Yong Hong Ding

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.

The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits.

IntroductionBiological and biophysical factors have been shown to play an important role in the initiation, progression, and rupture of intracranial aneurysms. The purpose of this study was to evaluate the association between hemodynamic forces and markers of vascular remodeling in elastase-induced saccular aneurysms in rabbits.MethodsElastase-induced aneurysms were created at the origin of the right common carotid artery in rabbits. Hemodynamic parameters were estimated using computational fluid dynamic simulations based on 3-D-reconstructed models of the vasculature. Expression of matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and markers of vascular remodeling were measured in different spatial regions within the aneurysms.ResultsAltered expression of biological markers relative to controls was correlated with the locations of subnormal time-averaged wall shear stress (WSS) but not with the magnitude of pressure. In the aneurysms, WSS was low and expression of biological markers was significantly altered in a time-dependent fashion. At 2xa0weeks, an upregulation of active-MMP-2, downregulation of TIMP-1 and TIMP-2, and intact endothelium were found in aneurysm cavities. However, by 12xa0weeks, endothelial cells were absent or scattered, and levels of pro- and active-MMP-2 were not different from those in control arteries, but pro-MMP-9 and both TIMPs were upregulated.ConclusionThese results reveal a strong, spatially localized correlation between diminished WSS and differential expression of biological markers of vascular remodeling in elastase-induced saccular aneurysms. The ability of the wall to function and maintain a healthy endothelium in a low shear environment appears to be significantly impaired by chronic exposure to low WSS.

Cellular Mechanisms of Aneurysm Occlusion after Treatment with a Flow Diverter

PURPOSEnTo characterize the progression of healing across aneurysm necks following treatment with a flow diverter in a rabbit aneurysm model.nnnMATERIALS AND METHODSnWith 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.nnnRESULTSnThe 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.nnnCONCLUSIONnThe 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.

Change in Diffusion-Weighted Imaging Infarct Volume Predicts Neurologic Outcome at 90 Days Results of the Acute Stroke Accurate Prediction (ASAP) Trial Serial Imaging Substudy

Background and Purpose— Predictive models of outcome after ischemic stroke have incorporated acute diffusion-weighted MRI (DWI) information with mixed results. We hypothesized that serial measurements of DWI infarct volume would be predictive of functional outcome after ischemic stroke. Methods— The prospective Acute Stroke Accurate Prediction (ASAP) Study included a prespecified serial imaging subgroup who underwent DWI studies at baseline (<24 hours after symptom onset) and Day 5 (±2 days). DWI infarct volumes were calculated using the Analyze software (Rochester, Minn). Clinical outcomes were assessed at 3 months. Univariate and multivariable regression analysis was performed to assess the relationship between change in DWI lesion volume and excellent neurological outcome (modified Rankin Scale 0, 1, and Barthel Index ≥95). Results— In total, 169 cases from the ASAP study had serial DWI scans with a measurable lesion at baseline, follow-up, or both. The median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 3 to 13). For each 10 cm3 of growth in DWI infarct volume, the OR for achieving an excellent outcome by modified Rankin Scale was 0.52 (95% CI, 0.38 to 0.71) and for the Barthel Index was 0.64 (95% CI, 0.51 to 0.79). Adjusting for clinically important covariates, the OR for an excellent modified Rankin Scale outcome was 0.57 (95% CI, 0.37 to 0.88) and excellent Barthel Index outcome was 0.75 (95% CI, 0.56 to 1.01). Conclusions— Based on these data, the likelihood of achieving an excellent neurological outcome diminishes substantially with growth in DWI infarct volume in the first 5 days after ischemic stroke of mild to moderate severity.

Clinical and Imaging Data at 5 Days as a Surrogate for 90-Day Outcome in Ischemic Stroke

Background and Purpose— A simple, easily measured surrogate outcome measure for use in early treatment trials for acute ischemic stroke therapies would be highly valued. We hypothesized that day-5 NIH stroke scale score (NIHSS) and day-5 diffusion weighted imaging (DWI) volume would predict clinical outcome better than either alone and could be considered as a possible surrogate outcome in early phase acute stroke trials. Methods— The prospective Acute Stroke Accurate Prediction (ASAP) trial included a prespecified subgroup evaluated for early outcome. Logistic regression analysis was used to assess the prediction of modified Rankin (mRankin) of 0 or 1. Results— A total of 204 subjects completed the substudy, and 116 (57%) had excellent outcome at 3 months. The area under the ROC curve (AUC) for day-5 NIHSS predicting 3-month excellent outcome was 0.84; for DWI volume predicting outcome was 0.76, and for the multivariable model combining both was 0.84. Conclusions— The results of the early outcome substudy of the ASAP trial suggest that early stroke severity and infarct volume measures are predictive of 3-month excellent outcome. In our data set the DWI volume does not add clinically relevant information in predicting 3-month outcome. Validation of these results is required.

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.

Modified technique to create morphologically reproducible elastase-induced aneurysms in rabbits

IntroductionThe purpose of this study was to create morphologically reproducible elastase-induced model aneurysms in rabbits.MethodsWe created 120 elastase-induced aneurysms in rabbits using two different methods: the standard technique (group 1, n=62) and a modified technique (group 2, n=58). In the standard technique a small cutdown with a focal area of exposure of the mid-right common carotid artery (RCCA) was employed, while in the modified technique the RCCA was completely exposed to its origin. We measured aneurysm sizes (neck diameter, width and height) in the two groups. The aneurysm sizes were compared between the two groups using Student’s t test, and the standard deviations of the aneurysm sizes were compared between the groups using the F test.ResultsThe mean aneurysm neck size, width and height in group 1 were 3.4±1.2xa0mm, 3.8±1.0xa0mm and 8.0±1.7xa0mm, respectively, and in group 2, were 3.2±0.9xa0mm, 3.7±0.6xa0mm and 9.1±1.8xa0mm, respectively. The differences in mean aneurysm neck and width between the two groups were not significant (P>0.05). However, there were significant differences in the standard deviation of these two parameters between the two groups (P<0.05 and P<0.01, respectively). The mean aneurysm height in group 2 was larger than in group 1 (P<0.001), but no significant difference in the standard deviation of this parameter between the two groups was found (P>0.05).ConclusionThe results indicate that more consistent aneurysm diameters can be created using the modified technique.

