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BACKGROUND AND PURPOSE: Identifying and predicting which aneurysms are likely to quickly occlude and which ones are likely to remain open following treatment with flow-diverting devices is important to develop optimal patient management strategies. The purpose of this study was to evaluate predictions based on computational fluid dynamics models using the elastase rabbit aneurysm model. MATERIALS AND METHODS: A series of 13 aneurysms created in rabbits were treated with flow diverters, and outcomes were angiographically assessed at 8 weeks’ follow-up. Computational fluid dynamics models were constructed from pretreatment 3D rotational angiograms and Doppler ultrasound flow velocity measurements. Postimplantation mean aneurysm inflow rate and flow velocity were used to prospectively predict aneurysm occlusion blinded to the actual outcomes. Specifically, if both variables were below their corresponding thresholds, fast occlusion was predicted, while if one of them was above the threshold, slow or incomplete occlusion was predicted. RESULTS: Of the 13 aneurysms included, 8 were incompletely occluded 8 weeks after treatment, and 5 were completely occluded. A total of 10 computational fluid dynamics–based predictions agreed with the angiographic outcome, reaching 77% accuracy, 80% sensitivity, and 75% specificity. Posttreatment mean velocity alone was able to achieve the same predictive power as the combination of inflow rate and velocity. CONCLUSIONS: Subject-specific computational fluid dynamics models of the hemodynamic conditions created immediately after implantation of flow-diverting devices in experimental aneurysms created in rabbits are capable of prospectively predicting, with a reasonable accuracy, which aneurysms will completely occlude and which ones will remain incompletely occluded.

Background Flow diverters (FDs) are an effective treatment for intracranial aneurysms, though not free from hemorrhagic complications. A previous study demonstrated increased vascular contractility after FD-implantation as a potential mechanism of distal complications. Our study aimed to investigate whether L-arginine medication affects vascular contractility following FD deployment in a rabbit model. Methods FDs were implanted in the aorta of normal rabbits (+FD, n = 10), with sham-operated aorta as controls (n = 5). L-Arginine was given in the drinking water (2.25% L-arginine hydrochloride) of half of the +FD animals (+FD/+Arg). Force contraction vascular contractility studies were performed on the aortic rings proximal and distal to the FD using an organ bath. Total eNOS, eNOS(pS1177), eNOS(pT495), COX-2, and S100A4 were quantified by western analysis on total protein lysates from aortic segments, normalizing to GAPDH. Results Mean vascular contractility was 53% higher in distal relative to proximal aortic segments (P = 0.0038) in +FD animals, but were not significantly different in +FD/+Arg animals, or in sham-operated controls. The +FD animals expressed significantly reduced levels of eNOS(pS1177) than sham-operated controls (P = 0.0335), while both the +FD and +FD/+Arg groups had reduced levels of eNOS(pT495) relative to sham-operated controls (P = 0.0331 and P = 0.0311, respectively). Conclusion These results suggest that L-arginine medication reduces distal vascular contractility after FD treatment via nitric oxide production and thus might mitigate risk for downstream complications.

BackgroundWEB Shape Modification (WSM) over time is frequent after aneurysm treatment. In this study, we explored the relationship between histopathological changes and angiographic evolution over time in experimental aneurysms in rabbits treated with the Woven EndoBridge (WEB) procedure.MethodsQuantitative WSM was assessed using flat-panel computed tomography (FPCT) during follow-up by calculating height and width ratio (HR, WR), defined as the ratio between either measurement at an index time point and the measurement immediately after WEB implantation. The index time point varied from 1 day to 6 months. HR and WR were evaluated with angiographic and histopathological assessments of aneurysm healing.ResultsFinal HR of devices varied from 0.30 to 1.02 and final WR varied from 0.62 to 1.59. Altogether, at least 5% of HR and WR variations were observed in 37/40 (92.5%) and 28/40 (70%) WEB devices, respectively, at the time of final assessment. There was no significant correlation between complete or incomplete occlusion groups and HR or WR (p=0.15 and p=0.43). Histopathological analysis revealed a significant association between WR and aneurysm healing and fibrosis 1 month following aneurysm treatment (both pConclusionUsing longitudinal FPCT assessment, we observed that WSM affects both the height and width of the WEB device. No significant association was found between WSM and aneurysm occlusion status. Although presumably a multifactorial phenomenon, the histopathological analysis highlighted a significant association between width variations, aneurysm healing and fibrosis in the first month following aneurysm treatment.

Background Growing data suggest that clot composition can impact revascularization outcomes and can potentially guide treatment strategies for stroke patients with large vessel occlusion. We performed an in vitro study to determine which magnetic resonance (MR) signaling characteristics correlate with clot compositions. Methodology A total of 25 clot analogs were prepared by mixing human plasma and red blood cells (RBCs) with five different combinations (five samples for each combination), namely, Group A, fibrin-rich (95% plasma:5% RBCs); Group B, fibrin-rich (75% plasma:25% RBCs); Group C, intermediate (50% plasma:50% RBCs); Group D, RBC-rich (25% plasma:75% RBCs), and Group E, RBC-rich (5% plasma:95% RBCs). The prepared samples were then scanned with quantitative T2* mapping, T2 fast spin-echo (FSE), T2 gradient-echo (GRE), fluid-attenuated inversion recovery (FLAIR), and susceptibility-weighted angiography (SWAN). Thrombus-T2* relaxation time (TT2*RT) and signal intensity (SI) from different scanning sequences were measured in all groups. SIs between different groups were compared using a one-way analysis of variance. Correlation between TT2*RT and SI was determined using the Pearson correlation test. Results The average TT2*RT decreased from 126 ms to 37 ms from fibrin-rich to RBC-rich clots (Groups A to E). Mean SIs of Groups D and E were lower than Groups A, B, and C on T2 mapping, T2 FSE, T2 GRE, FLAIR, and SWAN images (p < 0.00001). TT2*RT and SI were positively correlated on T2 mapping (R = 0.9628, p = 0.009). Conclusion Different compositions of blood clots can show different TT2*RT and SI on MR imaging. Quantitative T2* mapping and multicontrast MR scanning can help in the characterization of clots causing large vessel occlusion, which is useful to establish treatment strategies for stroke patients.

BACKGROUND: Rupture of brain aneurysms is associated with high fatality and morbidity rates. Through remodeling of the collagen matrix, many aneurysms can remain unruptured for decades, despite an enlarging and evolving geometry. OBJECTIVE: Our objective was to explore this adaptive remodeling for the first time in an elastase induced aneurysm model in rabbits. METHODS: Saccular aneurysms were created in 22 New Zealand white rabbits and remodeling was assessed in tissue harvested 2, 4, 8 and 12 weeks after creation. RESULTS: The intramural principal stress ratio doubled after aneurysm creation due to increased longitudinal loads, triggering a remodeling response. A distinct wall layer with multi-directional collagen fibers developed between the media and adventitia as early as 2 weeks, and in all cases by 4 weeks with an average thickness of 50.6 ± 14.3 μm. Collagen fibers in this layer were multi-directional (AI = 0.56 ± 0.15) with low tortuosity (1.08 ± 0.02) compared with adjacent circumferentially aligned medial fibers (AI = 0.78 ± 0.12) and highly tortuous adventitial fibers (1.22 ± 0.03). A second phase of remodeling replaced circumferentially aligned fibers in the inner media with longitudinal fibers. A structurally motivated constitutive model with both remodeling modes was introduced along with methodology for determining material parameters from mechanical testing and multiphoton imaging. CONCLUSIONS: A new mechanism was identified by which aneurysm walls can rapidly adapt to changes in load, ensuring the structural integrity of the aneurysm until a slower process of medial reorganization occurs. The rabbit model can be used to evaluate therapies to increase aneurysm wall stability.

