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Experimental Studies |
1 From the Departments of Radiology (D.F.K., T.A.A., H.M.D.), Neurological Surgery (G.A.H., S.B.H.), and Pathology (J.W.M.), University of Virginia Health Services, Box 170, Charlottesville, VA 22908; and the Department of Radiology, Emory University, Atlanta, Ga (H.J.C.). Received September 22, 1998; revision requested November 20; revision received January 19, 1999; accepted April 30. T.A.A. supported in part by the RSNA Research and Education Foundation as a 1997 Research Resident. D.F.K. supported in part by the RSNA Research and Education Foundation as a 1997 Bracco/RSNA Scholar. Address reprint requests to D.F.K. (e-mail: dfk3b@virginia .edu).
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Abstract |
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MATERIALS AND METHODS: Saccular aneurysms were created in New Zealand White rabbits by using vessel ligation with intraluminal elastase incubation. Aneurysms were subsequently embolized by using platinum coils. Subjects were sacrificed at various intervals up to 12 weeks following coil embolization. The aneurysm cavities and adjacent vessels were embedded in methylmethacrylate, were sectioned, and were stained for histologic examination.
RESULTS: Two weeks following coil implantation, aneurysms were filled predominantly with unorganized thrombus. Six weeks following coil implantation, histologic features included complete filling of the aneurysm lumen with either prominent laminated but unorganized thrombus or areas of unorganized thrombus interspersed among areas of cellular infiltration. At 12 weeks following coil implantation, aneurysms were filled with the loosely packed, disordered cells contained within the extracellular matrix. Fibrosis or smooth muscle cell infiltration was not present in any of the 6- or 12-week samples.
CONCLUSION: Platinum coils placed into experimental saccular aneurysms in New Zealand White rabbits failed to elicit a fibrotic response. This model can be used for the testing of biologic modifications of platinum coils aimed at increasing intraaneurysmal fibrosis.
Index terms: Aneurysm, carotid, 172.73, 904.73 • Aneurysm, therapy, 172.1264, 904.1264, 904.73 • Carotid arteries, therapeutic blockade, 172.1264, 904.1264
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Introduction |
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Preclinical testing of modified coils will require animal models of aneurysms that closely simulate the behavior of intracranial aneurysms in humans. The ideal aneurysm model would (a) demonstrate long-term patency in untreated control specimens; (b) be constructed in a species with a coagulation system similar to that of humans; (c) simulate bifurcation, terminal, or other aneurysm morphologies that subject the neck of the aneurysm to high shear stress; (d) be constructed in vessels of a size similar to that of intracranial vessels in humans; (e) be constructed without local surgery to minimize the healing response that might cloud experiments aimed at increasing the biologic activity of the implanted coils; and (f) simulate the limitations encountered in the embolization of human aneurysms with the Guglielmi detachable coil (ie, aneurysm neck regrowth and coil compaction in the setting of imperfect aneurysmal fibrosis after embolization with standard coils). The presence of a venous rather than arterial wall in the aneurysm and the presence of suture material in the aneurysm neck have an unknown effect on the biologic milieu of the aneurysm; ideally, these should be avoided when testing biologic modifications to the coils.
The purpose of this study was to characterize the histologic findings after platinum coil embolization of nonsurgical, elastase-induced, saccular aneurysms in a rabbit model. We propose this model as a preclinical tool for the evaluation of emerging biologic modification techniques for platinum coils.
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MATERIALS AND METHODS |
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With sterile technique, the right or left common carotid artery was exposed at surgery. Proximal and distal control of the vessel was obtained by using a 4.0 silk suture. A 1–2-mm bevelled arteriotomy was made, and a 4-F vascular sheath (Cordis Endovascular, Miami Lakes, Fla) was passed in retrograde fashion into the midportion of the common carotid artery (Fig 1a). Iodinated contrast material (Omnipaque 300 [iohexol]; Nycomed Amersham, Princeton, NJ; 2–3 mL) was injected through the sheath into the common carotid artery to serve as a guide for subsequent balloon positioning.
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Thus, naturally occurring arterial trifurcations and bifurcations were transformed into bifurcation aneurysms and aneurysms along a prominent curve of the parent vessel, respectively. Both of these transformations resulted in high shear stresses across the aneurysm neck. We used the arterial bifurcation of the right subclavian artery and right common carotid artery to create a right common carotid arterial aneurysm (Fig 1b, 1d), or we used the arterial trifurcation of the brachiocephalic trunk, left common carotid artery, and aortic arch to create a left common carotid arterial aneurysm (Fig 1c).
Coil Embolization Procedures
Our long-term goal was to use the animal model to test biologic modifications in embolic devices that were designed to promote improvements in intraaneurysmal fibrosis. As such, it was imperative that the model demonstrate suboptimal fibrosis when it was treated with standard platinum coils. Toward this end, we planned the coil procedures to yield relatively loose coil packing, with the assumption that the low-density coil packing would help to delay or inhibit intraaneurysmal fibrosis.
Anesthesia was induced with an intramuscular injection of ketamine and xylazine followed by maintenance anesthesia with intravenous pentobarbital sodium. By using sterile technique, the right common femoral artery was exposed at surgery. The artery was ligated distally by using 4.0 silk suture, and a 22-gauge catheter was advanced in retrograde fashion into the artery. A 0.018-inch–diameter guide wire was passed through the catheter, and serial dilations of the artery were performed prior to placement of a 4-F vascular sheath. Heparin (Elkins-Sinn, Cherry Hill, NJ; 100 U/kg) was administered intravenously. A 4-F catheter (Cordis Endovascular) was advanced into the aneurysm cavity.
By using the coaxial technique, with continuous flushing with a heparin and normal saline solution, a two-marker microcatheter (Tracker 10; Boston Scientific Target) was advanced into the aneurysm cavity. The size of the aneurysm cavity was assessed by means of direct comparison with radiopaque sizing devices. The aneurysm was embolized with one or two T10 soft or T10 Guglielmi detachable coils, depending on aneurysm diameter. After coil embolization, the catheters were removed. The vascular sheath was removed, and the proximal aspect of the femoral artery was ligated with 4.0 silk suture. The skin was closed with a running suture. Animals were allowed to recover and were sacrificed at 2 (n = 3), 6 (n = 6), or 12 weeks (n = 2) after embolization.
Histologic Evaluation
At the time of sacrifice, the subjects were deeply anesthetized. Surgical access of the left common femoral artery was achieved, with a method similar to that used to access the right common femoral artery, as described previously. A 4-F catheter was placed into the aortic arch, and digital subtraction angiography was performed. Immediately after angiography, the subjects were sacrificed by using a lethal injection of pentobarbital. Saline and then formalin were rapidly injected through the indwelling catheter. The mediastinum was dissected, and the aortic arch and proximal great vessels, including the coil-embolized segment of artery, were exposed and dissected free from surrounding tissues. The tissue was immediately placed in formalin. After fixation for at least 24 hours, samples were embedded in methylmethacrylate, sectioned with a tungsten carbide knife (Microedge; Dorn and Hart, Villa Park, Ill) at 30-mm increments, and stained with hematoxylin-eosin. Sections were viewed by an experienced pathologist (J.W.M.) who paid particular attention to the cell type and the appearance of the extracellular matrix within and around the coil mass.
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RESULTS |
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Six-week Implantation
Among the samples harvested 6 weeks after coil implantation, two distinct histologic patterns were noted. In two of these samples (subjects 4 and 5) prominent laminations of thrombus in various stages of breakdown were present, and hemosiderin staining was noted (Fig 3, Table). Coil winds were found primarily along the periphery of the aneurysms, and small areas of cellular infiltration were present adjacent to some coil winds. The morphology of these cells was somewhat similar to that of the vessel wall. Many coil winds, however, were surrounded by involuting thrombus alone.
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DISCUSSION |
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Since we noted a progression from unorganized thrombus in early samples to greater degrees of infiltration with the loose matrix in later samples, we hypothesize that the matrix represents the transformation of blood elements, such as macrophages, into other cellular components. The finding of focal areas of hemosiderin deposition scattered throughout the matrix supported this hypothesis. In any event, because of the dearth of fibrosis noted after short-, medium-, and long-term coil embolization, our model is valid for the testing of biologic modifications to the Guglielmi detachable coil, which are aimed at improving intraaneurysmal fibrosis. Such modifications include but are not limited to the addition of collagen fibers, collagen coatings, ion implantation, and fibroblast allografts to the coil (9–14).
In a single subject, we noted prompt filling of the aneurysm cavity with cells that resembled the smooth muscle cells of the vessel wall. This sample was the smallest-diameter aneurysm used in this study. In previous work, we showed that the placement of the Guglielmi detachable coil into normal arteries resulted in complete obliteration of the vessel lumen with smooth muscle cells within 1 month of coil placement (unpublished data, 1998). The small aneurysm used in our study probably had imperfect elastin degradation, and thus the aneurysm reacted in a fashion similar to that of normal vessels. In the larger aneurysms used in our study, there was an absence of ingrowth of smooth muscle cells. The explanation for rapid ingrowth of smooth muscle cells in small aneurysms may relate to the ability of the vessel wall to contract around the coil. The elastase-induced degradation of the elastic lamina in the large aneurysms may prevent vessel contraction and thus smooth muscle ingrowth.
Although there is a relative dearth of histologic data for human aneurysms treated with the platinum coils, available evidence suggests that, at least in large aneurysms, the intraluminal thrombus remains chronically unorganized (15,16). Intraaneurysmal fibrosis would be considered desirable since it might combat the compaction of coils and also stimulate regrowth of the endothelium across the neck of the aneurysm. The exact mechanism that impedes the formation of organized thrombus in human aneurysms treated with the platinum coils remains unknown. Even so, the availability of an animal model that demonstrates persistence of unorganized thrombus and lack of intraaneurysmal fibrosis would facilitate the testing of coil modifications.
Large animal models, including canine and swine models, have been used extensively for preclinical testing of endovascular devices (9–12,17–24). Model aneurysms in these species are created surgically, with either a sidewall or terminal aneurysm morphology. Although canine sidewall aneurysms demonstrate high rates of patency, these aneurysms fail to recreate the morphologic and hemodynamic characteristics of most human intracranial aneurysms. In addition, we and others (23) have found that surgically created, sidewall canine aneurysms embolized with the Guglielmi detachable coil demonstrate extensive fibrosis and the formation of new vessels around the coil mass, even when embolization is delayed for longer than 1 month after their creation. As a result, these models cannot be used to test coil modifications aimed at improving intraaneurysmal fibrosis because fibrosis within the aneurysm is complete with the standard Guglielmi detachable coil.
Rabbits have been used previously for the creation of model aneurysms (25–32). Long-term patency has been shown in a small number of these surgically created, vein-pouch bifurcation aneurysms. However, the surgical procedure is lengthy (26), and high rates of mortality and inadvertent parent artery occlusion are seen (29). Furthermore, the vessel wall is venous rather than arterial, and an extensive healing response to the surgery would be expected in the local environment of the aneurysm. This healing response may cloud the effect of biologic modifications to platinum coils.
Elastase-induced aneurysms in rabbits have been reported previously. Cawley et al (25) used intraluminal elastase incubation of the stump of the external carotid artery to create rabbit aneurysms that, unlike those in our model, are sidewall in nature and far removed from the aortic arch, where flow rates and shear stress would be less than those in our model.
In our study, we did not attempt to achieve maximal packing of the aneurysms with coils. Our purpose in the development of the model was to simulate the histologic findings seen in large human aneurysms that are treated with the Guglielmi detachable coil, where incomplete packing of coils is typical and unorganized thrombus is present chronically. We have demonstrated the persistence of unorganized thrombus in our animal model in the setting of loose coil packing, and this scenario will allow testing of biologic modifications to the Guglielmi detachable coil. This study was not designed to determine coil compaction and aneurysm neck regrowth in this aneurysm model.
Immunohistochemical staining might have allowed us to identify with greater precision the origins of the various cells seen within the aneurysms. Unfortunately, immunohistochemical staining of methylmethacrylate-embedded samples is difficult. Last, we did not include angiographic follow-up as a part of this experiment. Our primary interest was that of determining the histologic reaction to the coils rather than coil morphology, to provide a sound foundation from which future studies can be conducted to examine the effects of targeted biologic modifications of the coils.Practical application: Because the standard platinum coil did not elicit a fibrotic response in our aneurysm model, it can be used to test embolic devices that are designed to improve intraaneurysmal fibrosis.
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Acknowledgments |
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Footnotes |
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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