Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gobin, Y. P.
Right arrow Articles by Chow, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gobin, Y. P.
Right arrow Articles by Chow, K.
(Radiology. 2000;214:113-119.)
© RSNA, 2000

Experimental Studies

Embolization with Radiopaque Microbeads of Polyacrylonitrile Hydrogel: Evaluation in Swine1

Y. Pierre Gobin, MD, Fernando Viñuela, MD, Harry V. Vinters, MD, Cheng Ji, MD and Kira Chow, MD

1 From the Department of Radiological Sciences and Leo Rigler Radiological Research Center (Y.P.G., F.V., C.J., K.C.), and the Department of Pathology (H.V.V.), UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095-1721. Received July 2, 1998; revision requested August 18; final revision received April 19, 1999; accepted July 28. Address reprint requests to Y.P.G. (e-mail: pgobin@mednet.ucla.edu).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To perform in vitro and in vivo studies of radiopaque microbeads of polyacrylonitrile (PAN) hydrogel to evaluate their characteristics as embolic material.

MATERIALS AND METHODS: PAN microbeads were analyzed in vitro for swelling in different concentrations of contrast material and saline solution and injected through various microcatheters. In three nonsurvival swine, various organs were embolized with PAN microbeads. In eight survival swine, the rete mirabile was embolized with PAN microbeads or polyvinyl alcohol particles. Follow-up angiograms were obtained regularly, and histopathologic analysis was performed at 1 and 6 months.

RESULTS: The microbeads were black with a regular shape and smooth surface. They were easily visible in the syringe and easy to inject through the microcatheters. When wet, their diameters increased by 40%. The microbeads were sufficiently radiopaque to be visible in all vascular territories. Vascular occlusion was not permanent, and even when embolization was adequate, some revascularization was detected at 3 months. The microbeads were intact and still radiopaque at 6 months. Histopathologic examination demonstrated variable inflammatory reactions and foreign-body giant cell reaction and no angionecrosis or hemorrhage.

CONCLUSION: Because PAN microbeads are biocompatible, radiopaque, and easy to handle during embolization procedures, they have potential as a therapeutic embolic agent.

Index terms: Angiography, **.12> 2 • Arteries, therapeutic embolization, **.12642 • Microspheres • Polyacrylonitrile hydrogel • Veins, therapeutic embolization, **.12642


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Therapeutic embolization has a wide range of applications, for which different embolic agents are needed for different anatomic and hemodynamic challenges. Embolic agents include particles (eg, polyvinyl alcohol [PVA] and gelatin powder), liquids (eg, cyanoacrylate), and mechanical devices (detachable balloons and coils). Although PVA is a widely used embolic agent (1–7), it lacks many of the important properties of a suitable embolic agent. First, PVA is not radiopaque, so the precise site of arterial occlusion cannot be seen directly, but rather it has to be assessed indirectly with analysis of repeated angiographic studies during embolization. Second, the predictability of embolization—that is, the ability to occlude a vessel of a specific size—with PVA is poor because the particles are irregularly shaped and difficult to calibrate (7,8). To address the limitations of PVA, we developed radiopaque microbeads of polyacrylonitrile (PAN) hydrogel (Medtronic-MIS, Sunnyvale, Calif) for therapeutic embolization. In this article, we present the results of in vitro and in vivo animal studies of PAN, which were conducted to evaluate this material as an embolic agent.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
PAN Microbeads
PAN microbeads are made of polyacrylonitrile hydrogel (9). Hydrogels are widely present in the human body, and hydrogel implants are generally biocompatible (10) because they are soft and hydrated like living tissue. Hydrogels have low friction and do not adhere to surrounding tissue (9). Hydrogels are permeable to water and water-soluble substances, and when they absorb these substances by diffusion, they expand by swelling until they reach their equilibrium content (9). Because their absorption of water-soluble substances is reversible, PAN hydrogels have been studied for possible use in drug delivery (9). PAN hydrogel is a multiblock copolymer that is formed from a combination of hard blocks (nitrile group) and soft blocks (hydrophilic groups), the proportion of which can be changed to modify the physical properties (9). PAN hydrogels have good biocompatibility and low toxicity. Compared with other hydrogels, PAN hydrogels have a high tear strength.

To use PAN hydrogels as embolization material, different nonbiodegradable formulas of this hydrogel have been studied in liquid and particulate forms (11), and the microbeads have been made radiopaque by the addition of tantalum or tungsten (12). In the process of fabricating PAN microbeads, soft beads with a smooth surface were created and made radiopaque by the addition of tantalum. The microbeads were prepared in a wide range of sizes and then partitioned by means of successive passes through sieves of decreasing sizes. Pan microbeads that ranged in diameter from 50 to 1,000 µm were used in this study.

