Y. H. Ding

A Second-Generation, Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms

BACKGROUND AND PURPOSE: We report a preclinical study of a second-generation endoluminal device (Pipeline Embolization Device [PED-2] for aneurysmal occlusion and compare the PED-2 with its first-generation predecessor (PED-1). MATERIALS AND METHODS: Our Institutional Animal Care and Use Committee approved all studies. The PED-2 is a braided endoluminal, flow-diverting device and was implanted across the necks of 18 elastase-induced aneurysms in New Zealand white rabbits and followed for 1 month (n = 6), 3 months (n = 6), and 6 months (n = 6). A second PED-2 was implanted in the abdominal aorta to cover the origins of the lumbar arteries. Angiographic occlusion rates were documented as complete, near-complete, and incomplete. Parent artery percent diameter stenosis was calculated. Results were compared with a previous publication focused on the PED-1, with use of the same model. We compared ordinal outcomes using Fisher Exact or χ2 tests. We compared continuous data using analysis of variance. RESULTS: Occlusion rates (complete and incomplete) for the PED-2 were noted in 17 cases (94%) and 1 (6%), respectively, compared with 9 cases of complete (53%) and 8 (47%) of incomplete occlusion with the PED-1 (P = .0072). No incidents of branch artery occlusion or distal emboli in vessels downstream of the parent artery were observed with the PED-2. Parent artery neointimal hyperplasia was minimal in most cases and was significantly less than in the PED-1. CONCLUSIONS: The PED-2 is a biocompatible and hemocompatible device that occludes saccular aneurysms while preserving the parent artery and small-branch vessels in our animal model.

The Woven EndoBridge: A New Aneurysm Occlusion Device

BACKGROUND AND PURPOSE: The WEB device is an intrasaccular ellipsoid braided-wire embolization device designed to provide flow disruption along the aneurysm neck. The purpose of this study was to evaluate, in an in vivo aneurysm model, the acute and chronic performance of the WEB device regarding immediacy, degree, and durability of aneurysm occlusion. MATERIALS AND METHODS: The WEB device was implanted in 24 elastase-induced aneurysms in New Zealand white rabbits and followed for 1, 3, 6, and 12 months (n = 6 at all time points). Degree of intra-aneurysmal flow disruption was graded on a 4-point scale based on DSA within 10 minutes following device implantation. Chronic aneurysm occlusion was rated by using a 3-point scale. All aneurysms were harvested for histologic analysis. RESULTS: Immediate postimplant grade 1 (complete flow cessation) was noted in 7 (29%) of 24 cases. Grade 2 (near-complete flow cessation) was noted in 13 (54%) of 24 cases. At follow-up, complete occlusion was noted in 8 (33%) of 24 cases. Near-complete aneurysm occlusion was noted in 14 (58%) of 24 cases, while incomplete occlusion was noted in 2 (8%) cases. Stable aneurysm occlusion was present in 7 (29%) of 24 cases; progressive occlusion, in 14 (58%); and recanalization, in 3 (13%) cases. Histologic findings included aneurysm cavities filled with organized thrombus with connective tissue across the aneurysm neck. CONCLUSIONS: The WEB device in experimental aneurysms demonstrated promising rates of immediate and long-term aneurysm occlusion.

Preliminary Results of the Luna Aneurysm Embolization System in a Rabbit Model: A New Intrasaccular Aneurysm Occlusion Device

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.

Patency of Branches after Coverage with Multiple Telescoping Flow-Diverter Devices: An In Vivo Study in Rabbits

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 <15% and 18% for 6 and 12 months, respectively. There was no significant inflammatory response in any group. CONCLUSIONS: Small branch arteries remain patent even when covered by multiple overlapped PED flow-diverter devices.

Sensitivity of CFD Based Hemodynamic Results in Rabbit Aneurysm Models to Idealizations in Surrounding Vasculature

