachable coils,
in some scenarios a greater number of pushable coils are needed to achieve the same
result as a single detachable coil, and therefore using them can drive up the overall
procedural cost.[14]
As described above the inherent weaknesses of coils have provided opportunities to
innovate, with several advancements being achieved. However, research continues and
the areas of complex embolization and long-term vessel recanalization rates, particularly
with newly developed coil materials would benefit from further attention.
Vascular Plugs
Large arteries often require the delivery of multiple coils to achieve a successful
occlusion, increasing the cost and time of a procedure. Vascular plugs were engineered
to address this issue and provide permanent occlusion of larger arteries using a single
device.[15] The Amplatzer Vascular Plug (AVP) (Abbott Medical, Chicago, IL, USA) was the first
commercially available plug.[15]
[16]
[17] Unfortunately, the AVP, which comprises a nitinol mesh, can only be delivered through
access sheaths and large base catheters, limiting its usability in many target vessels.
Furthermore, despite the initial goals, incomplete occlusion rates and lengthy time
to occlusion requiring the concomitant use of coils to achieve rapid, complete occlusion
is an issue.
In light of these issues, several new devices have been developed including the Microvascular
Plug (MVP) (Medtronic, Dublin, IR), Azur Vascular Plug (Terumo, Tokyo, Japan), Caterpillar
(BD, Franklin Lakes, NJ), Lobo vascular occlude (Okami Medical, Aliso Viejo, CA),
Hourglass (EMBA Medical, Dublin, IR), Pillow Occluder (AndraTec, Koblenz, Germany),
and IMPEDE (Shape Memory Medical, Santa Clara, CA).[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26] Many of these plugs have been engineered with a polytetrafluoroethylene-covering
or membrane which enables faster occlusion times.[19]
[20] However, it should be noted that this membrane can also increase the risk of migration
when delivered in high flow situations.[23] Many of these second-generation devices are deliverable through smaller systems,
and therefore can be used in smaller, more distal vessels relative to the AVP. While
these newer plug technologies represent progress and address several key issues with
vascular plugs remain. They still require larger catheters and sheath for larger vessels
(5–8 mm or above based on the plug) and time to occlusion can still be less than ideal,
at times still requiring coils. Furthermore, improvements in the areas of trackability
and reliance on a patient's clotting cascade would fill current needs.
Particles
As the earliest described embolics, particles have seen significant evolution since
conception and have remained a primary embolic staple in interventional radiology.[27] In fact, the application of particle embolization has surged in the past couple
of decades, including uterine fibroid embolization, embolization for benign prostatic
hyperplasia, and drug eluting-particles for oncologic purposes among others.[28] Particles, as the name implies, are small (typically sizes are measured by micrometer)
embolics that are delivered through a catheter/microcatheter. After leaving the catheter
tip particles flow along with the blood to the distal vascular system. This distal
embolization can often lead to tissue ischemia, sometimes a desired and other times
an undesirable result. Both resorbable and permanent particles are available on the
market. Resorbable particles are designed to provide temporary occlusion of the target
vessels and the most commonly available material is Gel-foam.[29] However, how quickly Gel-foam is resorbed appears highly variable and it is not
clear whether vessels recanalize or undergo neovascular remodeling.[29]
[30] Because of the allure of temporary occlusion, which theoretically could provide
a desired clinical effect without enduring the long-term negative repercussions of
permanent vessel occlusion, significant research into new resorbable materials is
ongoing.[30]
In contrast, as the name suggests, permanent particles are so termed because they
are never resorbed by the body. However, it is important to note that recanalization
can occur despite the fact particles are not resorbed. Permanent particles are typically
further subdivided into spherical and non-spherical categories. Non-spherical particles
such as polyvinyl alcohol (PVA) have the advantage of being relatively inexpensive.
Conversely, they can clog delivery catheters and due to their irregular shape, the
exact level of occlusion is not predictable.[31]
[32] Spherical particles, which are made of several materials including tris-acryl gelatin
and polymethylmethacrylate, polyethylene glycol PEG, are relatively uniform in size
and shape and therefore have a more predictable level of occlusion and are less likely
to clog a delivery system.[33] It should be noted that they are also typically more expensive and that the advantages
of spherical particles described above have not always translated to improved clinical
outcomes.[34]
Finally, drug-eluting beads (DEB) is another particle category worth mentioning. DEBs
can be loaded with various drugs through an ion-exchange mechanism; however, only
certain drugs are amenable to being loaded.[35]
[36] After delivery, the DEBs slowly release the “loaded” chemical into the target tissue.
This function has been utilized in cancer therapy[1] but has theoretical applications in other areas as well.
While several features of particle embolics require consideration (including compressibility,
shape, size, degree of inflammation, and injectability) and are therefore targets
of innovation, two-particle features, visibility, and resorbability, have generated
significant research interest.[28] Because of the theoretical advantages of resorbable particles discussed above several
studies have been evaluating new materials. For example, Sommer et al demonstrated
reduced post-procedure complications when using a novel biodegradable microsphere
in comparison with established permanent microspheres.[37] Another theoretical advantage of particle resorption is minimizing the risk of long-term
immune reactions. Similarly, the development of visible particles has been an active
area of research with several studies reporting computed tomography (CT) and magnetic
resonance imaging (MRI) visible particles.[28]
[38] In theory, particle visibility on follow-up imaging would enable a greater understanding
of collateral pathways, embolization dynamics, reduce non-target embolization, as
well as aid in the understanding of the relationship between particle distribution
and clinical failure. However, it is yet unknown how changing the chemical composition
to make particles visible will affect other aspects of their performance.