In Vitro Study
The PAN microbeads were supplied dry. Dry and wet forms of the microbeads were examined under a microscope. Microbeads of various sizes (50–150 µm, 150–250 µm, 250–350 µm, 350–500 µm, 500–700 µm, and 700–1,000 micron µm) were soaked in solutions of isotonic saline, contrast material (iopamidol [Isovue 300]; Bracco Diagnostics, Princeton, NJ), and a mixture of one-half saline and one-half contrast material. The increase in mean diameter of the microbeads was measured under the microscope. The microbeads were injected through various microcatheters, and the ease of injection was subjectively evaluated by an interventional neuroradiologist (Y.P.G.).

Animal Study
Animal experiments were conducted in accordance with the guidelines set by the National Institutes of Health and the policies of the chancellor's animal research committee of the University of California, Los Angeles. Eleven 30–40 kg, 3–4-month-old Red Duroc swine were used in this study. After the animals had fasted for 12 hours overnight, they were premedicated with an intramuscular injection of 20 mg/kg ketamine and 2 mg/kg xylazine, intubated, and maintained under general anesthesia with mechanical ventilation and inhalation of 1%–2% halothane. Arterial access was gained by means of percutaneous placement of a 6-F sheath into the right or left superficial femoral artery.

In three animals, PAN microbeads of various sizes were used for embolization of the carotid arterial branches and the intercostal, renal, hepatic, and splenic arteries. The swine were sacrificed at the end of the procedure.

In eight animals, the rete mirabile was embolized with either PAN microbeads or PVA particles. A 6-month study was performed to evaluate these swine for potential long-term revascularization. Angiograms were obtained at 1 and 2 weeks and at 1, 2, and 3 months after embolization (Table). At the end of the follow-up period (1 or 6 months), a final angiogram was obtained before the animals were sacrificed by means of pentobarbital injection. The rete mirabile in these animals was harvested and fixed in 10% neutral formalin. The specimens were embedded in paraffin, and sections were prepared by using standard techniques and hematoxylin-eosin stain for light microscopic examination.


View this table:
[in this window]
[in a new window]

  		Results of Embolization at Angiography
 

   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
In Vitro Study
The microbeads were black and either spherical or ovoid, and had a smooth surface when hydrated (Fig 1). After being soaked in various solutions of saline and contrast material, the mean diameter of the microbeads increased by 30%–50%. Figure 2 shows the increase in the mean diameter of the 250–350-µm microbeads soaked in solutions of saline, contrast material, and half saline, half contrast material. In all the microbeads, the swelling was fastest and most prominent in the saline solution (40%–50% increase in mean diameter); it was fastest and most prominent next in the mixed solution of saline and contrast material (30%–40% increase in mean diameter), and then in the pure contrast material (25%–35% increase in mean diameter).



View larger version (148K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. PAN microbeads (355-500 µm) examined under a microscope (original magnification, x10). Dry microbeads (left) have a slightly irregular surface. When hydrated, the microbeads (right) swell by means of absorption, and their surface becomes smooth and regular.

 


View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Rate of hydration of 250-350-µm PAN microbeads placed in 9% saline (•), 300 mg/mL contrast material (Isovue 300) ({block}), and a half saline, half contrast material mixture ({blacktriangleup}). The diameter of the microbeads was measured under a microscope and reported as a percentage increase. The mean diameter of the microbeads increased by approximately 40%. Swelling was fastest and most prominent in the saline, then in the mixed saline-contrast material solution, and then in the pure contrast material.

 
The smaller microbeads reached their maximum size in 2 minutes, whereas the larger microbeads reached their maximum size in 15 minutes. Because volume increase is proportional to the third power of the radius, a diameter increase of 40% corresponds to a volume increase of 174%. This increase in volume was due to the absorption of the isotonic saline, contrast material, or half contrast material, half saline solution.

In preparation for embolization, the beads were soaked in contrast material (iohexol [Omnipaque 300]; Nycomed Amersham, Princeton, NJ) for 2–20 minutes. The beads did not aggregate and were easily aspirated into the injection syringe. The black color of the PAN beads allowed a simple estimation of the number of beads aspirated in the embolization syringe. The PAN beads sank into the syringe (the larger beads sank faster) and could be easily manipulated by gravity (Fig 3). The 45–90-µm PAN microbeads could not be distinguished individually but were seen as a black powder; thus, a contaminated syringe could not be used inadvertently.



View larger version (95K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. PAN microbeads placed in contrast material solution in syringes. Note how the black microbeads are easily visualized.

 
The PAN microbeads up to 700 µm in diameter could be injected easily—that is, without excessive pressure—through 0.018-inch microcatheters such as the Fast Tracker 18 (Target Therapeutics, Fremont, Calif) and Jet Stream 18 (Micro Interventional System, Sunnyvale, Calif). The microbeads up to 350 µm in diameter could be easily injected through 0.010-inch microcatheters such as the Fast Tracker 10 (Target Therapeutics) and Jet Stream 10 (Micro Interventional System). The microbeads could be injected in a more controllable manner with less clogging of the microcatheter compared with the injection of PVA particles through the same microcatheters.