Relationship Between Aneurysm Volume and Histologic Healing after Coil Embolization in Elastase-Induced Aneurysms: A Retrospective Study

BACKGROUND AND PURPOSE: There are, to our knowledge, no histologic data correlating aneurysm volume with histologic healing following coil embolization of aneurysms. We report a retrospective study comparing histologic outcome with aneurysm volume in elastase-induced aneurysms in rabbits. MATERIALS AND METHODS: Aneurysm volume and histologic healing after coil embolization were retrospectively analyzed in 37 elastase-induced aneurysms in rabbits. Aneurysm dimensions (including neck, width, height, and volume) were measured and calculated. Packing density (PD) was calculated. Angiographic results were evaluated as recurrence, stable, and progressive occlusion. An ordinal grading system was used to evaluate the histologic healing after embolization. Correlations among aneurysm volume, PD, and histologic healing were analyzed by conducting linear regression analysis. RESULTS: For all the aneurysms in this study, mean aneurysm volume was 80.8 ± 48.6 mm3 (from 22 to 192 mm3), mean PD was 30.4 ± 8.3% (from 17% to 49%), and mean histologic score was 6.1 ± 2.0 (from 0.5 to 9.5), respectively. Correlations between aneurysm volume and PD, aneurysm volume and histologic healing, and aneurysm packing and histologic healing were all significant (P < .01). CONCLUSION: In this study, aneurysms with smaller volumes and higher PD were associated with the most complete histologic healing. The incomplete healing seen in the larger aneurysms is consistent with the higher incidence of recurrences after endovascular treatment that is seen in large human aneurysms.

Endovascular Treatment of Experimental Aneurysms with Use of Fibroblast Transfected with Replication-Deficient Adenovirus Containing Bone Morphogenetic Protein-13 Gene

BACKGROUND AND PURPOSE: Modified coils have failed to improve long-term recanalization of aneurysms. This study examined whether ex vivo transduction of replication-deficient adenovirus containing the bone morphogenetic protein-13 gene (Ad-BMP-13) in fibroblast allografts would improve angiographic results via increased collagen synthesis, compared with fibroblast-coated platinum coils (FBC) and bare platinum coils (PA). Materials and METHODS: Aneurysms were embolized with Ad-BMP-13-coated coils (n = 20). Rabbits were sacrificed at 14 days and at 1, 3, and 6 months after implantation. Digital subtraction angiography (DSA) evaluated stability after embolization. Histologic specimens were examined with a qualitative grading system. Masson trichrome evaluated collagen deposition. Findings were compared with previously reported controls for PA and FBC in the same model and time points. RESULTS: The grading system showed a greater total score (P = .0002) in Ad-BMP-13 (6.8 ± 1.6) and FBC (6.3 ± 2.4) compared with PA (4.7 ± 2.4). A group main effects test showed that aneurysm neck tissue coverage in Ad-BMP-13 (2.5 ± 1.1) was higher (P = .0007) than both FBC (1.6 ± 1.4) and PA (0.9 ± 1.1). Ad-BMP-13 had more (P < .0001) collagen deposition than the FBC and PA. One- and 3-month Ad-BMP-13 collagen depositions increased (P < .05) over the FBC and PA. Finally, Ad-BMP-13 showed radiographic stability in 15 (75%) cases, coil compaction in 4 (20%) cases, and progressive occlusion in 1 (5%) case. There were no differences in angiographic results (P = .6522). CONCLUSION: The Ad-BMP-13-coated coils can improve neck coverage and dome fibrosis in the rabbit model, even in the absence of observed differences in angiographic outcome.

Intra-venous digital subtraction angiography: an alternative method to intra-arterial digital subtraction angiography for experimental aneurysm imaging

Conventional intra-arterial digital subtraction angiography (IADSA), which necessitates surgical exposure and ligation of the femoral artery, is an invasive and expensive method of evaluation for experimental elastase-induced aneurysms in rabbits. The purpose of this study was to examine and validate intra-venous digital subtraction angiography (IVDSA) as an alternative to IADSA by comparing their diagnostic accuracies. We performed both IVDSA and IADSA for 24 elastase-induced saccular aneurysms in a rabbit model, 1xa0month following creation. Aneurysm sizes (neck, width and height) from both the IVDSA and IADSA procedures were evaluated and measured. Comparison of the aneurysm sizes between IVDSA and IADSA were performed with the Wilcoxon paired signed-rank test. All the aneurysms were seen clearly in both the IVDSA and IADSA techniques. Mean sizes of the IVDSA aneurysm neck, width and height were 3.41±0.80xa0mm, 3.61±0.93xa0mm and 8.07±2.11xa0mm, respectively. Mean sizes of the IADSA aneurysm neck, width and height were 3.43±0.80xa0mm, 3.66±0.92xa0mm and 8.16±2.25xa0mm, respectively. No significant difference was found in the sizes of the aneurysm neck, width and height between the two groups (P=0.311, P=0.086 and P=0.258, respectively). IVDSA appears to be an alternative method for evaluating elastase-induced aneurysms in rabbits.