Thromboembolism in the cerebrovasculature can cause high morbidity and mortality. Embolectomy is one of the emergency procedures performed to remove emboli; however, the approach such as aspiration or stent retriever are empirically selected. An inappropriate selection of approach can influence the success rate during embolectomy and affect levels of brain damage. Therefore, understanding the composition of clots and their mechanical properties can lead to an appropriate treatment strategy for physicians. In this study, we investigated how the composition of human clots can affect their mechanical properties as quantified using acoustic radiation force optical coherence elastography (ARF-OCE) in a non-contact manner. Five red blood cells (RBCs) concentrations were fabricated from fibrin rich (21% RBC) to RBC rich (95% RBC). A 7.5 MHz highly focused transducer was used to provide acoustic radiation force exerted on the surface of the clots and an optical coherence tomography system was used to measure the wave propagation. The study showed that the trend of the wave velocities decreased with the RBC concentration increased. The study demonstrated that ARF-OCE could be a promising tool to quantify the mechanical properties of clots to inform treatment strategy for clinical interventionalists.

Thromboembolism in a cerebral blood vessel is associated with high morbidity and mortality. Mechanical thrombectomy (MT) is one of the emergenc proceduresperformed to remove emboli. However, the interventional approaches such as aspiration catheters or stent retriever are empirically selected. An inappropriate selection of surgical devices can influence the success rate during embolectomy, which can lead to an increase in brain damage. There has been growing interest in the study of clot composition and using a priori knowledge of clot composition to provide guidance for an appropriate treatment strategy for interventional physicians. Developing imaging tools which can allow interventionalists to understand clot composition could affect management and device strategy. In this study, we investigated how clots of different compositions can be characterized by using acoustic radiation force optical coherence elastography (ARF–OCE) and compared with ultrasound shear wave elastography (SWE). Five different clots compositions using human blood were fabricated into cylindrical forms from fibrin-rich (21% red blood cells, RBCs) to RBC-rich (95% RBCs). Using the ARF–OCE and SWE, we characterized the wave velocities measured in the time-domain. In addition, the semi-analytical finite element model was used to explore the relationship between the phase velocities with various frequency ranges and diameters of the clots. The study demonstrated that the wave group velocities generally decrease as RBC content increases in ARF–OCE and SWE. The correlation of the group velocities from the OCE and SWE methods represented a good agreement as RBC composition is larger than 39%. Using the phase velocity dispersion analysis applied to ARF–OCE data, we estimated the shear wave velocities decoupling the effects of the geometry and material properties of the clots. The study demonstrated that the composition of the clots can be characterized by elastographic methods using ARF–OCE and SWE, and OCE demonstrated better ability to discriminate between clots of different RBC compositions, compared to the ultrasound-based approach, especially in clots with low RBC compositions.

BackgroundTo develop a preclinical thromboembolic occlusion model for studying revascularization strategies.MethodsClot analog with barium sulfate was injected into the distal aorta in 9 New Zealand white rabbits. The situation of aorta occlusion was compared among fibrin-rich (n=4), red blood cell (RBC)-rich (n=3), and whole blood clot analogs (n=2) using digital subtraction angiography. Arterial geometries, histologic features and circumferential stretch of the distal aorta in rabbits were compared with the common carotid artery in swine and the distal internal carotid artery (ICA) in humans. Aspiration thrombectomy and mechanical thrombectomy using a stent retriever were performed in two rabbits.ResultsThe aortic bifurcation was occluded after a single delivery of clot in 4 cases. It was occluded after the second clot injection in the 5 remaining rabbits. Fragmentation of RBC-rich clots occurred during clot injection in 2 cases. The mean diameters of the distal aorta and right common iliac artery in rabbits were 3.7±0.4 and 2.8±0.3 mm, respectively; the mean diameters of human ICA, and first and second segments of the middle cerebral artery (M1, M2) were 3.6±0.4, 3.1±0.4, and 2.4±0.4 mm, respectively. Arterial revascularization was achieved in both rabbits. Geometric, mechanical and histological factors of the distal aorta in rabbit were more close to human distal ICA than swine carotid artery.ConclusionArterial occlusion can be achieved at the aortic bifurcation in rabbits, which is comparable to human ICA bifurcation. This thrombectomy model has the potential to be used for testing of thrombectomy devices.

Embolectomy is one of the emergency procedures performed to remove emboli. Assessing the composition of human blood clots is an important diagnostic factor and could provide guidance for an appropriate treatment strategy for interventional physicians. Immunostaining has been used to identity compositions of clots as a gold-standard procedure, but it is time-consuming and cannot be performed in situ. Here, we proposed that the optical attenuation coefficient of optical coherence tomography (OCT) can be a reliable indicator as a new imaging modality to differentiate clot compositions. Fifteen human blood clots with multiple red blood cell (RBC) compositions from 21% to 95% were prepared using healthy human whole blood. A homogeneous gelatin phantom experiment and numerical simulation based on the Lambert-Beer's law were examined to verify the validity of the attenuation coefficient estimation. The results displayed that optical attenuation coefficients were strongly correlated with RBC compositions. We reported that attenuation coefficients could be a promising biomarker to guide the choice of an appropriate interventional device in a clinical setting and assist in characterizing blood clots.

BackgroundCT is the most commonly used imaging modality for acute ischemic stroke evaluation. There is growing interest to use pre-operative imaging to characterize clot composition in stroke. We performed an in-vitro study examining the ability of various CT techniques in differentiation between different clot types.MethodsFive clot types with varying fibrin and red blood cells (RBCs) densities (5% RBC and 95% fibrin; 25% RBC and 75% fibrin; 50% RBC and 50% fibrin; 75% RBC and 25% fibrin; 95% RBC and 5% fibrin) were prepared and scanned using various CT scanning protocols (single-energy, dual-energy, photon-counting detector CT, mixed images, and virtual monoenergetic images). Martius Scarlett Blue trichrome staining was performed to confirm the composition of each clot. Mean CT values of each type of clot under different scanning protocol were calculated and compared.ResultsMean CT values of the CT numbers in the five clot specimens for 5%, 25%, and 50% RBC clot were similar across modalities, and increased significantly for 75% and 95% RBC clots (PConclusionMono +50 keV dual-energy CT scan may be helpful for differentiating between RBC-rich and fibrin-rich thrombi seen in large-vessel occlusion patients.

Purpose Optical coherence tomography (OCT) has been reported for potential use for differentiation of clot composition in cardiac patients. We tried to further validate its use for stroke patients using in-vitro clots with different percentage of red blood cells (RBCs) and fibrin. Methods Blood was collected from a healthy volunteer and separated into plasma, buffy-coat, and erythrocyte-rich layers after centrifugation. The plasma and erythrocytes were harvested separately and then recombined in controlled ratios to form five different clot analogues with 2% thrombin added (5 analogues for each composition): Group A, fibrin-rich (95% plasma:5% RBCs; Group B, fibrin-rich (75% plasma:25% RBCs); Group C, intermediate (50% plasma:50% RBCs); Group D, RBC-rich (25% plasma:75% RBCs,) and Group E, RBC-rich (5% plasma:95% RBCs). The blood mixture was injected in 6F guide angiographic catheter though a syringe. OPTISTM Integrated System (St. Jude Medical Inc., St. Paul, Minnesota) was used to perform OCT testing for each clot. A Dragonfly™ OPTIS™ imaging catheter (St. Jude Medical GmbH, St. Paul, Minnesota) was advanced into the catheter to pass the clot. The rate of automatic pullback was 0.5 mm/s. The blood clot was identified by OCT on mass images with different signal characters. OCT images were processed and analyzed according to the intensity of OCT signals from different compositions of clot. Results Homogeneous signal of clot was shown in all the clots in Group A and B, less signal attenuation from its surface to inside was noted, which indicated high penetration (low-back scattering). Intermediate signal attenuation from its surface to inside was shown in all the clots in Group C, in which some signals still existed at the periphery of the clot. Clot in Group D and E was superficial signal rich with more signal attenuation from its surface to inside, which indicated low penetration (high-back scattering). Three clots in Group E showed signal-free shadowing (figures A to E). Conclusion Different composition of clots can be assessed by OCT. Fibrin-rich clots have homogeneous signal with high penetration (low-back scattering), while RBC-rich clot can be recognized as superficial signal rich with low penetration (high-back scattering). Disclosures Y. Ding: None. M. Abbassi: None. D. Jakaitis: None. D. Dai: None. R. Kadirvel: None. D. Kallmes: None. W. Brinjikji: None.