Immediate Results of Embolization
The microbeads had suitable radiopacity, which allowed satisfactory visualization of them during embolization (Figs 4, 5). However, they could not be seen while moving and had to be injected as a suspension in contrast material. The beads were better seen in the rete mirabile or other immobile structures than in the viscera (eg, in the liver and kidney) because of respiratory motion artifact. The anatomic occlusion of the rete mirabile was accomplished before all of its vascular meshwork was filled with beads. This early occlusion was attributed to associated thrombosis secondary to the slowing of blood flow. Complete occlusion of the proximal part of the rete mirabile and of the ascending pharyngeal artery was always achieved. The distal portion of the rete mirabile was recanalized through an anastomosis from the contralateral rete mirabile and from collateral branches arising from the external carotid artery (Fig 4). The rete mirabile was adequately occluded with 250–350-µm or larger PAN beads.



View larger version (184K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4a. Embolization with PAN microbeads in the rete mirabile of a swine. (a) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained during selective catheterization of the right ascending pharyngeal artery (short arrow) shows injection of the microbeads into the rete mirabile (long arrow). Embolization was performed first with 250-350-µm PAN microbeads and then with 350-500-µm microbeads. (b) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained after embolization shows the radiopaque PAN microbeads inside the rete mirabile (long arrow) and the ascending pharyngeal artery (short arrow). Note that the microbeads are in the proximal lateral two-thirds of the rete mirabile. (c) Right posterior oblique (20° obliquity) angiogram of the carotid artery 6 months after embolization shows the right ascending pharyngeal artery (short arrow) is partially reopened, and the distal rete mirabile (long arrow) is partially revascularized by means of anastomosis from the external carotid artery. (d) Nonsubtracted right posterior oblique (20° obliquity) angiogram 6 months after embolization shows slightly decreased radiopacity of the PAN microbeads in the ascending pharyngeal artery (short arrow) and the rete mirabile (long arrow).

 


View larger version (191K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4b. Embolization with PAN microbeads in the rete mirabile of a swine. (a) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained during selective catheterization of the right ascending pharyngeal artery (short arrow) shows injection of the microbeads into the rete mirabile (long arrow). Embolization was performed first with 250-350-µm PAN microbeads and then with 350-500-µm microbeads. (b) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained after embolization shows the radiopaque PAN microbeads inside the rete mirabile (long arrow) and the ascending pharyngeal artery (short arrow). Note that the microbeads are in the proximal lateral two-thirds of the rete mirabile. (c) Right posterior oblique (20° obliquity) angiogram of the carotid artery 6 months after embolization shows the right ascending pharyngeal artery (short arrow) is partially reopened, and the distal rete mirabile (long arrow) is partially revascularized by means of anastomosis from the external carotid artery. (d) Nonsubtracted right posterior oblique (20° obliquity) angiogram 6 months after embolization shows slightly decreased radiopacity of the PAN microbeads in the ascending pharyngeal artery (short arrow) and the rete mirabile (long arrow).

 


View larger version (192K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4c. Embolization with PAN microbeads in the rete mirabile of a swine. (a) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained during selective catheterization of the right ascending pharyngeal artery (short arrow) shows injection of the microbeads into the rete mirabile (long arrow). Embolization was performed first with 250-350-µm PAN microbeads and then with 350-500-µm microbeads. (b) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained after embolization shows the radiopaque PAN microbeads inside the rete mirabile (long arrow) and the ascending pharyngeal artery (short arrow). Note that the microbeads are in the proximal lateral two-thirds of the rete mirabile. (c) Right posterior oblique (20° obliquity) angiogram of the carotid artery 6 months after embolization shows the right ascending pharyngeal artery (short arrow) is partially reopened, and the distal rete mirabile (long arrow) is partially revascularized by means of anastomosis from the external carotid artery. (d) Nonsubtracted right posterior oblique (20° obliquity) angiogram 6 months after embolization shows slightly decreased radiopacity of the PAN microbeads in the ascending pharyngeal artery (short arrow) and the rete mirabile (long arrow).

 


View larger version (202K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4d. Embolization with PAN microbeads in the rete mirabile of a swine. (a) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained during selective catheterization of the right ascending pharyngeal artery (short arrow) shows injection of the microbeads into the rete mirabile (long arrow). Embolization was performed first with 250-350-µm PAN microbeads and then with 350-500-µm microbeads. (b) Nonsubtracted right posterior oblique (20° obliquity) angiogram obtained after embolization shows the radiopaque PAN microbeads inside the rete mirabile (long arrow) and the ascending pharyngeal artery (short arrow). Note that the microbeads are in the proximal lateral two-thirds of the rete mirabile. (c) Right posterior oblique (20° obliquity) angiogram of the carotid artery 6 months after embolization shows the right ascending pharyngeal artery (short arrow) is partially reopened, and the distal rete mirabile (long arrow) is partially revascularized by means of anastomosis from the external carotid artery. (d) Nonsubtracted right posterior oblique (20° obliquity) angiogram 6 months after embolization shows slightly decreased radiopacity of the PAN microbeads in the ascending pharyngeal artery (short arrow) and the rete mirabile (long arrow).