Liquid Embolics
Liquid embolic agents represent perhaps the most actively developing category of embolic.
Liquid embolics offer several advantages relative to other materials, in that, unlike
particles, coils, and plugs they do not rely on the patient's native clotting ability.
In fact, liquid embolics can result in embolization through a biochemical response.[39] Conversely, these properties as well as their ability to penetrate deep into the
vascular arcade make liquid embolics very powerful and necessitate operator familiarity
for safe usage. That said, liquid embolics, perhaps more than any other embolic material,
have seen an increase in published indications over the last several years.[39] In general, there are three categories of liquid embolics: polymerizing, precipitating,
and phase transitioning agents.
Polymerizing liquid embolics comprise monomers or micro-monomers in a carrier, which
solidifies when coming into contact with an initiating agent. Perhaps the most commonly
utilized polymerizing liquid embolic agent is N-butyl-2- cyanoacrylate (NBCA), which
consists of several different chemical derivations and resultant variations in properties.
NBCA has demonstrated safety and efficacy in treating a variety of pathologies including
arteriovenous (AVM) and venous malformations, as well as gastrointestinal (GI) hemorrhage
and portal vein embolization.[39]
[40]
[41] The disadvantage of polymerizing agents and NBCA is that if the polymerization occurs
too quickly, the embolic can clog or “glue” the delivery catheter into the vessel,
but if it occurs too late then non-target embolization can occur. Therefore, precise
knowledge of the time to polymerization is required. NBCA is typically diluted with
lipiodol; the degree of dilution affects polymerization time. Fortunately, there is
a linear and reliable relationship between lipiodol dilution and time to polymerization.[42]
Precipitating agents are comprised of a polymer in a dissolvent. When the polymer
and dissolvent leave the catheter the change in conditions lead to precipitation of
the polymer chains and subsequent solidification. One disadvantage of this system
is the potential impact that the dissolving agent can have on the vascular system.
Onyx (Medtronic, Dublin, Ireland), which is made up of ethylene-co-vinyl alcohol dissolved
in dimethyl sulfoxide (DMSO), is a precipitating agent and has been reported as an
effective treatment for a wide variety of pathologies including peripheral and central
AVMs, GI hemorrhage, peripheral aneurysms, and varices.[43]
[44]
[45]
[46] One disadvantage of Onyx is that it relies on tantalum powder to provide radiolucency,
which requires it to be shaken for a significant period prior to use and leads to
an artifact of CT and MRI follow-up imaging.
Phase transitioning embolics require an external stimulus, such as temperature, pH,
or salt concentrations, which leads to the transition of the liquid to gel. While
no phase transitioning embolics are available on the market currently, several are
in the pipeline and may reach the market in the coming years.[47]
[48]
As alluded to above, there is significant development ongoing in liquid embolics,
with several new materials available in some markets but not others, or soon to be
released. We will briefly review some of these materials to make the reader aware
of them.
In terms of polymerizing agents, Hydrogel Embolic System (HES; Instylla Inc., Bedford,
MA, USA), is being developed and has been demonstrated to provide significantly higher
occlusion rates when compared with 40 μm microspheres in a rabbit model, as well as
distal penetration into the lumen of arterioles as small as 10 μm.[49]
Given the clinical success of Onyx, significant effort has been placed into the development
of precipitating agents including Squid (Emboflu, Gland, Switzerland), Precipitating
hydrophobic injectable liquid (PHIL Terumo, Tokyo, Japan), Easyx (Antia Therapeutics
AG, Berne, Switzerland) and Lava (Black Swan Vascular Inc, Hayward CA).[50]
[51]
[52]
[53]
[54]
[55] These products aim to have improved features including distal penetration, a reduced
beam-hardening artifact on post-procedural imaging, minimize adhesiveness and increase
ease of delivery as compared with Onyx.[39]
As described above no phase transitioning liquid embolic is available on the market
at this time. However, GPX (Fluidx Medical Technology) and PuraMatrix (3D Matrix Co.,
Tokyo, Japan) are both phase transitioning liquid embolics, which are being actively
developed and may come to market in the future.[47]
[48] Finally, gel embolic material (GEM) (Obsidio Inc, Columbia, South Carolina) is a
unique liquid embolic that is made of gelatin and nano silicates. It becomes a liquid
when pressure is applied but forms a solid when that pressure is removed (after leaving
the catheter), it has shown promise in preclinical studies.[56]
Conclusions and Future Perspectives
Conclusions and Future Perspectives
The role of embolization in the treatment of a variety of diseases is likely to continue
to expand. At the same time, research and commercial need has driven innovation with
new and revised materials continually becoming available. This emphasizes the importance
of understanding each embolic class and specific product's strengths and weaknesses.
While new materials often address weaknesses of previous devices, they require knowledge
to use effectively and safely. Furthermore, the role of each embolic class is continuously
changing, with new indications being reported frequently.[1] These changes are exciting and allow interventional radiologists to help patients
in new and exciting ways. However, it also leads to a requirement that these same
physicians constantly update and refresh their knowledge, of this fundamental procedure
and its materials.