Purpose There are growing data to suggest that clot composition can impact revascularization outcomes and strategies in large vessel occlusion patients. In many centers, MRI is the primary modality of acute stroke imaging so identifying clot composition on MRI imaging may be important. We performed an in vitro study to determine the MR signaling characteristics of stroke clots of various compositions. Methods Fifteen thrombus analogs of five compositions (n=3 for each composition) [Group A, fibrin-rich (95% plasma:5% RBCs); Group B, fibrin-rich (75% plasma:25% RBCs); Group C, intermediate (50% plasma:50% RBCs); Group D, RBC-rich (25% plasma:75% RBCs,) and Group E, RBC-rich (5% plasma:95% RBCs)] were scanned with fast spin-echo (FSE) T2WI (TR/TE 2500/101 milliseconds (ms)) and quantitative T2* mapping sequence. Signals from FSE T2WI were collected, and thrombus T2* relaxation time (TT2*RT) was measured in all the groups. Correlation between the thrombus-T2* relaxation time and red blood cell content was analyzed. Results Signal intensity changed gradually from high (bright) to low (dark) from Group A to E gradually from all the 3 clots in each group, which indicated the signal intensity was decreased as the composition of RBC increased. The average TT2*RT decreased from 60 ms (green) to 25 ms (red) from fibrin-rich clot to RBC-rich clot (Group A to E), which reflected inverse correlation between thrombus-T2* relaxation time and red blood cell content (figures A to E). Conclusion FSE T2 WI and quantitative T2* mapping MR can help in characterization of emboli in large vessel occlusion patients. Disclosures Y. Ding: None. M. Abbassi: None. J. Felmlee: None. D. Dai: None. R. Kadirvel: None. D. Kallmes: None. W. Brinjikji: None.

Background and Objective Notwithstanding the widespread implementation of flow diverters (FDs) in the treatment of intracranial aneurysms, the exact mechanism of action of these devices remains elusive. The aim of this study is to advance the understanding of cellular responses to FD implantation using a 3D tissue engineered in vitro aneurysm model. Methods Aneurysm-like blood vessel mimics (aBVMs) were constructed by first electrospinning polycaprolactone nanofibers on desired aneurysm-like geometries to create scaffolds. After conditioning, aBVMs were mounted into sterile bioreactor chambers and incubated with a cell culture media under steady state flow. Then aBVMs were sodded with human carotid smooth muscle cells (SMCs) followed by endothelial cells (ECs). Then, appropriately sized FDs (Pipeline Embolic Device, Medtronic, CA) were deployed in the parent vessel of aBVMs under fluoroscopic guidance, covering the neck. AVBMs with implanted flow diverters were cultivated for 7, 14 or 28 days (n=3 for each time point). En face immunofluorescence imaging of the aBVMs was performed for EC and SMC markers. The cell coverage in the neck was measured semi-quantitatively. Results The mean diameter of the parent vessel of aBVMs was 4.50 mm. The mean neck diameter, width, and height were 6 mm, 5.0 mm, 5.0 mm, respectively. The device segment in the parent artery was completely endothelialized at 7 days. The majority of device struts, but not the pores between struts, at the parent artery and the neck interface were partially covered with ECs and SMCs. The device struts in the middle of the neck were lacking cell coverage. At 14 days, histology verified that a neointimal lining like human tissue had formed coverage. Translucent tissue islands partially covering both the struts and pores in the center of the neck were observed. Almost the entire necks of aBVMs were covered with translucent neointimal layer at 28 days. A higher degree of cellular coverage was seen on the struts and pores at the neck at 28 days compared to both 7 and 14 days. Conclusion Implantation of FDs in the tissue engineered aneurysm model simulates the cellular responses demonstrated in the experimental rabbit model. ABVMs would be a valuable alternative tool for evaluating the healing mechanisms of endovascular aneurysm devices. Disclosures W. Liu: None. D. Ding: None. Y. Ding: None. K. Temnyk: None. T. Shen: None. K. O’Halloran Cardinal: None. D. Kallmes: None. R. Kadirvel: 1; C; NIH grant# NS076491.

BackgroundNotwithstanding the widespread implementation of flow diverters (FDs) in the treatment of intracranial aneurysms, the exact mechanism of action of these devices remains elusive. We aimed to advance the understanding of cellular responses to FD implantation using a 3D tissue-engineered in vitro aneurysm model.MethodsAneurysm-like blood vessel mimics (aBVMs) were constructed by electrospinning polycaprolactone nanofibers onto desired aneurysm-like geometries. aBVMs were seeded with human aortic smooth muscle cells (SMCs) followed by human aortic endothelial cells (ECs). FDs were then deployed in the parent vessel of aBVMs covering the aneurysm neck and were cultivated for 7, 14, or 28 days (n=3 for each time point). The EC and SMC coverage in the neck was measured semi-quantitatively.ResultsAt day 7, the device segment in contact with the parent vessel was partially endothelialized. Also, the majority of device struts, but not pores, at the parent vessel and neck interface were partially covered with ECs and SMCs, while device struts in the middle of the neck lacked cell coverage. At 14 days, histology verified a neointimal-like lining had formed, partially covering both the struts and pores in the center of the neck. At 28 days, the majority of the neck was covered with a translucent neointimal-like layer. A higher degree of cellular coverage was seen on the struts and pores at the neck at 28 days compared with both 7 and 14 days.ConclusionaBVMs can be a valuable alternative tool for evaluating the healing mechanisms of endovascular aneurysm devices.

BackgroundIntracranial aneurysms represent a significant health concern and are poorly understood despite decades of research. Our study focused on understanding temporal patterns of endothelial cell distribution in different spatial locations within the aneurysm early after creation in a rabbit model.MethodsElastase induced saccular aneurysms were created in rabbits and harvested on day 1 (n=3) and after 2 (n=5), 4 (n=4), 8 (n=5), and 12 (n=6) weeks. Sham operated controls (n=3) were harvested on the same day. Aneurysm and control tissue samples were subjected to en face whole mount CD31 staining for endothelial cells. Semiquantitative scoring was performed on the basis of endothelial coverage of the vessel wall (proximal, middle, and distal portions of the aneurysm dome). Mixed effects models were used to assess the effect of time and aneurysm section on endothelial coverage.ResultsAneurysmal segments were near completely de-endothelialized at 4 and 8 weeks but had re-endothelialized by 12 weeks. Compared with controls, aneurysms at all time points showed decreased endothelialization, but the difference was only significant compared with the 4 and 8 week groups. Both time (P=0.03) and aneurysm section (P=0.07) were significantly associated with the degree of endothelialization. Proximal locations showed increased endothelialization compared with distal locations (P=0.03).ConclusionIn experimental aneurysms of rabbits, endothelial cells regress during the first month after creation, followed by ascending re-endothelialization that stays incomplete. These findings suggest that re-population of endothelial cells comes from resident cells in the adjacent parent artery and that deranged hemodynamics may affect full reconstitution of endothelial cells long term.