 


View larger version (186K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5a. Angiograms obtained during embolization of the intercostal arteries show the advantage of using radiopaque microbeads to control the distal progression of embolization. (a) Selective angiogram (nonsubtracted anteroposterior view) of the T9 intercostal artery. A 5-F catheter is placed in the common trunk of the right and left intercostal arteries (black arrows). The dorsospinal branches (white arrows) of the intercostal arteries also can be seen. (b) Angiogram (anteroposterior nonsubtracted view) obtained after complete embolization of the T9 and T10 intercostal arteries. The T9 intercostal artery is occluded with 250-350-µm microbeads (black and white arrows), and the T10 intercostal artery is occluded with 350-500-µm microbeads (arrowheads). The postembolization angiogram (not shown) demonstrated complete occlusion of the intercostal arteries with both microbead sizes, but it did not give information on the most distal point of embolization. However, the smaller microbeads reached the dorsospinal branches (white arrows) and thus provided more distal embolization. Using radiopaque beads enables one to tailor the size of the embolizing particles to each particular vascular bed. Both the risk of revascularization if the emboli are too large and too proximal and the risk of necrosis or lung migration if the emboli are too small are reduced.

 


View larger version (123K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5b. Angiograms obtained during embolization of the intercostal arteries show the advantage of using radiopaque microbeads to control the distal progression of embolization. (a) Selective angiogram (nonsubtracted anteroposterior view) of the T9 intercostal artery. A 5-F catheter is placed in the common trunk of the right and left intercostal arteries (black arrows). The dorsospinal branches (white arrows) of the intercostal arteries also can be seen. (b) Angiogram (anteroposterior nonsubtracted view) obtained after complete embolization of the T9 and T10 intercostal arteries. The T9 intercostal artery is occluded with 250-350-µm microbeads (black and white arrows), and the T10 intercostal artery is occluded with 350-500-µm microbeads (arrowheads). The postembolization angiogram (not shown) demonstrated complete occlusion of the intercostal arteries with both microbead sizes, but it did not give information on the most distal point of embolization. However, the smaller microbeads reached the dorsospinal branches (white arrows) and thus provided more distal embolization. Using radiopaque beads enables one to tailor the size of the embolizing particles to each particular vascular bed. Both the risk of revascularization if the emboli are too large and too proximal and the risk of necrosis or lung migration if the emboli are too small are reduced.

 
The smaller beads migrated through the rete mirabile and were observed in the cortical arteries of the brain in two swine. The migration of the microbeads was delayed as long as 5 minutes. One swine had bilateral cerebral embolism. It did not recover well from the procedure and was euthanized 24 hours later. The second swine tolerated the cerebral embolization with a small amount of beads and had no sequelae.

Figure 5 is an example of intercostal arterial embolization in which the radiopacity of the PAN microbeads enabled good control of the end point of occlusion.

Angiographic Follow-up
Eight swine were included in a long-term study with angiographic follow-up and histopathologic analysis. The first swine had to be sacrificed 1 day after embolization because it was not thriving well, and no histopathologic analysis was performed. Embolization was performed with 150–250-µm PAN microbeads, which migrated through the rete mirabile and induced embolism of the brain bilaterally. After this occurred, embolization was performed with larger microbeads to avoid trans–rete mirabile migration and brain embolism. Two swine were sacrificed prematurely—one because of anemia and the other because of an enlarging groin hematoma. Thus, angiographic follow-up and histopathologic analysis of the rete mirabile were performed at 6 months in five swine and at 1 month in two swine (Table). Revascularization was detected on the 1-month angiogram in one swine. This revascularization was thought to be due to inadequate embolization with too few microbeads. In the other cases, revascularization was detected on the 3-month follow-up angiogram and increased at 6-month angiography. The beads had lost some radiopacity by the 1-week follow-up angiographic examination, probably because of diffusion of the contrast material in which they were soaked. The radiopacity remained stable afterward through the 6-month period of the study (Fig 4).

Histopathologic Results
The beads were easily visible at macroscopic observation of the rete mirabile specimens harvested at 1 and 6 months. At microscopic examination, the microbeads appeared as a homogeneous basophilic material with a black particulate component (Fig 6a). Thirty percent to 50% of the vascular lumens of the rete mirabile were filled with microbeads. The vascular and perivascular inflammatory reactions were variable, ranging from minimal to brisk, and characterized by a predominant macrophage and foreign body giant cell reaction (Fig 6b, 6c). There was a variable, minimal to brisk chronic adventitial reaction with a lymphohistiocytic response. No histopathologic evidence of acute or chronic angionecrosis or hemorrhage was detected. Some PAN microbeads were in the blood vessel walls and in extravascular locations.



