Ramanathan Kadirvel

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

Background and Purpose— We report a preclinical study of a new endoluminal device for aneurysm occlusion to test the hypothesis that the device, even without use of intrasaccular coil placement, could occlude saccular aneurysms without causing substantial parent artery compromise or compromise of adjacent, small branch arteries. Methods— The Pipeline Neuroendovascular Device (Pipeline NED; Chestnut Medical Technologies, Inc) is a braided, tubular, bimetallic endoluminal implant aimed at occlusion of saccular aneurysms through flow disruption along the aneurysm neck. The device was implanted across the necks of 17 elastase-induced aneurysms in the New Zealand white rabbit model and followed for 1 month (n=6), 3 months (n=5), and 6 months (n=6). In each subject, a second device was implanted in the abdominal aorta to cover the origins of lumbar arteries. Aneurysm occlusion rates by angiography (grade 1, complete occlusion; grade 2, near-complete occlusion; and grade 3, incomplete occlusion) were documented. Percent area stenosis of the parent arteries was calculated. Presence of distal emboli in the downstream vessels in the parent artery and branch artery stenosis or occlusion was noted. Results— Grades 1, 2, and 3 occlusion rates were noted in 9 (53%), 6 (35%), and 2 (12%) of 17 aneurysms, respectively, indicating an 88% rate of complete or near complete occlusion. No cases of branch artery occlusion or distal emboli in the downstream vessels of the parent artery, specifically the subclavian artery, were seen. Parent artery compromise from neointimal hyperplasia was minimal in most cases. Conclusions— The Pipeline NED is a trackable, bio- and hemocompatible device able to occlude saccular aneurysms with preservation of the parent artery and small, adjacent branch vessels.

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.

Cellular Mechanisms of Aneurysm Occlusion after Treatment with a Flow Diverter

PURPOSE To characterize the progression of healing across aneurysm necks following treatment with a flow diverter in a rabbit aneurysm model. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Mechanisms of Healing in Coiled Intracranial Aneurysms: A Review of the Literature

SUMMARY: Recanalization of intracranial aneurysms following endovascular coiling remains a frustratingly common occurrence. An understanding of the molecular and histopathologic mechanisms of aneurysm healing following coil embolization is essential to improving aneurysm occlusion rates. Histopathologic studies in coiled human and experimental aneurysms suggest that during the first month postcoiling, thrombus formation and active inflammation occur within the aneurysm dome. Several months following embolization, the aneurysm is excluded from the parent vessel by formation of a neointimal layer, which is often thin and discontinuous, across the aneurysm neck. Numerous coil modifications and systemic therapies have been tested in animals and humans in an attempt to improve the aneurysm-healing process; these modifications have met with variable levels of success. In this review, we summarize the histopathologic and molecular biology of aneurysm healing and discuss how these findings have been applied in an attempt to improve angiographic outcomes in patients with intracranial aneurysms.

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.

Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates

Purpose To compare gadolinium tissue concentrations of multiple linear and macrocyclic chelates in a rat model to better understand the scope and extent of tissue deposition following multiple intravenous doses of gadolinium-based contrast agent (GBCA). Materials and Methods In this Institutional Animal Care and Use Committee-approved study, healthy rats received 20 intravenous injections of 2.5 mmol gadolinium per kilogram (gadolinium-exposed group) or saline (control group) over a 26-day period. Unenhanced T1 signal intensities of the dentate nucleus were measured from magnetic resonance (MR) images obtained prior to GBCA injection and 3 days after final injection. Rat brain and renal, hepatic, and splenic tissues were harvested 7 days after final injection and subjected to inductively coupled plasma mass spectrometry and transmission electron microscopy for quantification and characterization of gadolinium deposits. Results Gadolinium deposition in brain tissue significantly varied with GBCA type (F = 31.2; P < .0001), with median concentrations of 0 μg gadolinium per gram of tissue (95% confidence interval [CI]: 0, 0.2) in gadoteridol-injected rats, 1.6 μg gadolinium per gram of tissue (95% CI: 0.9, 4.7) in gadobutrol-injected rats, 4.7 μg gadolinium per gram of tissue (95% CI: 3.5, 6.1) in gadobenate dimeglumine-injected rats, and 6.9 μg gadolinium per gram of tissue (95% CI: 6.2, 7.0) in gadodiamide-injected rats; a significant positive dose-signal intensity correlation was identified (ρ = 0.93; P < .0001). No detectable neural tissue deposition or MR imaging signal was observed in control rats (n = 6). Similar relative differences in gadolinium deposition were observed in renal, hepatic, and splenic tissues at much higher tissue concentrations (P < .0001). Gadolinium deposits were visualized directly in the endothelial capillary walls and neural interstitium in GBCA-injected rats, but not in control rats. Conclusion Tissue deposition of gadolinium was two- to fourfold higher following administration of the linear agents gadodiamide and gadobenate dimeglumine compared with the macrocyclic agents gadobutrol and gadoteridol. These findings suggest that organ tissue deposition is reduced but not eliminated following administration of macrocyclic GBCA chelates in lieu of linear chelates.

Endovascular Treatment of Experimental Aneurysms by Use of Fibroblast-Coated Platinum Coils An Angiographic and Histopathologic Study

Background and Purpose— The purpose of this study was to determine whether implanting exogenous fibroblasts on platinum coils could enhance intra-aneurysmal fibrosis. Hypotheses included: (1) fibroblast-coated (FBC) platinum coils can improve angiographic results after embolization; and (2) FBC platinum coils can accelerate histological healing of embolized aneurysms. Methods— Experimental aneurysms in rabbits were embolized with control platinum coils (n=18) or FBC coils (n=18). Subjects were euthanized at 14 days, 1 month, 3 months and 6 months after implantation. Digital subtraction angiography was used to evaluate stability after embolization. Histological samples were examined with a grading system (range, 0 to 12) based on neck and dome healing. Results— Histology total scores and fibrosis ratio at 14 days were significantly greater in the FBC coil group compared with controls (6.6±1.9 versus 2.5±1.1, 1.2±0.6% versus 0.2±0.3%, respectively; P=0.0090). Cavities embolized with FBC coils showed cellular proliferation and thrombus organization, with an endothelialized membrane bridging the neck. There were no differences between groups in the later timepoints. The FBC coil group showed radiographic stability in 11 (61%) cases, coil compaction in 2 (11%) cases, and progressive occlusion in 5 (28%) cases. No progressive occlusion was seen in controls; 3 (17%) of 18 control cases exhibited coil compaction (P=0.0546). Conclusions— FBC coils can accelerate early histological healing compared with control coils in the rabbit aneurysm model.

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.