BackgroundSemiquantitative scales correlate histopathologic findings in the walls of human aneurysms with rupture status.ObjectiveTo apply a semiquantitative scale to the rabbit elastase-induced aneurysm model to determine whether rabbit histologic types mimic the full range of histologic subtypes of humans.Materials and methodsTwenty-seven elastase-induced female rabbit aneurysms were studied, harvested at 2 weeks (n=5) and 12 weeks (n=22). Paraffin-embedded sections received hematoxylin-eosin and Verhoeff-Van Gieson staining. Immunohistochemistry was performed for α-smooth muscle actin and CD31 for endothelial cells. A semiquantitative scale was used for scoring based on human aneurysm tissue, divided into four subtypes according to cellular and extracellular matrix findings: type A, linear organized smooth muscle cells (SMCs) and intact endothelium; type B, thickened wall with disorganized, proliferating SMCs; type C, thick, collagenized and hypocellular wall with or without organizing thrombosis, and type D, extremely thin, hypocellular wall. Separate scoring was performed of the aneurysm neck and proximal and distal zones.ResultsFindings compatible with all subtypes of human aneurysm tissue were identified. Types A and C were found in 13 (48%) and 11 (41%) of 27 aneurysms and in the proximal and distal wall at both time points. Type B was found in 16 aneurysms (59%), exclusively at the neck at both time points; type D, in 14 aneurysms (52%), exclusively at proximal and distal zones of 12-week aneurysms.ConclusionsThe wall of elastase-induced rabbit aneurysm demonstrates histologic findings similar to the four categories of human cerebral aneurysms based on cellular and extracellular wall content.

BACKGROUND AND PURPOSE: The efficacy and safety of transvenous embolization for brain arteriovenous malformations remains unclear, given the very limited number of cases reported. This prospective study was performed to assess this technique in ruptured AVMs. MATERIALS AND METHODS: Twenty-one consecutive patients with ruptured brain AVMs who underwent transvenous embolization were prospectively followed between November 2016 and November 2018. The Spetzler-Martin grade was I in 3 AVMs (14.3%), II in four (19.0%), III in eleven (52.4%), and IV in three (14.3%). The complete AVM occlusion rate was calculated from 6-month follow-up DSA images. Occurrence of hemorrhage and infarction after embolization was evaluated using CT and MR imaging within 1 month after the operation. The mRS was used to assess the functional outcomes. RESULTS: Complete AVM nidus obliteration was shown in 16 (84%) of 19 patients with technically feasible AVMs immediately after embolization. One (5%) patient with a small residual nidus after treatment showed complete obliteration at 13-month follow-up. There were 5 hemorrhages and 1 infarction; 4 patients9 symptoms improved gradually. The percentage of cases with mRS ≤ 2 rose from 57.1% (12/21) before embolization to 66.7% (14/21) at 1-month follow-up. Both the morbidity and mortality rates were 4.8% (1/21). CONCLUSIONS: Transvenous embolization can be performed only in highly selected hemorrhagic brain AVMs with high complete obliteration rates, improved functional outcomes, and acceptable morbidity and mortality rates, but it should not be considered as a first-line treatment.

SUMMARY: The poorly understood mechanisms of aneurysm healing contribute substantially to the pressing medical problem of coiled aneurysm recanalization. Using an established saccular aneurysm model, we developed an animal model system in rabbits to study aneurysm and skin wound healing concurrently in the same animal. We found treated aneurysm healing to be similar to skin wound healing both histologically and in biomarker gene and protein expression, but in a delayed fashion.

PurposeLong-term occlusion of coiled aneurysms frequently fails, probably because of poor intrasaccular healing and inadequate endothelialization across the aneurysm neck. The purpose of this study was to determine if attachment of autologous mesenchymal stem cells (MSCs) to platinum coils would improve the healing response in an elastase-induced aneurysm model in rabbits.Materials and methodsWith approval from the institutional animal care and use committee, aneurysms were created in rabbits and embolized with control platinum coils (Axium; Medtronic) (n=6) or coils seeded ex vivo with autologous adipose-tissue MSCs (n=7). Aneurysmal occlusion after embolization was evaluated at 1 month with angiography. Histological samples were analyzed by gross imaging and graded on the basis of neck and dome healing on H&E staining. Fibrosis was evaluated using a ratio of the total area presenting collagen. Endothelialization of the neck was quantitatively analyzed using CD31 immunohistochemistry. χ2 and Student's t-test were used to compare groups.ResultsHealing score (11.5 vs 8.0, p=0.019), fibrosis ratio (10.3 vs 0.13, p=0.006) and endothelialization (902 262 μm2 vs 31 810 μm2, p=0.041) were significantly greater in the MSC group. The MSC group showed marked cellular proliferation and thrombus organization, with a continuous membrane bridging the neck of the aneurysm. Angiographic stable or progressive occlusion rate was significantly lower in the MSC group (0.00, 95% CI 0.00 to 0.41) compared with controls (0.67, 95% CI 0.22 to 0.96) (p=0.02).ConclusionsAutologous MSCs attached to platinum coils significantly improve histological healing, as they result in improved neck endothelialization and collagen matrix formation within the aneurysm sac.

Background and purposeFlow diverters (FD) can cause rare but devastating delayed aneurysm ruptures in which matrix metalloproteinases (MMPs) have been potentially implicated. Concomitant coiling or anti-inflammatory medications have been proposed to prevent the risk of delayed ruptures. The aim of this study was to evaluate concomitant coiling and ciclosporin in regulating the expression of MMPs in FD-treated aneurysms.Materials and methodsElastase-induced aneurysms were created in 20 rabbits. Aneurysms were treated with (1) FD alone; (2) FD with concomitant coiling; (3) FD+ ciclosporin; or (4) left untreated as controls. At sacrifice, MMP levels were analyzed by zymography. Kruskal–Wallis one-way non-parametric ANOVA was performed for each enzyme. If significant results were observed for the Kruskal–Wallis test, pairwise group comparisons were performed using Dunn's test with Bonferroni multiple-testing correction.ResultsSignificant differences were observed among groups for pro-MMP9 (p=0.0337). Pairwise comparison demonstrated higher levels of pro-MMP9 with concomitant coiling compared with untreated aneurysms (p=0.012), with higher though not significantly different levels of pro-MMP9 in FD with concomitant coiling versus FD alone. While not statistically significant, trends were noted regarding differences in active-MMP9 across groups, with a lower level of active-MMP9 with concomitant coiling compared with the other FD groups. No significant differences were observed for pro- or active-MMP2 across groups, or for FD + ciclosporin compared with FD alone.ConclusionsFD implantation increases the level of pro-MMP9 expression in aneurysms. Provocative trends regarding modulation of active-MMP9 expression with concomitant coiling suggest the need for larger confirmatory preclinical studies. Anti-inflammatory treatment with ciclosporin appears to have a minimal biological effect.Trial registration numberR01NS076491

BackgroundFlow diverters (FDs) are increasingly used in the treatment of intracranial aneurysms, and carry the risk of thromboembolic complications, even in patients treated with dual antiplatelet therapy. The effect of FDs on the downstream vascular is unknown. The aim of the study was to investigate vascular wall pulse wave velocity (PWV) and contractility changes following FD treatment in a rabbit model.MethodsFDs (Pipeline Embolic Device, Medtronic Inc., Irvine, California, USA) were implanted in the aorta of normal rabbits and sham-operated aorta were used as controls (n=6 per group). Pulse wave imaging with ultra-fast ultrasound at 1600 frames per second (Vantage, Verasonics, Inc., Kirkland, WA) was performed in the vessel wall distal to FD prior to device implantation and at 8- week follow-up to measure the PWV. Force contraction vascular reactivity studies were conducted in the aortic rings using an organ bath.ResultsThe difference in mean PWV in the follow-up compared with pre-implantation was significantly higher in the distal vessels compared with sham controls (1.18 m/s [SD=0.54] vs. 0.37 m/s [SD=1.09], P=0.03). Conversely, the aortic segments distal to the FD exhibited a 55% increase in vascular contractility compared with proximal segments (P=0.002). We observed a significant positive correlation between mean PWV and mean vascular contractility.ConclusionImplantation of FD was associated with increased PWV and vascular contractility, suggesting that FD implantation causes changes to the vascular wall. Further studies are needed to understand the clinical implication of changes in vascular PWV and contractility.

Shape memory polymer (SMP) foam-coated coils (FCCs) are new embolic coils coated with porous SMP designed to expand for increased volume filling and enhanced healing after implantation. The purpose of this study was to compare chronic aneurysm healing after treatment with SMP FCCs to bare platinum coil (BPC) controls in the rabbit elastase aneurysm model. BPCs or SMP FCCs were implanted in rabbit elastase-induced aneurysms for follow-up at 30 days (n = 10), 90 days (n = 5), and 180 days (n = 12 for BPCs; n = 14 for SMP FCCs). Aneurysm occlusion and histologic healing, including a qualitative healing score, neointima thickness, collagen deposition, and inflammation were compared between the two groups. The mean neointima thickness was significantly greater in groups treated with SMP FCCs for all three time points. Histologic healing scores and collagen deposition quantification suggested that aneurysms treated with SMP FCCs experience more complete healing of the dome by 90 days, but the differences were not statistically significant. More progressive occlusion and recanalization were observed in aneurysms treated with SMP FCCs, but neither difference was statistically significant. Additionally, the SMP foam used in the FCCs was found to degrade faster in the rabbit elastase model than expected based on previous studies in a porcine sidewall aneurysm model. This study suggests that SMP FCCs can promote neointima formation along the aneurysm neck, and may lead to more complete healing of the dome and neck. These findings indicate potential benefits of this device for aneurysm occlusion procedures. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2466-2475, 2019.

Purpose To classify the tissue patterns and cellular components at aneurysm neck following treatment with single layer (SL) and single layer sphere (SLS) WEB-17 devices in an elastase induced rabbit aneurysm model. Materials and methods With institutional animal care and use committee approval, saccular aneurysms were created in 12 rabbits and treated with WEB-17 device (n=6 for SL, n=6 for SLS). The device-bearing aneurysms were harvested at 3 months after implantation. Following the macroscopic examination of aneurysm neck, a whole tissue mount en face staining of the wet specimen was performed for endothelial cells (CD-31) and smooth muscle cells (SMA). Tissue coverage presenting at the neck was scored as: 0) device struts were completely bare, with no tissue coverage; 1) tissue coverage is less than 50% of neck orifice; 2) the tissue coverage is 50%–75% of neck orifice; 3) tissue coverage is greater than 75% of neck orifice. Results Three tissue patterns that appeared at the neck along with the device struts were discovered as 1) multiple, isolated, light brown-colored tissue islands of varied sizes (figure 1A), composed of inflammatory cells (figure 1D); 2) A confluent, brown-colored tissue patch (figure 1B) representing an incompletely organized thrombus containing scattered or diffused inflammatory cells and an acellular matrix (figure1E); and 3) A white, membrane-like tissue (figure 1C) that was positive for SMA and CD31 (figure 1F). The membrane-like issue was mainly located at the periphery, where it continued up the parent artery wall (figure 1C). Patterns 1 and 2 were seen in 6/6 (100%) for both of the SL and SLS groups. Membranous tissue was present in 4 of 6 (67%) for the SL group and 50% for the SLS group. The mean neck tissue coverage score was 1.5 and 1.8 for the SL and SLS groups, respectively. There was no statistical difference regarding the neck tissue coverage and rate of different tissue patterns between the two groups. Conclusion The primary tissue that appeared at the aneurysm neck following WEB-17 treatment was thrombus and the adherence of clusters of inflammatory cells. The endothelialization mainly started from the periphery and was derived exclusively from the adjacent aneurysm/parent artery wall. Disclosures D. Dai: None. Y. Ding: None. S. Asnafi: None. D. Kallmes: None. R. Kadirvel: None.

Purpose The Trellix (Shape Memory Medical, Inc., Santa Clara, CA) is a new generation shape memory polymer coated coil designed to expand for increased volume filling after implantation. The purpose of this study was to compare the efficacy of the Trellix coil in the rabbit aneurysm model. Methods Trellix and bare platinum coils were implanted in rabbit elastase-induced aneurysms and followed up at 30 days (n=10 for each group) and 90 days (n=5 for each group). Angiographic aneurysm occlusion was rated as stable, progressive or recanalization. Aneurysm specimen were harvested and subjected to histological studies (H and E staining). Comparisons of angiographic outcome, histologic healing score and neointimal thickness between two groups were performed. Results The angiographic stable or progressive aneurysm occlusion rate in Trellix group was 4 vs 4 at 30 days and 1 vs 3 at 90 days compared to control group. Mean histologic healing score was not significant between Trellix and control group at 30 days (5.5±2.3 vs 5.9±2.2), but 70% higher in Trellix group at 90 days (7.8±2.1 vs 4.5±2.4). Mean neointima thickness covering the neck was significantly higher in Trellix group at both follow up time points (0.16±0.06 vs 0.05±0.04 mm, p=0.0001 at 30 days; and 0.13±0.02 vs 0.03±0.01 at 90 days, p=0.00001). Microscopic evaluation demonstrated Trellix group at 90 day had high level of connective tissue filled in the aneurysm cavity compared to other groups (figure 1). Conclusion Trellix coil can promote neointima formation along aneurysm neck, which might be helpful for long term aneurysm healing. Disclosures Y. Ding: None. D. Dai: None. S. Herting: None. A. Boyle: None. L. Nash: None. S. Asnafi: None. D. Jakaitas: None. C. Johnson: None. D. Maitland: None. D. Kallmes: None. R. Kadirvel: None.

BACKGROUND AND PURPOSE: While WEB devices have been shown to be safe and effective for aneurysm treatment, WEB-shape modification compression has been associated with incomplete aneurysm occlusion. We explored the relationship between occlusion rates and WEB-shape modification in different WEB device types in an experimental aneurysm model. MATERIALS AND METHODS: Elastase-induced aneurysms were created in rabbits and treated with dual-layer (n = 12), single-layer (n = 12), or single-layer sphere (n = 12) WEB devices. Aneurysms were followed up either at 3 or 12 months. Angiographic occlusion was graded using the WEB Occlusion Scale: grade I, complete; grade II, complete but recess filling; grade III, residual neck; or grade IV, residual aneurysm. WEB-shape modification and histologic features were also analyzed. RESULTS: Grade I or II occlusion was seen in 16 (44%) aneurysms, and grade I, II, or III (“adequate”) occlusion was observed in 22 (61.1%) aneurysms at follow-up. WEB-shape modification was observed in 22 (61.1%) aneurysms. WEB-shape modification was higher in single-layer (9/12) and dual-layer (10/12) devices compared with single-layer sphere devices (3/12). Aneurysms with WEB-shape modification had a higher level of thrombus organization in the dome compared with those without WEB-shape modification (68% [15/22] versus 50% [7/14]). WEB-shape modification was not correlated with angiographic or histologic outcomes but was significantly correlated with levels of fibrosis and smooth muscle cells in the aneurysm. CONCLUSIONS: WEB-shape modification is not associated with incomplete aneurysm occlusion of WEB devices in the rabbit model but may be related to connective tissue formation and the healing response to WEB device implantation.

We report histopathological findings from a human cerebral aneurysm following treatment with a flow diverter. A 75-year-old male underwent flow diversion treatment (Pipeline Embolization Device (PED)) and coil embolization for treatment of an aneurysm at the basilar tip. At four months, angiography showed complete aneurysm occlusion; at 12 months angiography demonstrated that the aneurysm had reopened. The patient expired from brainstem compression. The aneurysm cavity was primarily filled with unorganized thrombus. Thick, interrupted neointima crossed the neck interface indicating blood flow into aneurysm through small channels. Along the parent artery the PED was covered by neointima having a measured thickness of 0.19 ± 0.01 mm; the maximal stenosis of the proximal parent artery was 27%. The perforating arteries that were crossed by the PED remained patent. Findings in this human case are similar to those in the elastase-induced aneurysms in rabbits.

BACKGROUND AND PURPOSE: Thin film nitinol can be processed to produce a thin microporous sheet with a low percentage of metal coverage ( 2 ) for flow diversion. We present in vivo results from the treatment of experimental rabbit aneurysms by using a thin film nitinol–based flow-diversion device. MATERIALS AND METHODS: Nineteen aneurysms in the rabbit elastase aneurysm model were treated with a single thin film nitinol flow diverter. Devices were also placed over 17 lumbar arteries to model perianeurysmal branch arteries of the intracranial circulation. Angiography was performed at 2 weeks ( n = 7), 1 month ( n = 8), and 3 months ( n = 4) immediately before sacrifice. Aneurysm occlusion was graded on a 3-point scale (grade I, complete occlusion; grade II, near-complete occlusion; grade III, incomplete occlusion). Toluidine blue staining was used for histologic evaluation. En face CD31 immunofluorescent staining was performed to quantify neck endothelialization. RESULTS: Markedly reduced intra-aneurysmal flow was observed on angiography immediately after device placement in all aneurysms. Grade I or II occlusion was noted in 4 (57%) aneurysms at 2-week, in 6 (75%) aneurysms at 4-week, and in 3 (75%) aneurysms at 12-week follow-up. All 17 lumbar arteries were patent. CD31 staining showed that 75% ± 16% of the aneurysm neck region was endothelialized. Histopathology demonstrated incorporation of the thin film nitinol flow diverter into the vessel wall and no evidence of excessive neointimal hyperplasia. CONCLUSIONS: In this rabbit model, the thin film nitinol flow diverter achieved high rates of aneurysm occlusion and promoted tissue in-growth and aneurysm neck healing, even early after implantation.

BACKGROUND: Intracranial dolichoectasia is associated with high morbidity, and its pathophysiology remains poorly understood. OBJECTIVE: To develop a technique for the creation of a murine model of dolichoectasia. METHODS: C57/BL6 mice were injected with 0 milliunit (mu) (control, n = 5), 15 mu (n = 7), 25 mu (n = 10), 35 mu (n = 10), and 55 mu (n = 6) of elastase in the cisterna magna. Fourteen days after injection, the vasculature of the brain was perfused with MicroFil polymerizing compound. Tortuosity index and the percentage increase in arterial diameter were calculated for the basilar artery, posterior communicating arteries, and the A1 segment of the anterior cerebral arteries. Tortuosity index >10 combined with 25% increase in diameter were used to indicate success in achieving dolichoectasia. RESULTS: The mortality rate was 28%, 30%, 80%, and 83% in the 15, 25, 35, and 55 mu groups, respectively. As the 35 and 55 mu groups experienced unacceptable mortality rates, they were excluded from further analysis. The tortuosity index and percent increase arterial diameter of the 15 and 25 mu groups for the left anterior cerebral arteries, right anterior cerebral arteries, left posterior communicating arteries, right posterior communicating arteries, and basilar artery were significantly higher (TI >10 and arterial diameter >25%) than in the control. There was no significant difference in tortuosity index or artery diameter between the 15 and 25 mu groups for any of the 5 artery segments. CONCLUSION: Elastase injection through the cisterna magna can induce intracranial dolichoectasia in mice. Fifteen to 25 mu of elastase is an appropriate dose to use with acceptable mortality.

Background: Flow diverters (FD) are increasingly used in the treatment of intracranial aneurysms. The risk of distal thromboembolic complications with FD is high, even in patients treated with dual antiplatelet therapy. The aim of the study was to understand the downstream vascular wall changes, by measuring the pulse wave velocity and vascular contractility following flow diverter treatment in a rabbit model. Methods: FD (Pipeline Embolic Device, Medtronic) were implanted in normal rabbits and sham-operated aorta were used as controls (n=5 for each group). Pulse wave imaging with ultra-fast ultrasound at 1600 frames per second (Vantage, Verasonics, Inc.) was performed in the vessel wall distal to FD, prior to device implantation and at 8 weeks follow up to measure the pulse wave propagation. Force contraction studies were conducted in the aortic rings using organ bath to assess the vascular functions. Results: The difference in pulse wave velocity (PWV) in the follow-up compared to pre-implantation was significantly higher (p=0.03,Fig 1A) in the distal vessels compared to sham controls (mean difference of PWV was 1.18 m/s and -0.37m/s, respectively as shown in Fig 1B). Conversely, the distal aortic segments to FD exhibited 55% increase in the level of vascular contractility compared to that of proximal segments (p=0.002). There is a significant positive correlation between mean PWV and mean vascular contractility. Conclusion: Our study found changes in the PWV after implantation of the FD, which correlated with vascular contractility. These results could explain vascular wall changes downstream following FD implantation.

Purpose The first generation thin film nitinol (TFN) flow diverter (metal coverage 2 ) has been reported to achieve flow diverter in experimental aneurysms. In this study, further effects of new generation TFN flow diverter (metal coverage 2 ) on flow diversion were tested in elastase-induced aneurysms. Methods The new TFN device was deployed in 8 elastase-induced aneurysms in the rabbits; devices were also placed over 5 lumbar arteries to test the patency of small branch arteries of the parent artery. Follow up angiography was performed two months after deployment to assess aneurysm occlusion and lumbar artery flow. Aneurysm occlusion was graded on a 3-point scale (grade I, complete occlusion; grade II, near-complete occlusion; grade III, incomplete occlusion). Results Mean aneurysm neck, width and height sizes were 3.7±0.7, 4.8±2.1, and 10.2±1.3 mm, respectively. Dramatically reduced intra-aneurysmal flow was observed on angiography immediately after device placement in all aneurysms (block arrow in figure B). Complete occlusion (arrow in figure C) was achieved in 5 (63%) aneurysms, two other aneurysms (25%) showed near complete occlusion at 2 month follow-up. The total complete or near complete occlusion rate was (88%). In another aneurysm (12%) the TFN flow diverter did not fully cover the aneurysm neck region, in which only incomplete occlusion was achieved in this aneurysm. All lumbar arteries (5 pairs) treated with the device were patent immediately after deployment and at follow-up. Conclusions High rates of complete or near-complete aneurysm occlusion at 2 month follow-up can be achieved using new generation TFN device. Branch arteries remain patent after device deployment. Disclosures Y. Ding: None. D. Dai: None. S. Asnafi: None. R. Kadirvel: None. C. Kealey: 5; C; Dr. Kealey is an employee of NeuroSigma, Inc, which is the manufacturer of the TFN device in this study. D. Kallmes: None.

Background and Purpose Unruptured aneurysms pose a significant risk of rupture and remain poorly understood despite decades of preclinical and clinical research. Our study focused on understanding the patterns of endothelial cell distribution in different spatial locations within the aneurysm in a rabbit model. Methods Aneurysms were created in 20 rabbit subjects using the elastase-induced model technique. Aneurysm tissues were harvested at 2 weeks (n=5), 4 weeks (n=4), 8 weeks (n=5) and 12 weeks (n=6) following aneurysm creation. Aneurysm tissues were processed and en face whole tissuemount CD31 staining of aneurysm tissue for endothelial cells was performed. A semi-quantitative scoring of the aneurysm was performed and categorized into 5 divisions based on the endothelial coverage of the vessel wall (Score5-highly confluent, 0- no endothelial cells) at the proximal, middle and distal portions of the aneurysm dome. Scoring was done by a single person who was blinded to the time point of sacrifice. Results Our study revealed a endothelialized wall in all the regions the aneurysm with median score of 1.8 (proximal dome and middle dome) and 1.6 (distal dome) at 2 weeks. However, the endothelialization reduced at 4 weeks (median=0) in all 3 regions. In the 8 weeks group reendothelialization was prominent in the proximal region (median=1.6) in comparison to middle and distal regions (median=0). In 12 weeks group reendothelialization was prominent in proximal (median=1.5), middle (median=2.4) and distal (median=1.1) regions of aneurysm wall. Conclusion The wall of the elastase-induced rabbit aneurysm can be categorized into 5 types based on the degree of endothelialization of aneurysm. Based on the CD31 distribution within the aneurysm, the pattern of deendothelialization and reendothelialization over time can be correlated. Disclosures P. Kolumam Parameswaran: None. D. Dai: None. Y. Ding: None. R. Kadirvel: None. D. Kallmes: 1; C; NIH : NS08825602.

BACKGROUND AND PURPOSE: The development of new generation flow-diverting devices will improve the result of flow diversion in challenging aneurysms. The Flow-Redirection Endoluminal Device system is a dual-layer flow-diversion device. The purpose of this study was to evaluate the effectiveness and safety of the Flow-Redirection Endoluminal Device in a sidewall aneurysm model and in the abdominal aorta in rabbits. MATERIALS AND METHODS: Single Flow-Redirection Endoluminal Devices were implanted in the right common carotid artery across sidewall, vein-pouch aneurysms and within the abdominal aorta in 22 New Zealand white rabbits and followed for 1 (n = 5), 3 (n = 5), 6 (n = 4), and 12 months (n = 8). Aneurysm occlusion was graded on a 3-point scale based on digital subtraction angiography (grade I, complete occlusion; grade II, near-complete occlusion; and grade III, incomplete occlusion). Toluidine blue and basic fuchsin staining was used for the evaluation of thrombus organization within the aneurysm and neck coverage with neointima. A scanning electron microscope was used for confirmation of the patency of branch vessels along with DSA. RESULTS: Grades I and II occlusion rates were noted in 19 (86%) and 3 (14%) aneurysms, respectively, which indicated a 100% rate of complete or near-complete occlusion. No parent artery and branch artery occlusion was shown on DSA. Histologic images indicated partial or complete intraluminal thrombus organization and neointima coverage across the aneurysm neck. A scanning electron microscope indicated that all the vessel branches along the length of the device remained patent. CONCLUSIONS: The Flow-Redirection Endoluminal Device in experimental aneurysms demonstrated high rates of progressive and complete aneurysm occlusion while preserving the patency of branch vessels.

Background and purposeImplanted, actual flow diverter pore density is thought to be strongly influenced by proper matching between the device size and parent artery diameter. The objective of this study was to characterize the correlation between device sizing, metal coverage, and the resultant occlusion of aneurysms following flow diverter treatment in a rabbit model.MethodsRabbit saccular aneurysms were treated with flow diverters (iso-sized to proximal parent artery, 0.5 mm oversized, or 1.0 mm oversized, respectively, n=6 for each group). Eight weeks after implantation, the angiographic degree of aneurysm occlusion was graded (complete, near-complete, or incomplete). The ostium of the explanted aneurysm covered with the flow diverter struts was photographed. Based on gross anatomic findings, the metal coverage and pore density at the ostium of the aneurysm were calculated and correlated with the degree of aneurysm occlusion.ResultsAngiographic results showed there were no statistically significant differences in aneurysm geometry and occlusion among groups. The mean parent artery diameter to flow diverter diameter ratio was higher in the 1.0 mm oversized group than in the other groups. Neither the percentage metal coverage nor the pore density showed statistically significant differences among groups. Aneurysm occlusion was inversely correlated with the ostium diameter, irrespective of the size of the device implanted.ConclusionsDevice sizing alone does not predict resultant pore density or metal coverage following flow diverter implantation in the rabbit aneurysm model. Aneurysm occlusion was not impacted by either metal coverage or pore density, but was inversely correlated with the diameter of the ostium.

SUMMARY Quantification and characterization of the hemodynamic environment created after flow diversion treatment of cerebral aneurysms is important to understand the effects of flow diverters and their interactions with the biology of the aneurysm wall and the thrombosis process that takes place subsequently. This paper describes the construction of multi-modality image-based subject-specific CFD models of experimentally created aneurysms in rabbits and subsequently treated with flow diverters. Briefly, anatomical models were constructed from 3D rotational angiography images, flow conditions were derived from Doppler ultrasound measurements, stent models were created and virtually deployed, and the results were compared with in vivo digital subtraction angiography and Doppler ultrasound images. The models were capable of reproducing in vivoobservations, including velocity waveforms measured in the parent artery, peak velocity values measured in the aneurysm, and flow structures observed with digital subtraction angiography before and after deployment of flow diverters. The results indicate that regions of aneurysm occlusion after flow diversion coincide with slow and smooth flow patterns, whereas regions still permeable at the time of animal sacrifice were observed in parts of the aneurysm exposed to larger flow activity, that is, higher velocities, more swirling, and more complex flow structures. Copyright © 2014 John Wiley & Sons, Ltd.

To characterize the progression of healing across aneurysm necks following treatment with a flow diverter in a rabbit aneurysm model.With institutional animal care and use committee approval, saccular aneurysms were created in 20 rabbits and treated with flow diverters. On days 1, 3, and 7 and weeks 4 and 8 after implantation, the aneurysm and the device-implanted vessel were harvested. En face staining of the gross specimen was performed for endothelial cells, endothelial progenitor cells, smooth muscle cells, and inflammatory cells.The parent artery segments covered by the flow diverters were completely devoid of endothelial cells at 1 and 3 days but had completely reendothelialized by 7 days. At all time points, the struts along the patent portions of the aneurysm necks harbored scattered tissue islands composed exclusively of inflammatory cells. At 4 and 8 weeks, all samples contiguous with the tissue along the parent arteries had translucent tissue present along the occluded segments of the aneurysm neck. The vast majority of endothelial cells were contiguous with the parent artery and had smooth muscle cells underlying them. Endothelial progenitor cells were not observed along the neck of any aneurysm. Aneurysm closure was noted only when complete or nearly complete endothelialization over the device struts was present.The initial event following flow diversion treatment is adherence of clusters of inflammatory cells across the aneurysm neck. Endothelialization is relatively delayed and derived exclusively from cells in the adjacent parent artery.

ObjectiveTo assess the feasibility of using MicroFil polymer perfusion to detect concomitant saccular aneurysms in an intracranial arterial dolichoectasia (IADE) model in mice, and to report detailed histomorphometric features of these aneurysms.Materials and methodsIADE models were created in C57/BL6 mice via microsurgical injection of 25 mU elastase into the cisterna magna. The cerebral vasculature was perfused with MicroFil polymer and harvested at 1, 3, and 7 days, and 2 and 4 weeks (n=8 for each group). IADE was defined by a tortuosity index >10 combined with a 25% increase in diameter of the A1 segment of the anterior cerebral artery (ACA), internal carotid artery (ICA), or basilar artery compared with the baseline of controls, which received heat-inactivated elastase. Saccular aneurysm occurrence rate, location, and morphological parameters were investigated using macroscopic and microscopic analysis.ResultsIADE was present in 95% (36/38) of the subjects, with a mortality rate of 5% (2/40). Fifteen concomitant saccular aneurysms were detected in 8 (21%) of the 38 surviving mice, including 6 at the posterior communicating artery, 1 along the ACA, 2 along the anterior communicating artery complex, 3 along the ICA, and 3 along the middle cerebral artery. Rupture was confirmed in two aneurysms. Histological examination indicated that the aneurysms develop via arterial-wall remodelling, which is characterized by internal elastic lamina disruptions and muscular layer discontinuity in the media.ConclusionsThe proportion of subjects developing saccular aneurysms in addition to IADE in our mouse model is similar to the 15% of patients with IADE who have concomitant saccular aneurysms.

BACKGROUND AND PURPOSE: In clinical practice, durability of occlusion following coil embolization is superior in densely packed, compared with loosely packed, aneurysms. In a rabbit model, we probed, by using proteomics tools, the biologic mechanisms associated with densely packed and completely occluded aneurysms, compared with loosely packed and incompletely occluded aneurysms, to explore the biologic mechanisms of intra-aneurysmal healing following embolization. MATERIALS AND METHODS: Elastase-induced, saccular aneurysms were created in 24 rabbits. Aneurysms were allowed to mature, after which aneurysms were either densely (packing attenuation >25%) or loosely (packing attenuation n = 6 for both groups) and 4 weeks ( n = 6 for both groups) of implantation, aneurysm samples harboring coils were harvested. Soluble proteins were extracted from the necks and domes of aneurysms, and proteins were studied using proteomics and bioinformatics tools. RESULTS: In dome tissue, 128 proteins at 2 weeks, and 8 proteins at 4 weeks, were differentially expressed in densely packed, compared with loosely packed, aneurysms. In the neck tissue, 2 proteins at 4 weeks were differentially expressed in densely packed aneurysms. Specific pathway analysis revealed that compared with loosely packed aneurysms, densely packed aneurysms were associated with up-regulation of cell-to-cell signaling and cell adhesion at 2 weeks. Conversely, at 4 weeks, densely packed aneurysms showed a decrease in the expression of structural proteins compared with loosely packed aneurysms. CONCLUSIONS: These findings may focus efforts on specific targets aimed at improving the long-term healing of intracranial, saccular aneurysms.

BACKGROUND AND PURPOSE: The safety of placing multiple overlapped endoluminal flow diverters remains unclear because small eloquent branch arteries theoretically could become occluded by these devices. We placed single and multiple flow diverters over small branch arteries in rabbit aortas to determine the incidence of branch artery occlusion. MATERIALS AND METHODS: Flow diverters (PED) were placed into 22 female New Zealand white rabbits abdominal aortas to cover ≥1 lumbar artery. Animals were divided into 3 groups (single PED, n = 9; double PED with 2 telescoped/overlapped devices, n = 7; and triple PED, with 3 telescoped/overlapped devices, n = 6) and were followed for 6 or 12 months. DSA was performed at follow-up. Subsequently, the tissue was processed, sectioned, and stained with H&E for histologic evaluation, histomorphometry, and analysis. RESULTS: All the lumbar arteries covered by devices were clearly patent on angiography. Partial neointima covered the ostia of the branch vessels, but demonstrable patent lumens at the ostia in all cases were present. Neointima hyperplasia was minimal in the single-PED-group animals. The measured neointima was thicker for the double- and triple-PED groups compared with the single-PED group (P < .05). However, in all groups, the mean thickness of the neointima was ≤0.2 mm, and the percentage stenosis of the parent artery was

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BACKGROUND AND PURPOSE: Animal models provide a mechanism for fundamental studies of the coupling between hemodynamics and pathophysiology in diseases such as saccular aneurysms. In this work, we evaluated the capability of an elastase-induced saccular aneurysm model in rabbits to reproduce the anatomic and hemodynamic features typical for human intracranial aneurysms. MATERIALS AND METHODS: Saccular aneurysms were created in 51 rabbits at the origin of the RCCA. Twelve weeks' postcreation, the lumen geometry of the aneurysm and surrounding vasculature was acquired by using 3DRA. Geometric features of these models were measured. Pulsatile 3D CFD studies were performed with rabbit-specific inlet profiles. RESULTS: Geometric features, including aneurysm height, width, neck diameter, aspect ratio, and NSI of all 51 rabbit aneurysm models fell within the range reported for human IAs. The distribution and range in values of pressure, WSS, and OSI were also typical for human IAs. A single recirculation region was observed in 33 (65%) of 51 cases, whereas a second transient recirculation zone was observed in 18 (35%) cases. Both of these flow types are commonly observed in human IAs. CONCLUSIONS: Most hemodynamic and geometric features in a commonly used elastase-induced rabbit saccular aneurysm model are qualitatively and quantitatively similar to those seen in large numbers of human cerebral aneurysms. AO : aortic arch AR : aspect ratio BF : bottleneck factor CFD : computational fluid dynamics D : maximum aneurysm diameter D/N : bottleneck factor DDPA : hydraulic diameter of the distal parent artery DPA : distal parent artery DPPA : hydraulic diameter of the proximal parent artery 3DRA : 3D rotational angiography H : height of the aneurysm H/N : aspect ratio IA : intracranial aneurysm LCCA : left common carotid artery N : neck diameter NSI : nonsphericity index OSI : oscillatory shear index PA : parent artery PPA : proximal parent artery RCCA : right common carotid artery Re : Reynolds number S : aneurysm surface area TAWSS : time-averaged wall shear stress V : aneurysm volume WSS : wall shear stress

BACKGROUND AND PURPOSE: Recent advances in endovascular devices have been aimed at providing high density, mesh-like metallic materials across the aneurysm neck, in place of coil technology. Therefore our aim was to report the in vivo preclinical performance of a self-expanding intrasaccular embolization device. MATERIALS AND METHODS: Elastase-induced aneurysms were created in 12 rabbits. Each aneurysm was embolized with a Luna AES. DSA was performed preimplantation; 5, 10, and 30 minutes postimplantation; and at 1 month in 12 rabbits and at 3 months in 8 rabbits. Early postimplantation intra-aneurysmal flow was graded as unchanged, moderately diminished, or completely absent. One- and 3-month DSAs were graded by using a 3-point scale (complete, near-complete, or incomplete occlusion). Aneurysms were harvested for gross and microscopic histologic evaluation at 1 month ( n = 4) and at 3 months ( n = 8). Tissues within the aneurysm dome and across the aneurysm neck were assessed by using HE staining. RESULTS: Ten (83%) of 12 aneurysms demonstrated complete cessation of flow within 30 minutes of device implantation. At 1-month follow-up, 10 (83%) of 12 aneurysms were completely occluded. At 3 months, 7 of 8 (88%) aneurysms remained completely occluded. One-month gross examination in 4 rabbits demonstrated that membranous tissue completely covered the device in 3 subjects (75%). Microscopic examination showed that 3 aneurysms had loose connective tissue filling the aneurysm cavity. Three-month gross and microscopic examinations demonstrated membranous tissue completely covering the device, loose connective tissue filling the aneurysm cavity, and neointima formation crossing the aneurysm neck in 8 of 8 (100.0%) subjects. CONCLUSIONS: The Luna AES achieved high rates of complete angiographic occlusion and showed promising histologic findings in the rabbit aneurysm model. AES : Aneurysm Embolization System An. : aneurysm CA : completely absent CO : complete occlusion DSA : digital subtraction angiography HE : hematoxylin-eosin IVDSA : intravenous digital subtraction angiography MD : moderately diminished NO : near-complete occlusion