View larger version (145K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6a. Microscopic sections of the rete mirabile 6 months after embolization. (a) Histologic specimen shows a PAN microbead (asterisk) filling the vascular lumen. The retraction of the material from the vessel wall (arrows) represents processing artifact. (Hematoxylin-eosin stain; original magnification, x190.) (b) Histologic specimen shows a PAN microbead (asterisk) essentially filling the vascular lumen. Note the intact vessel wall with normal smooth muscle (arrows). (Hematoxylin-eosin stain; original magnification, x35.) (c) Histologic specimen shows intravascular PAN (arrows) surrounded by macrophages and multinucleated giant cells (arrowheads). (Hematoxylin-eosin stain; original magnification, x95.)

 


View larger version (146K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6b. Microscopic sections of the rete mirabile 6 months after embolization. (a) Histologic specimen shows a PAN microbead (asterisk) filling the vascular lumen. The retraction of the material from the vessel wall (arrows) represents processing artifact. (Hematoxylin-eosin stain; original magnification, x190.) (b) Histologic specimen shows a PAN microbead (asterisk) essentially filling the vascular lumen. Note the intact vessel wall with normal smooth muscle (arrows). (Hematoxylin-eosin stain; original magnification, x35.) (c) Histologic specimen shows intravascular PAN (arrows) surrounded by macrophages and multinucleated giant cells (arrowheads). (Hematoxylin-eosin stain; original magnification, x95.)

 


View larger version (149K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6c. Microscopic sections of the rete mirabile 6 months after embolization. (a) Histologic specimen shows a PAN microbead (asterisk) filling the vascular lumen. The retraction of the material from the vessel wall (arrows) represents processing artifact. (Hematoxylin-eosin stain; original magnification, x190.) (b) Histologic specimen shows a PAN microbead (asterisk) essentially filling the vascular lumen. Note the intact vessel wall with normal smooth muscle (arrows). (Hematoxylin-eosin stain; original magnification, x35.) (c) Histologic specimen shows intravascular PAN (arrows) surrounded by macrophages and multinucleated giant cells (arrowheads). (Hematoxylin-eosin stain; original magnification, x95.)

 

   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
To our knowledge, radiopaque microspheres were the first artificial material used for embolization; they were used by Luessenhop et al (13) in 1959 to treat an arteriovenous malformation of the brain. Since then, many radiopaque or radiolucent microspheres have been developed for embolization, but none have gained wide application (14–25).

PAN microbeads have interesting characteristics: They are black, and even the smallest beads are easily visualized in a syringe or in the hub of a catheter. This visibility decreases the risk of contamination during embolization procedures. Because the PAN microbeads have a smooth surface and are compressible, they are easily injected through microcatheters. When suspended in contrast material, the microbeads sink; thus, they can be manipulated by gravity within the syringe, and the amount injected can be controlled.

Another advantage of PAN microbeads is their radiopacity. The use of radiolucent embolic material such as PVA does not enable accurate identification of the embolization site. For example, during embolization of a lesion with PVA, repeated angiograms may not demonstrate a substantial change in the lesion flow pattern. This may have two explanations: (a) The PVA particles injected were too small and passed through the vascular network of the lesion, or (b) the amount of particles injected was insufficient to substantially reduce blood flow. If one inappropriately switches to larger particles, then the embolization will be too proximal, and this is associated with a high rate of revascularization. On the other hand, continuing embolization with particles that are too small may result in migration through the lesion into the pulmonary arteries, with the risk of severe pulmonary hypertension and death (26). The use of radiopaque microbeads addresses this problem, because the site of occlusion can be visualized at fluoroscopy (Fig 5).

The PAN microbeads are nonadhesive because they are made of hydrogel, which has a low coefficient of friction and a low adherence to surrounding tissue (9). These properties have numerous implications. First, there is a lower risk of clogging microcatheters. Second, embolization is anatomically better because the microbeads stop only when they reach vessels of their own size. In our experiments, the microbeads consistently passed through the rete mirabile when their diameter was smaller than that of the rete mirabile. Small microbeads consistently traveled more distally than large microbeads (Fig 5). This is a substantially positive difference compared with the embolism produced by using PVA.

Sometimes, PVA particles clump together to form an occlusive embolus that may be larger than intended, and on other occasions, a single PVA particle occludes a small vessel (27). This is considered a technical problem, because a good embolic agent should produce a predictable blockage of vessels of a preset size (11). Moreover, rather than wedge in distal vessels, PVA particles adhere to each other and to the walls of larger diameter vessels (3). Because PAN microbeads do not adhere to the vascular wall, embolization is more predictable.

The disadvantage of the nonadhesive property of PAN microbeads is their inability to occlude a vessel larger than the size of an individual microbead. This limits their use in the treatment of arteriovenous malformations, because most of these malformations include large arteriovenous shunts, through which all but the largest microbeads will pass. Microbead diameters of 1,500 or 2,000 µm are needed to prevent their passage through arteriovenous malformations of the brain (28), and 1,000-µm-diameter microbeads are needed to prevent their passage through arteriovenous malformations of the spinal cord (20). The large microbead size needed to produce embolism of arteriovenous malformations precludes the use of microcatheters. Tumor embolization can be performed with smaller microbeads as long as the tumor does not have large arteriovenous shunts.