Computational fluid dynamics (CFD) studies provide a valuable tool for evaluating the role of hemodynamics in vascular diseases such as cerebral aneurysms and atherosclerosis. However, such models necessarily only include isolated segments of the vasculature. In this work, we evaluate the influence of geometric approximations in vascular anatomy on hemodynamics in elastase induced saccular aneurysms in rabbits. One representative high aspect ratio (AR-height/neck width) aneurysm and one low AR aneurysm were created at the origin of the right common carotid artery in two New Zealand white rabbits. Three-dimensional (3D) reconstructions of the aneurysm and surrounding arteries were created using 3D rotational angiographic data. Five models with varying extents of neighboring vasculature were created for both the high and low AR cases. A reference model included the aneurysm sac, left common carotid artery (LCCA), aortic arch, and downstream trifurcation/quadrification. Three-dimensional, pulsatile CFD studies were performed and streamlines, wall shear stress (WSS), oscillatory shear index, and cross sectional velocity were compared between the models. The influence of the vascular domain on intra-aneurysmal hemodynamics varied between the low and high AR cases. For the high AR case, even a simple model including only the aneurysm, a small section of neighboring vasculature, and simple extensions captured the main features of the steamline and WSS distribution predicted by the reference model. However, the WSS distribution in the low AR case was more strongly influenced by the extent of vasculature. In particular, it was necessary to include the downstream quadrification and upstream LCCA to obtain good predictions of WSS. The findings in this work demonstrate the accuracy of CFD results can be compromised if insufficient neighboring vessels are included in studies of hemodynamics in elastase induced rabbit aneurysms. Consideration of aspect ratio, hemodynamic parameters of interest, and acceptable magnitude of error when selecting the vascular domain will increase reliability of the results while decreasing computational time.

Analysis of hemodynamics and aneurysm occlusion after flow-diverting treatment in rabbit models.

BACKGROUND AND PURPOSE: Predicting the outcome of flow diversion treatment of cerebral aneurysms remains challenging. Our aim was to investigate the relationship between hemodynamic conditions created immediately after flow diversion and subsequent occlusion of experimental aneurysms in rabbits. MATERIALS AND METHODS: The hemodynamic environment before and after flow-diversion treatment of elastase-induced aneurysms in 20 rabbits was modeled by using image-based computational fluid dynamics. Local aneurysm occlusion was quantified by using a voxelization technique on 3D images acquired 8 weeks after treatment. Global and local voxel-by-voxel hemodynamic variables were used to statistically compare aneurysm regions that later thrombosed to regions that remained patent. RESULTS: Six aneurysms remained patent at 8 weeks, while 14 were completely or nearly completely occluded. Patent aneurysms had statistically larger neck sizes (P = .0015) and smaller mean transit times (P = .02). The velocity, vorticity, and shear rate were approximately 2.8 times (P < .0001) larger in patent regions—that is, they had larger “flow activity” than regions that progressed to occlusion. Statistical models based on local hemodynamic variables were capable of predicting local occlusion with good precision (84% accuracy), especially away from the neck (92%–94%). Predictions near the neck were poorer (73% accuracy). CONCLUSIONS: These results suggests that the dominant healing mechanism of occlusion within the aneurysm dome is related to slow-flow-induced thrombosis, while near the neck, other processes could be at play simultaneously.

Five-year follow-up in elastase-induced aneurysms in rabbits.

BACKGROUND AND PURPOSE: There is no report regarding patency of elastase-induced aneurysms for more than a 2-year period. Our aim was to report aneurysm patency rates up to 5 years in the elastase-induced aneurysm model in rabbits. MATERIALS AND METHODS: Twenty-five elastase-induced aneurysms were created in New Zealand white rabbits and followed for up to 5 years. Thirteen (52%) rabbits died during follow-up for reasons unrelated to the aneurysms. DSA was performed at 1 month and at 2 and 5 years in the 12 surviving subjects. Aneurysm patency and dimensions, including neck diameter and aneurysm width and height, were evaluated at each time point in relation to external sizing devices. Differences of aneurysm sizes (neck width and aneurysm width and height) among time points were compared by using the Student t test. RESULTS: Eleven (92%) of the 12 aneurysms in the subjects that survived for 5 years remained fully patent throughout follow-up. A single narrow-neck aneurysm showed partial thrombosis at the 2- and 5-year time points. CONCLUSIONS: Experimental elastase-induced aneurysms in rabbits demonstrate high rates of patency up to 5 years following creation. When planning for very long-term studies, investigators should plan for relatively high rates of mortality unrelated to aneurysm pathology.

Angiographic and Histologic Comparison of Experimental Aneurysms Embolized with Hydrogel Filaments

BACKGROUND AND PURPOSE: The embolization of aneurysms with hydrogel filaments allow postprocedural CT and MR imaging studies without artifacts. We compared the performance of 3 hydrogel filament formulations in rabbit experimental aneurysms by using angiography and histologic samples. MATERIALS AND METHODS: Embolization of 35 rabbit elastase or bifurcation aneurysms was performed with 3 different formulations of detachable hydrogel filaments, including 1) polyethylene glycol opacified with aromatic iodine (PEG-I; n = 12), 2) polyethylene glycol opacified with barium sulfate (PEG-B; n = 12), or 3) polypropylene glycol opacified with barium sulfate (PPG-B; n = 11). Follow-up angiography was performed before the rabbits were killed at 2 (n = 7), 6 (n = 9), 10 (n = 8), or 26 (n = 11) weeks. Angiographic occlusion was scored according to the Raymond scale, and interval changes were assessed. The harvested aneurysms were evaluated on histologic examination. From the sections, we determined the percentage of the sac excluded from the vasculature and occupied by embolic devices by using image analysis. We compared results using the analysis of variance/t test or χ2 test. RESULTS: The mean number of devices used to treat aneurysms in the PPG-B group was significantly greater than that used for the other 2 groups, though aneurysm volumes were similar among groups. Compared with immediate posttreatment occlusion scores, mean angiographic occlusion at follow-up was increased for all 3 hydrogel filament groups. On histologic examination, thrombus organization, neointima formation, and inflammation were similar to that observed in rabbit experimental aneurysms with other embolic devices containing platinum coils. CONCLUSIONS: The embolization of experimental aneurysms with hydrogel filaments resulted in durable angiographic and histologic occlusion from 2 to 26 weeks. With improvements, hydrogel filaments free from metallic coils show promise for endovascular use.

Can aspect ratio be used to categorize intra-aneurysmal hemodynamics?—A study of elastase induced aneurysms in rabbit

Clinical studies suggest that aneurysm aspect ratio (AR) is an important indicator of rupture likelihood. The importance of AR is hypothesized to arise from its influence on intra-aneurysmal hemodynamics. It has been conjectured that slower flow in high AR sacs leads to a cascade of biological activities that weaken the aneurysm wall (Ujiie et al.,1999). However, the connection between AR, hemodynamics and wall weakening has never been proven. Animal models of saccular aneurysms provide a venue for evaluating this conjecture. The focus of this work was to evaluate whether a commonly used elastase induced aneurysm model in rabbits is suitable for a study of this kind from a hemodynamic perspective. In particular, to assess whether hemodynamic factors in low and high AR sacs are statistically different. To achieve this objective, saccular aneurysms were created in 51 rabbits and pulsatile computational fluid dynamics (CFD) studies were performed using rabbit specific inflows. Distinct hemodynamics were found in the low AR (AR<1.8, n=25), and high AR (AR>2.2, n=18) models. A single, stable recirculation zone was present in all low AR aneurysms, whereas a second, transient recirculation zone was also found in the superior aspect of the aneurysm dome for all high AR cases. Aneurysms with AR between 1.8 and 2.2 displayed transitional flow patterns. Differences in values and distributions of hemodynamic parameters were found between low and high AR cases including time averaged wall shear stress, oscillatory shear index, relative residence time and non-dimensional inflow rate. This work lays the foundation for future studies of the dependence of growth and remodeling on AR in the rabbit model and provides a motivation for further studies of the coupling between AR and hemodynamics in human aneurysms.

Gene Expression Profiling of Experimental Saccular Aneurysms Using Deoxyribonucleic Acid Microarrays

BACKGROUND AND PURPOSE: The molecular characteristics of the pathophysiology of saccular aneurysms remain poorly understood. The purpose of the current study was to investigate the expression of various groups of genes at different stages of aneurysm age in elastase-induced saccular aneurysms in rabbits through the use of deoxyribonucleic acid (DNA) microarrays. MATERIALS AND METHODS: A microarray consisting of genes related to cell adhesion, apoptosis, cell signaling, growth, inflammation, vascular remodeling, and oxidative stress was constructed by using rabbit nucleotide sequences. Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery (CCA) in 12 rabbits. Two weeks (n=6) and 12 weeks (n=6) after aneurysm creation, ribonucleic acid (RNA) was isolated from the aneurysm and the control unoperated left CCA and was used for microarray experiments. Real-time polymerase chain reaction (RT-PCR) was performed for validation of microarray results. RESULTS: Of 209 genes, 157 (75%) at 2 weeks and 88 (42%) at 12 weeks demonstrated statistically significant differential expression between aneurysm tissue and the control left CCA tissue (P < .05). Multiple genes implicated in vessel wall remodeling were found to be elevated at 2 weeks and at 12 weeks. Expression of cell adhesion molecules and antioxidant enzymes was down-regulated at 2 weeks but was not significantly different from that of controls at 12 weeks. Most transcription factors, inflammatory genes, and structural genes showed underexpression at both time points. The expression profiles of selected genes were confirmed by RT-PCR. CONCLUSION: Multiple genes in diverse pathways have been differentially expressed in the rabbit aneurysm model.