Intravascular tissue reactions induced by various types of bioabsorbable polymeric materials: correlation between the degradation profiles and corresponding tissue reactions.

INTRODUCTION: Several different bioabsorbable polymeric coil materials are currently used with the goal of improving treatment outcomes of endovascular embolization of intracranial aneurysms. However, little is known about the correlation between polymer degradation profiles and concomitant tissue responses in a blood vessel. The authors describe in vitro degradation characteristics of nine different polymeric materials and their corresponding tissue responses induced in rabbit carotid arteries. METHODS: Mass loss and molecular weight loss of nine commercially available bioabsorbable sutures were evaluated in vitro up to16 weeks. The same nine materials, as well as platinum coils, were implanted into blind-end carotid arteries (n = 44) in rabbits, and their tissue reactions were evaluated histologically 14 days after the implantation. RESULTS: Five of the nine polymers elicited moderate to strong tissue reactions relative to the remaining materials. While polymer mass loss did not correlate with their histologic findings, polymers that showed a faster rate of molecular weight loss had a tendency to present more active tissue reactions such as strong fibrocellular response around the implanted material with a moderate inflammatory cell infiltration. Maxon exhibited the fastest rate of molecular weight loss and poly-l-lactic acid the slowest. CONCLUSIONS: The rate of molecular weight loss may be an important factor that is associated with the degree of bioactivity when bioabsorbable polymers are implanted into blood vessels. For further quantitative analysis, additional experiments utilizing established aneurysm models need to be conducted.

Balloon-assisted transarterial embolization of intracranial dural arteriovenous fistulas.

OBJECT: The authors report their preliminary experience using a balloon-assisted technique (BAT) in the transarterial embolization of intracranial dural arteriovenous fistulas (DAVFs). METHODS: The authors reviewed the prospectively collected data obtained in 7 consecutive patients with DAVFs in whom embolization was achieved using transarterially injected Onyx with either the venous or arterial BAT. Procedures were performed at the Division of Interventional Neuroradiology at the University of California at Los Angeles Medical Center between September 2005 and January 2008. RESULTS: Three patients presented with cortical venous reflux and 4 did not. Three patients underwent transarterial Onyx-based embolization combined with transvenous balloon protection; the balloon was inflated in the transverse sinus in 2 of these patients and in the superior sagittal sinus in the third. One of them underwent an additional transarterial Onyx embolization with arterial BAT, whereas 4 other patients were treated with arterial BAT alone. The occipital artery was temporarily occluded with the balloon in 4 of these cases, whereas in the fifth, the authors used temporary balloon occlusion of the middle meningeal artery. Angiograms obtained immediately after embolization demonstrated complete or near-complete obliteration of the fistula in 6 patients and partial occlusion in 1 patient. There were no immediate or postprocedural complications. Two patients who presented with intracranial hemorrhage never suffered a second hemorrhage, and all other patients experienced either complete resolution or significant improvement of their symptoms. CONCLUSIONS: The BAT provides a new complementary method in the transarterial embolization of DAVFs that are not amenable to transvenous embolization. The venous BAT protects the patency of critical venous pathways, whereas the arterial BAT provides better control of the Onyx-based embolization.

Alteration of intraaneurysmal hemodynamics by placement of a self-expandable stent. Laboratory investigation.

OBJECT: Development of a flexible self-expanding stent system and stent-assisted coiling technique facilitates endovascular treatment of wide-necked brain aneurysms. The hemodynamic effect of self-expandable stent placement across the neck of a brain aneurysm has not been well documented in patient-specific aneurysm models. METHODS: Three patient-specific silicone aneurysm models based on clinical images were used in this study. Model 1 was constructed from a wide-necked internal carotid artery-ophthalmic artery aneurysm, and Models 2 and 3 were constructed from small wide-necked middle cerebral artery aneurysms. Neuroform stents were placed in the in vitro aneurysm models, and flow structures were compared before and after the stent placements. Flow velocity fields were acquired with particle imaging velocimetry. RESULTS: In Model 1, a clockwise, single-vortex flow pattern was observed in the aneurysm dome before stenting was performed. There were multiple vortices, and a very small fast flow stream was newly formed in the aneurysm dome after stenting. The mean intraaneurysmal flow velocity was reduced by approximately 23-40%. In Model 2, there was a clockwise vortex flow in the aneurysm dome and another small counterclockwise vortex in the tip of the aneurysm dome before stenting. The small vortex area disappeared after stenting, and the mean flow velocity in the aneurysm dome was reduced by 43-64%. In Model 3, a large, counterclockwise, single vortex was seen in the aneurysm dome before stenting. Multiple small vortices appeared in the aneurysm dome after stenting, and the mean flow velocity became slower by 22-51%. CONCLUSIONS: The flexible self-expandable stents significantly altered flow velocity and also flow structure in these aneurysms. Overall flow alterations by the stent appeared favorable for the long-term durability of aneurysm embolization. The possibility that the placement of a low-profile self-expandable stent might induce unfavorable flow patterns such as a fast flow stream in the aneurysm dome cannot be excluded.

Thrombus organization and healing in an experimental aneurysm model. Part II. The effect of various types of bioactive bioabsorbable polymeric coils.

OBJECT: Bioabsorbable polymeric material coils are being used in the endovascular treatment of aneurysms to achieve better thrombus organization than is possible using bare platinum coils. We used immunohistochemical and molecular biological analysis techniques in experimental aneurysms implanted with three different bioabsorbable polymer coils and platinum coils. METHODS: The degradation kinetics of nine polymer candidates for further analysis were first analyzed in vitro, and three materials with different degradation rates were selected. Seventy-four aneurysms were created in 37 swine using the venous pouch technique. The aneurysms were surgically implanted with one of the materials as follows (time points = 3, 7, and 14 days): Group 1, Guglielmi detachable coils (platinum); Group 2, Polysorb (90:10 polyglycolic acid [PGA]/polylactic acid); Group 3, Maxon (PGA/trimethylene carbonate); and Group 4, poly-l-lactic acid. Histological, immunohistochemical, and cDNA microarray analyses were performed on tissue specimens. RESULTS: Groups 1 and 4 showed minimal inflammatory response adjacent to the coil mass. In Group 2, Polysorb elicited a unique, firm granulation tissue that accelerated intraaneurysmal thrombus organization. In Group 3 intermediate inflammatory reactions were seen. Microarray analysis with Expression Analysis Sytematic Explorer software showed functional-cluster-gene activation to be increased at Day 7, preceding the histologic manifestation of polymer-induced granulation tissue at Day 14. A profile of expression changes in cytokine-related and extracellular membrane-related genes was compiled. CONCLUSIONS: Degradation speed was not the only factor determining the strength of the biological response. Polysorb induced an early, unique granulation tissue that conferred greater mechanical strength to the intraaneurysmal coilthrombus complex. Enhancing the formation of this polymer-induced granulation tissue may provide a new direction for improving long-term anatomical outcomes in cases involving aneurysms embolized with detachable coils.

Initial clinical experience with matrix detachable coils for the treatment of intracranial aneurysms.

OBJECT: The Matrix detachable coil is a new bioactive, bioabsorbable coil used in the endovascular embolization of intracranial aneurysms. It has a platinum core covered with a bioactive, bioabsorbable polymer (polyglycolic acid/lactide). The authors report on their initial midterm clinical experience with the first-generation Matrix detachable coil. METHODS: One hundred twelve patients harboring 118 aneurysms were treated using Matrix coils. Forty-nine aneurysms (41.5%) were associated with acute subarachnoid hemorrhage (SAH). Twenty-four lesions (49%) were harbored by patients with Hunt and Hess Grade I, 11 (23.4%) by patients with Grade II, eight (16.3%) by those with Grade III, and six (12.2%) by those with Grade IV. Four aneurysms (3.4%) were harbored by patients who had presented with nonacute SAH. Sixty-five aneurysms (55%) were unruptured. Fifty-seven lesions (48.3%) were small with a small neck, 29 (24.6%) were small with a wide neck, 30 (25.4%) were large, and two (1.7%) were giant. All patients were followed up to obtain angiography and clinical outcome data. Technical complications occurred in six patients: two thromboembolic complications and four aneurysm perforations. Of these six patients, the status of two deteriorated because of aneurysm perforation and another two because of thrombus formation (morbidity 3.6%). There were five deaths--one due to rerupture after embolization. Angiography follow-up studies of 87 aneurysms were obtained. Seventy aneurysms demonstrated progressive occlusion or a stable neck (80.5%), and 17 had some degree of recanalization (19.5%). The aneurysms originally diagnosed as a neck remnant showed a 15% rate of recanalization. CONCLUSIONS: Matrix coils can be delivered into aneurysms with technical complications similar to those encountered using GDCs. Midterm anatomical outcomes to date have shown moderate improvement in the recanalization rate when compared with those realized using the GDC system. Because of the increased friction associated with the first-generation Matrix coil, the packing density in most aneurysms was less than that achieved with GDCs. Prolonged angiography follow-up evaluations are needed to document long-term efficacy.

Healing of intracranial aneurysms with bioactive coils.

Inadequate healing is an important mechanism for aneurysm development and recanalization after embolization. Matrix coils have been shown by experimental studies to enhance vascular repair and fibrosis, thus reducing the risk of recanalization. The clinical application of Matrix coils represents the transition from pure mechanical occlusion to adjunct biologic healing of aneurysms. Our preliminary clinical experience reveals evidence of a healing response in aneurysms treated with Matrix coils. This technology can be further improved through the incorporation of new knowledge on the molecular pathogenesis of aneurysms and the cellular and molecular mechanisms of healing.

Matrix and bioabsorbable polymeric coils accelerate healing of intracranial aneurysms: long-term experimental study.

BACKGROUND AND PURPOSE: Acceleration of intra-aneurysmal clot organization and fibrosis may be a solution to preventing aneurysm recanalization after endovascular treatment. The purpose of this study was to evaluate the short-term efficacy and long-term safety of the new Matrix coil system. METHODS: Matrix coils consist of thin platinum coils covered with a bioabsorbable, polymeric material (polyglycolic acid/lactide). Fifty-two experimental aneurysms were created in 26 swine. All of the aneurysms were tightly packed with Matrix or Guglielmi detachable coils (GDC). Comparative angiographic and histopathologic data were analyzed at 2 weeks (n=14), 3 months (n=6), and 6 months (n=6) after embolization. RESULTS: Three aneurysms treated with GDC ruptured despite tight packing. No recanalization or rupturing was observed in the aneurysms embolized with Matrix coils. At 14 days after embolization, the aneurysms treated with Matrix coils exhibited a more extensive area of organized thrombus when compared with the aneurysms treated with GDC (87% versus 75%, P=0.008, n=11). At 3 months, both Matrix and GDC-treated aneurysms demonstrated complete clot organization. Neck tissue thickness was higher in Matrix-treated aneurysms at 14 days and 3 months, but not at 6 months. No untoward parent artery stenosis was observed in aneurysms treated with Matrix during follow-up. The angiographic cross-sectional area of the Matrix-treated aneurysms was smaller than those treated with GDC at the 3 months. CONCLUSIONS: Matrix accelerated aneurysm fibrosis and neointima formation without parent artery stenosis. The Matrix system might prevent aneurysmal recanalization after endovascular treatment of cerebral aneurysms.

Cellular responses of bioabsorbable polymeric material and Guglielmi detachable coil in experimental aneurysms.

BACKGROUND AND PURPOSE: Acceleration of healing mechanisms is a promising approach to improve current limitations of endovascular aneurysm therapy with the use of platinum coils. We evaluated a new endovascular therapeutic, bioabsorbable polymeric material (BPM), which may promote cellular reaction in the aneurysms. METHODS: Four different concentrations of lactide/glycolic acid copolymer [poly(D-L-lactic-co-glycolic acid)] (PLGA), 85/15, 75/25, 65/35, and 50/50, were used as BPMs. Sixteen experimental aneurysms were created in 8 swine. Eight-millimeter-long spiral-shaped BPMs were surgically implanted in the aneurysms without tight packing (n=3 for each BPM). Guglielmi detachable coils (GDCs) were used as control (n=4). The animals were killed 14 days after embolization, and angiographic, histological, and immunohistochemical analyses were performed. RESULTS: Despite loose packing of aneurysms with BPMs, faster BPMs such as 50/50 or 65/35 PLGA demonstrated more mature collagen formation and fibrosis in the sac and neck of the aneurysm. One aneurysm treated with 65/35 PLGA, 1 treated with 75/25 PLGA, and all 3 treated with 85/15 PLGA showed a neck remnant on angiography. There was a linear relationship between collagen levels and polymer degradation properties (r=-0.9513). CONCLUSIONS: This preliminary animal study indicates that acceleration of aneurysm healing with the use of BPM is feasible. This concept can be applied to decrease and perhaps prevent aneurysmal recanalization after endovascular treatment of cerebral aneurysms.

Onyx embolization of anterior condylar confluence dural arteriovenous fistula.

The anterior condylar confluence (ACC) is a small complex venous structure located medial to the jugular vein and adjacent to the hypoglossal canal. To our knowledge, this is the first report of transvenous Onyx embolization for ACC dural arteriovenous fistula (DAVF). Three patients with ACC DAVF were treated using the Onyx liquid embolic agent with or without detachable coils. Complete angiographic obliteration of the fistulas was achieved in all cases without permanent lower cranial neuropathy. This report suggests that the controlled penetration of Onyx is advantageous in order to obliterate ACC DAVFs with a small amount of embolic material.

Comparison of simulated structural deformation with experimental results after Wingspan stenting.

OBJECTIVES: Biomechanical stress distribution correlates with the biological responses after stenting. Computational analyses have contributed to the optimization of stent geometry. In particular, structural analysis based on pre-operative angiography can be used to predict the stent-artery interaction before endovascular treatments. However, the simulated results need to be validated. In this report, we compared the simulated arterial structure with post-operative images after an intracranial Wingspan stent. METHODS: A Wingspan stent was deployed at a slightly curved ascending pharyngeal artery (APA) in the swine. Using a finite element method (FEM), the configuration after stenting was simulated and quantitatively compared with post-procedural 3D angiography. RESULTS: The finite element analysis demonstrated arterial straightening after stenting. The simulated images were similar to the experimental results with respect to the curvature index of the center line and the cross-sectional areas. CONCLUSION: We assessed the simulated structural deformation after Wingspan stenting, by comparison with experimental results.

Onyx embolization of anterior condylar confluence dural arteriovenous fistula.

The anterior condylar confluence (ACC) is a small complex venous structure located medial to the jugular vein and adjacent to the hypoglossal canal. To our knowledge, this is the first report of transvenous Onyx embolization for ACC dural arteriovenous fistula (DAVF). Three patients with ACC DAVF were treated using the Onyx liquid embolic agent with or without detachable coils. Complete angiographic obliteration of the fistulas was achieved in all cases without permanent lower cranial neuropathy. This report suggests that the controlled penetration of Onyx is advantageous in order to obliterate ACC DAVFs with a small amount of embolic material.

Flow control techniques for Onyx embolization of intracranial dural arteriovenous fistulae.

OBJECTIVES: Experience of flow control techniques during endovascular treatment of intracranial dural arteriovenous fistulas (DAVFs) using the Onyx liquid embolic system is reported, with an emphasis on high flow shunts. METHODS: Data were evaluated in patients with DAVFs treated endovascularly with Onyx. Adjunctive techniques with coils, acrylics and balloon assistance were utilized to reduce the rate of flow with transarterial and transvenous approaches. RESULTS: The following types of adjunctive techniques were used in 58 patients who underwent a total of 84 embolization sessions with Onyx: transvenous coiling with transvenous or transarterial Onyx embolization in 36 patients, transarterial coiling with transarterial Onyx embolization in eight patients, arterial or venous balloon assisted technique with transarterial or transvenous Onyx embolization in 11 patients, transarterial high concentration acrylics with transarterial Onyx embolization in one patient and staged transarterial or transvenous coiling and Onyx embolization in two patients. Complete obliteration of the fistulae was achieved in 41 patients (70.7%) and 27 patients (65.9%) with high flow fistulae after endovascular treatment alone. Periprocedural complications were encountered in 16 patients, and 13 complications were associated with the adjunctive techniques. There were four neurologic and two non-neurologic clinical sequelae. Distal Onyx migration occurred in four, microcatheter retention in three and cranial neuropathy in three patients. There was one instance each of cerebellar hemorrhage, thromboembolism, coil stretching and retention, and dissection. 56 survivors experienced complete resolution or significant improvement of their symptoms on follow-up. CONCLUSIONS: Flow control techniques are safe and effective adjunctive methods in primary endovascular Onyx embolization of high flow DAVFs.

Thin film nitinol microstent for aneurysm occlusion.

Thin film nitinol produced by sputter deposition was used in the design of microstents intended to treat small vessel aneurysms. Thin film microstents were fabricated by "hot-target" dc sputter deposition. Both stress-strain curves and differential scanning calorimetry curves were generated for the film used to fabricate stents. The films used for stents had an A(f) temperature of approximately 36 degrees C allowing for body activated response from a microcatheter. The 10 microm film was only slightly radio-opaque; thus, a Td marker was attached to the stents to guide fluoroscopic delivery. Thin film microstents were tested in a flow loop with and without nitinol support skeletons to give additional radial support. Stents could be compressed into and easily delivered with <3 Fr catheters. Theoretical frictional and wall drag forces on a thin film nitinol small vessel vascular stent were calculated, and the radial force exerted by thin film stents was evaluated theoretically and experimentally. In vivo studies in swine confirmed that thin film nitinol microstents could be deployed accurately and consistently in the swine cranial vasculature.

A rabbit model for efficacy evaluation of endovascular coil materials.

BACKGROUND: To investigate biomaterials seeking for their possible use for aneurysm treatment, in vivo screening tests using a number of potential materials are required. However, there is no established animal model that is suitable for such purpose. Some models require special preparation of tested materials for transcatheter delivery and others are inappropriate in view of their cost-effectiveness. The purpose of this study is to establish an animal model that overcomes these limitations and help us select potential materials before the preclinical evaluation. METHODS: Bilateral CCAs in a rabbit were surgically ligated, and a 2-cm segment of either a bare platinum coil or a polymeric coil (a platinum coil coated with PLGA 10/90) was implanted into each blind-ended arterial segment (n = 26). They were harvested at day 1, 7, 10, 14, or 30, respectively. Angiographic and histologic evaluations as well as quantitative analysis on the development of the organized thrombus were performed. RESULTS: One day after the implantation, both platinum and PLGA coils were surrounded by immature thrombus that was induced by blood flow stagnation in the arterial segment. At day 7, minimal thrombus organization was observed around both types of materials. At postimplantation days 10 and 14, fibrocellular responses, the early findings of the thrombus organization process, were observed in both material groups. Such histologic findings were more prominent in the PLGA coil group as compared to the platinum coil group (day 10, P = .051; day 14, P = .011). Well-organized thrombus was observed in both material groups at day 30 without showing statistical difference (P = .12). CONCLUSION: Given the cost-effectiveness, the simple material preparation process, and its feasible histologic evaluation methods, this new animal model can be useful in screening other potential biomaterials for the development of new coil devices.

Endovascular treatment of experimental aneurysms using a combination of thermoreversible gelation polymer and protection devices: feasibility study.

OBJECTIVE: We developed a new liquid embolic agent, an aqueous solution of thermoreversible gelation polymer (TGP) for the treatment of cerebral aneurysms. This polymer solution has the unique characteristics that allow it to solidify at a specific temperature without solvent. We performed an experimental aneurysm embolization using this liquid embolic agent with and without different protective devices to evaluate its technical feasibility for the treatment of aneurysms. METHODS: Fourteen side-wall aneurysms were surgically constructed on 14 common carotid arteries of 7 swine. Embolizations were conducted in combination with balloon protection (balloon group, n = 4), microstent protection (stent group, n = 4), and microcoil and microstent protection (stent-coil group, n = 4). Two aneurysms were used as controls. One control aneurysm was not embolized, and the other received control stent placement only. Angiographic follow-up was performed on day 14 and was followed by histopathological evaluation. RESULTS: Successful TGP solution delivery was conducted in all cases. Complete aneurysm occlusion was achieved in all cases without TGP migration. Follow-up angiograms demonstrated complete occlusion in the stent and stent-coil groups. A small recurrence was observed in the balloon group. Histopathological findings demonstrated neoendothelialization across the necks of the aneurysms. CONCLUSION: Experimental aneurysms were safely embolized using TGP. Further modifications related to mechanical stability and long-term safety evaluation results are necessary before clinical application.

Transarterial embolization of clival dural arteriovenous fistulae using liquid embolic agents.

OBJECTIVE: Dural arteriovenous fistulae (DAVFs) rarely involve the clivus. This report examines the clinical presentation, angiographic findings, endovascular management, and outcome of clival DAVFs. Particular attention was given to safety and efficacy of transarterial embolization using liquid embolic agents. METHODS: We reviewed the clinical and radiological data of 10 patients with spontaneous clival DAVFs who were treated endovascularly at the University of California at Los Angeles Medical Center between 1992 and 2006. RESULTS: Nine patients presented with ocular symptoms and one patient experienced pulsatile tinnitus. Cerebral angiograms showed that these clival DAVFs were supplied by multiple branches of the internal and external carotid arteries. The patterns of venous drainage were from the clival veins to the cavernous sinus and superior ophthalmic vein in nine patients and to the inferior petrosal sinus in two patients. Six clival DAVFs were embolized transarterially through the clival branches of the ascending pharyngeal artery. Onyx 18 (Micro Therapeutics Inc., Irvine, CA) was used in three patients and n-butyl cyanoacrylate was used in three patients. Immediate complete angiographic obliteration was achieved in three patients. All six patients experienced an angiographic and clinical cure without any complications at 3 months. Two patients were incompletely treated using particles and coils for the relief of the symptoms. Two other patients were completely treated after the recipient clival venous structures were occluded transvenously with coils. CONCLUSION: Clival DAVFs can be misdiagnosed as dural cavernous sinus fistulae. The best treatment is transarterial embolization of the dural feeders using liquid embolic agents. Transvenous occlusion of the cavernous sinus is unnecessary in most cases.