Another characteristic of PAN microbeads is their delayed migration several minutes after they have been deposited in the vascular tree. This phenomenon is called vascular redistribution, and it has been reported to occur also with dextran microspheres (15). It can be defined as the temporary crowding of the beads at an arterial bifurcation. Then, in response to arterial pulsation or because of increased pressure in the feeder due to embolization, the beads migrate further distally, and the vascular tree partially reopens (15).

The rete mirabile in the swine is a network of small (100–250-µm-diameter) arteries (29,30) replacing the intracavernous segment of the internal carotid artery. The rete mirabile is a good model to study the pathologic effects of embolic materials in arteries and perivascular tissue because its mechanical occlusion does not induce tissue infarction (29). Embolization of the rete mirabile results in occlusion of only the proximal portion of the vascular network, whereas collateral vessels arising from the external carotid artery and the contralateral rete mirabile maintain flow in the distal, nonoccluded tissue. In the absence of surrounding tissue necrosis, the effect of the embolic material on the vessel wall can be better analyzed (16,21,25,30).

The results of histopathologic analysis of the rete mirabile occluded with PAN microbeads showed that they had not biodegraded after 6 months; this result confirms previous reports (9). The inflammatory reactions induced by the microbeads included a foreign-body giant cell reaction similar to that seen with PVA. However, there was no angionecrosis or hemorrhage, phenomena that have been described with the use of cyanoacrylate, and, to a lesser degree, with the use of PVA (5,27,31).

Revascularization is a frequent phenomenon in therapeutic embolization of vascular malformations and tumors. It has been reported to occur with the use of several embolic agents, including PVA (27,32,33) and cyanoacrylate (34,35). There are three mechanisms of revascularization after embolization. First, collateral arteries may develop distal to a proximal occlusion. Second, delayed recanalization may occur in the thrombus associated with the embolic agent; this happens when the embolic agent is biodegradable or does not entirely fill the vascular lumen. The associated thrombus organizes, and angiogenesis occurs (27). In our study, occlusion of the rete mirabile occurred before all of the vascular meshwork was filled with the radiopaque microbeads, and this was attributed to associated thrombosis secondary to the slowing of blood flow. Performing the embolization with systemic anticoagulation could have minimized the associated thrombosis and allowed a better filling of the rete mirabile vessels with the PAN microbeads and thus minimized revascularization.

The third mechanism of recanalization involves extravascular migration of the embolic material. This phenomenon has been described in pathologic studies of arteriovenous malformations of the brain that were occluded with cyanoacrylate and with PVA (5,27,31). Vinters et al (31) described bucrylate being lined with endothelium, and, over time, becoming incorporated into the vessel wall. They proposed that the bucrylate migrated into the extravascular space as a consequence of vessel wall necrosis. Germano et al (27) described a severe inflammatory reaction from PVA and hypothesized that it was due to the action of inflammatory cells. In our study, recanalization of previously occluded parts of the rete mirabile was seen on angiograms at 3 months. This finding differs from those of a previous study by Link et al (36), who embolized the kidney and liver vessels in swine with PVA particles and PAN hydrogel microbeads similar to the PAN microbeads used in our study. They performed angiographic and pathologic examinations at 10 days and up to 56 days after embolization and found no recanalization of the arteries that were completely blocked with embolic material. They also found destruction of the arterial wall, which was more pronounced with the PAN microbeads than with the PVA particles. The recanalization observed in our study was probably due to the longer period of follow-up and to the use of the rete mirabile in swine as the embolization model.

PAN hydrogels absorb water-soluble solutions by diffusion into the molecular network of the polymer. By doing so, the hydrogel swells and becomes softer (9). In our study, the PAN microbeads increased 40% in diameter when they were put in a water and contrast material solution; this corresponds to an increase in volume of 174%. This means that PAN microbeads can absorb 174% of their volume of a water-soluble chemical. Thus, PAN microbeads could be used as a reservoir for targeted delivery of water-soluble substances, such as cytotoxic or sclerosing agents, to improve long-term arterial occlusion or for selective chemoembolization. The kinetic properties of release of the chemical at the site of embolization are complex, involve multiple parameters, and constitute an interesting subject for future research.

Practical application: PAN microbeads are a promising material for therapeutic embolization. They are biocompatible, radiopaque, and easy to handle during embolization procedures. In addition, PAN microbeads could be filled with water-soluble chemicals and used as a drug delivery device.


   Acknowledgments
 
We gratefully acknowledge Daniel P. Link, MD, for his suggestions and review of our manuscript.


   Footnotes
 
**. Multiple vascular systems Back

Abbreviations: PAN = polyacrylonitrile PVA = polyvinyl alcohol

Author contributions: Guarantor of integrity of entire study, Y.P.G.; study concepts and design, Y.P.G., F.V.; definition of intellectual content, Y.P.G., F.V.; literature research, Y.P.G., K.C.; experimental studies, Y.P.G., C.J.; data acquisition, Y.P.G., C.J., H.V.V.; data analysis, Y.P.G., H.V.V.; manuscript preparation and editing, Y.P.G., K.C.; manuscript review, F.V., H.V.V.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Tadavarthy SM, Moller JH, Amplatz K. Polyvinyl alcohol (Ivalon): a new embolic material. AJR 1975; 125:609-616.[Abstract]
  2. Kerber CW, Bank WO, Horton JA. Polyvinyl alcohol foam: prepackaged emboli for therapeutic embolization. AJR 1978; 130:1193-1194.[Medline]
  3. Quisling RG, Mickle JP, Ballinger WB, Carver CC, Kaplan B. Histopathologic analysis of intraarterial polyvinyl alcohol microemboli in rat cerebral cortex. AJNR 1984; 5:101-104.[Abstract]
  4. Purdy PD, Batjer HH, Risser RC, Samson D. Arteriovenous malformations of the brain: choosing embolic materials to enhance safety and ease of excision. J Neurosurg 1992; 77:217-222.[Medline]
  5. Schweitzer JS, Chang BS, Madsen P, et al. The pathology of arteriovenous malformations of the brain treated by embolotherapy. II. Results of embolization with multiple agents. Neuroradiology 1993; 35:468-474.[Medline]
  6. Davidson GS, Terbrugge KG. Histologic long-term follow-up after embolization with polyvinyl alcohol particles. AJNR 1995; 16:843-846.[Abstract]
  7. Derdeyn CP, Moran CJ, Cross DT, Dietrich HH, Dacey RG, Jr. Polyvinyl alcohol particle size and suspension characteristics. AJNR 1995; 16:1335-1343.[Abstract]
  8. Jack CR, Jr, Forbes G, Dewanjee MK, Brown ML, Earnest F, 4th. Polyvinyl alcohol sponge for embolotherapy: particle size and morphology. AJNR 1985; 6:595-597.[Abstract]
  9. Stoy VA. New type of hydrogel for controlled drug delivery. J Biomater Appl 1989; 3:552-604.
  10. Sprincl L, Vacik J, Kopecek J. Biological tolerance of ionogenic hydrophilic gels. J Biomed Mater Res 1973; 7:123-136.[Medline]
  11. Gu WZ, Link DP, Tesluk H, Blashka K. Experimental renal embolization: preliminary results with polyacrylonitrile-based multiblock copolymers. JVIR 1992; 3:119-125.[Medline]
  12. Link DP, Mourtada FA, Jackson J, Blashka K, Samphilipo MA. Hydrogel embolic agents: theory and practice of adding radio-opacity. Invest Radiol 1994; 29:746-751.[Medline]
  13. Luessenhop AJ, Spence WT. Artificial embolization of cerebral arteries: report of use in a case of arteriovenous malformation. JAMA 1960; 172:1153-1155.
  14. Boulos R, Kricheff II, Chase NE. Value of cerebral angiography in the embolization treatment of cerebral arteriovenous malformations. Radiology 1970; 97:65-70.[Medline]
  15. Dion JE, Rankin RN, Viñuela F, Fox AJ, Wallace AC, Mervart M. Dextran microsphere embolization: experimental and clinical experience with radiologic-pathologic correlation—work in progress. Radiology 1986; 160:717-721.[Abstract/Free Full Text]
  16. Lylyk P, Viñuela F, Vinters HV, et al. Use of a new mixture for embolization of intracranial vascular malformations. Neuroradiology 1990; 32:304-310.[Medline]
  17. Flandroy P, Grandfils C, Collignon J, et al. (D, L) polylactide microspheres as embolic agent: a preliminary study. Neuroradiology 1990; 32:311-315.[Medline]
  18. Thanoo BC, Sunny MC, Jayakrishnan A. Tantalum-loaded polyurethane microspheres for particulate embolization: preparation and properties. Biomaterials 1991; 12:525-528.[Medline]
  19. Thanoo BC, Jayakrishnan A. Tantalum loaded silicone microspheres as particulate emboli. J Microencapsul 1991; 8:95-101.[Medline]
  20. Rao VR, Ravimandalam K, Jayakrishnan A, et al. Hydrolysed microspheres from cross-linked polymethyl methacrylate (hydrogel): a new embolic material for interventional neuroradiology. J Neuroradiol 1991; 18:61-69.[Medline]
  21. Turjman F, Massoud TF, Vinters HV, et al. Collagen microbeads: experimental evaluation of an embolic agent in the rete mirabile of the swine. AJNR 1995; 16:1031-1036.[Abstract]
  22. Hamada J, Kai Y, Nagahiro S, Hashimoto N, Iwata H, Ushio Y. Embolization with cellulose porous beads. II. Clinical trial. AJNR 1996; 17:1901-1906.[Abstract]
  23. Hamada J, Ushio Y, Kazekawa K, Tsukahara T, Hashimoto N, Iwata H. Embolization with cellulose porous beads. I. An experimental study. AJNR 1996; 17:1895-1899.[Abstract]
  24. Laurent A, Beaujeux R, Wassef M, Rufenacht D, Boschetti E, Merland JJ. Trisacryl gelatin microspheres for therapeutic embolization. I. Development and in vitro evaluation. AJNR 1996; 17:533-540.[Abstract]
  25. Derdeyn CP, Graves VB, Salamat MS, Rappe A. Collagen-coated acrylic microspheres for embolotherapy: in vivo and in vitro characteristics. AJNR 1997; 18:647-653.[Abstract/Free Full Text]
  26. Repa I, Moradian GP, Dehner LP, et al. Mortalities associated with use of a commercial suspension of polyvinyl alcohol. Radiology 1989; 170:395-399.[Abstract/Free Full Text]
  27. Germano IM, Davis RL, Wilson CB, Hieshima GB. Histopathological follow-up study of 66 cerebral arteriovenous malformations after therapeutic embolization with polyvinyl alcohol. J Neurosurg 1992; 76:607-614.[Medline]
  28. Kricheff II, Madayag M, Braunstein P. Transfemoral catheter embolization of cerebral and posterior fossa arteriovenous malformations. Radiology 1972; 103:107-111.[Medline]
  29. Brothers MF, Kaufmann JC, Fox AJ, Deveikis JP. n-Butyl 2-cyanoacrylate: substitute for IBCA in interventional neuro-radiology—histopathologic and polymerization time studies. AJNR 1989; 10:777-786.[Abstract]
  30. Lee DH, Wriedt CH, Kaufmann JC, Pelz DM, Fox AJ, Viñuela F. Evaluation of three embolic agents in pig rete. AJNR 1989; 10:773-776.[Abstract]
  31. Vinters HV, Lundie MJ, Kaufmann JC. Long-term pathological follow-up of cerebral arteriovenous malformations treated by embolization with bucrylate. N Engl J Med 1986; 314:477-483.[Abstract]
  32. Biondi A, Merland JJ, Reizine D, et al. Embolization with particles in thoracic intramedullary arteriovenous malformations: long-term angiographic and clinical results. Radiology 1990; 177:651-658.[Abstract/Free Full Text]
  33. Nichols DA, Rufenacht DA, Jack CR, Jr, Forbes GS. Embolization of spinal dural arteriovenous fistula with polyvinyl alcohol particles: experience in 14 patients. AJNR 1992; 13:933-940.[Abstract]
  34. Rao VR, Mandalam KR, Gupta AK, Kumar S, Joseph S. Dissolution of isobutyl 2-cyanoacrylate on long-term follow-up. AJNR 1987; 10:135-141.[Abstract]
  35. Gobin YP, Laurent A, Merienne L, et al. Treatment of brain arteriovenous malformations by embolization and radiosurgery. J Neurosurg 1996; 85:19-28.[Medline]
  36. Link DP, Strandberg JD, Virmani R, Blashka K, Mourtada F, Samphilipo MA. Histopathologic appearance of arterial occlusion with hydrogel and polyvinyl alcohol embolic material in domestic swine. JVIR 1996; 7:897-905.[Medline]



This article has been cited by other articles:


Home page
 Am. J. Neuroradiol.Home page
J. Klisch, L. Yin, F. Requejo, B. Eissner, K. M. Scheufler, R. Kubalek, M. Buechner, A. Pagenstecher, H. Nagursky, and M. Schumacher
Liquid 2-Poly-Hydroxyethyl-Methacrylate Embolization of Experimental Arteriovenous Malformations: Feasibility Study
AJNR Am. J. Neuroradiol., March 1, 2002; 23(3): 422 - 429.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
T. Abruzzo, H. J. Cloft, G. G. Shengelaia, S. M. Waldrop, D. F. Kallmes, J. E. Dion, I. Constantinidis, and A. Sambanis
In Vitro Effects of Transcatheter Injection on Structure, Cell Viability, and Cell Metabolism in Fibroblast-impregnated Alginate Microspheres
Radiology, August 1, 2001; 220(2): 428 - 435.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
Y. P. Gobin, Y. Murayama, K. Milanese, K. Chow, N. R. Gonzalez, G. R. Duckwiler, and F. Vinuela
Head and Neck Hypervascular Lesions: Embolization with Ethylene Vinyl Alcohol Copolymer—Laboratory Evaluation in Swine and Clinical Evaluation in Humans
Radiology, November 1, 2001; 221(2): 309 - 317.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gobin, Y. P.
Right arrow Articles by Chow, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gobin, Y. P.
Right arrow Articles by Chow, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE