E Langan

Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion

Background and Purpose— The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. Methods— A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Results— Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). Conclusions— A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy.

Quantitative assessment of device–clot interaction for stent retriever thrombectomy

Purpose Rapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device–clot interaction as a potential mechanism for efficient embolectomy. Methods Two different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF). Results The CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004–0.007). Conclusions This study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot–device integration increased in both clot models by waiting 5 min.

Acute thrombus formation on phosphorilcholine surface modified flow diverters

Purpose Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED). Methods Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent. Results Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p<0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198). Conclusion In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.

In situ tissue engineering: endothelial growth patterns as a function of flow diverter design

Background Vascular remodeling in response to implantation of a tissue engineering scaffold such as a flow diverter (FD) leads to the cure of intracranial aneurysms. We hypothesize that the vascular response is dependent on FD design, and CD34+ progenitor cells play an important role in the endothelialization of the implant. Methods Sixteen rabbit aneurysms were randomly treated with two different single-layer braided FDs made of cobalt–chrome alloys. The FD-48 and FD-72 devices had 48 and 72 wires, respectively. Aneurysm occlusion rate was assessed during the final digital subtraction angiogram at 10, 20, 30, and 60 days (n=2 per device per time point). Implanted vessels were analyzed with scanning electron microscopy for tissue coverage, endothelialization, and immuno-gold labeling for CD34+ cells. Results Complete aneurysm occlusion rates were similar between the devices; however, complete or near complete occlusion was more frequently observed in aneurysms with neck ≤4.2 mm (p=0.008). Total tissue coverage at 10 days over the surface of the FD-48 and FD-72 devices was 56.4±11.6% and 76.6±3.6%, respectively. Endothelial cell growth over the surface was time-dependent for the FD-72 device (Spearmans r=0.86, p=0.013) but not for the FD-48 device (Spearmans r=−0.59, p=0.094). The endothelialization score was marginally correlated with the distance from the aneurysm neck for the FD-48 device (Spearmans r=1, p=0.083) but not for the FD-72 device (Spearmans r=0.8, p=0.33). CD34+ cells were present along the entirety of both devices at all time points. Conclusions This study gives preliminary evidence that temporal and spatial endothelialization is dependent on FD design. Circulating CD34+ progenitor cells contribute to endothelialization throughout the healing process.

Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia

Background Optical coherence tomography (OCT) is a high-resolution, intra-vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED). Methods In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline – cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations. Results OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r2=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED. Conclusion OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates.

Communicating malapposition of flow diverters assessed with optical coherence tomography correlates with delayed aneurysm occlusion

Background Optical coherence tomography (OCT) is a high resolution intravascular imaging method that allows visualization of flow diverter struts and the vessel wall. In this study, malapposition of the flow diverter that continues into the neck of the aneurysm, named communicating malapposition (CM), was investigated as a potential factor for delayed aneurysm healing. Methods 40 New Zealand White rabbits underwent elastase induced aneurysm creation, and were subsequently assigned to one of four treatment groups based on flow diverter type and administration of antiplatelet therapy. All animals underwent post device deployment balloon angioplasty and subsequent OCT to assess device/vessel apposition. The incidence of CM seen on OCT was assessed with a binary scoring system: 0–CM present; 1–CM absent. At 30 days, DSA was acquired to assess aneurysm healing. Aneurysm healing on terminal DSA was measured using a previously developed 5 point scale, with a score of 3 or 4 considered a positive outcome. Results All animals were grouped into a single cohort for analysis as no difference in the rate of CM or healing was seen in the four treatment groups. Significant interaction between the absence of CM and a positive outcome was confirmed by Fisher exact test (P=0.0034). Angioplasty was shown to treat 33% of the cases of CM seen at implant, and these treated cases overwhelmingly had a positive outcome (P<0.001). Conclusion The use of OCT to assess CM of flow diverters has been shown to be predictive of the 30 day healing rate of an animal model of aneurysms.

Robotic Assisted MRI-Guided Interventional Interstitial MR Guided Focused Ultrasound Ablation in a Swine Model

BACKGROUND Ablative lesions are current treatments for epilepsy and brain tumors. Interstitial magnetic resonance (MR) guided focused ultrasound (iMRgFUS) may be an alternate ablation technique which limits thermal tissue charring as compared to laser therapy (LITT) and can produce larger ablation patterns nearer the surface than transcranial MR guided focused ultrasound (tcMRgFUS). OBJECTIVE To describe our experience with interstitial focused ultrasound (iFUS) ablations in swine, using MR-guided robotically assisted (MRgRA) delivery. METHODS In an initial 3 animals, we optimized the workflow of the robot in the MR suite and made modifications to the robotic arm to allow range of motion. Then, 6 farm pigs (4 acute, 2 survival) underwent 7 iMRgFUS ablations using MRgRA. We altered dosing to explore differences between thermal dosing in brain as compared to other tissues. Imaging was compared to gross examination. RESULTS Our work culminated in adjustments to the MRgRA, iMRgFUS probes, and dosing, culminating in 2 survival surgeries; swine had ablations with no neurological sequelae at 2 wk postprocedure. Immediately following iMRgFUS therapy, diffusion-weighted imaging, and T1 weighted MR were accurate reflections of the ablation volume. T2 and fluid-attenuated inversion-recovery (FLAIR) images were accurate reflections of ablation volume 1-wk postprocedure. CONCLUSION We successfully performed MRgRA iFUS ablation in swine and found intraoperative and postoperative imaging to correlate with histological examination. These data are useful to validate our system and to guide imaging follow-up for thermal ablation lesions in brain tissue from our therapy, tcMRgFUS, and LITT.

Microcatheter navigation through the clot: does size matter?

Background Despite high recanalization rates achieved with endovascular treatment of acute ischemic strokes, around 50% of eligible patients will not achieve a good outcome. Parameters that may determine patient outcomes include: time from puncture to recanalization, the collateral status, the anesthesia regimen, blood pressure management, and distal emboli. Characterization of distal emboli generated during mechanical thrombectomy has been performed in previous studies. Objective To further investigate the risk of distal embolization associated with microcatheter navigation across the clot. Methods A contrast-enhanced clot analog was used in an in vitro model that mimicked a middle cerebral artery occlusion within a complete circle of Willis vascular replica. The clot was crossed with one of the following microcatheters: Pro18, XT-27 or 3MAX. The emboli generated during the procedure were collected and measured. Results The use of Pro18 and XT-27 resulted in a significant reduction of visible particles (size ≥500 µm) as compared with the 3MAX catheter (P<0.003). For the size range between 8 and 200 µm, there was a trend for Pro18 to generate fewer particles (−18%) than XT-27 but without statistical significance (P>0.05). In comparison with previously published data, acquired under the same conditions, it was found that the clot crossing maneuver accounts approximately for 12% of the total number of small emboli (<200 µm) induced during a stent retriever-mediated mechanical thrombectomy procedure via a balloon guide catheter. Conclusions The clot crossing maneuver has a significant effect on the total number of small particles induced during mechanical thrombectomy. Smaller microcatheter sizes should be favored when possible.

O-013 Communicating malapposition and its impact on aneurysm healing

Introduction/Purpose Malapposition has a negative correlation to aneurysm healing1. We examine the influence of malapposition communicating into the aneurysm, and the effect of malapposition incidence at any position along the parent artery on healing. We define communicating malapposition (CM) as any malapposition along the aneurysm neck (figure 1). We hypothesize that CM seen on optical coherence tomography (OCT) results in lower aneurysm occlusion rates after 30 days, and that malapposition at any other point along the parent artery has no effect. Materials and Methods Fifty New Zealand White rabbits underwent elastase-induced aneurysm creation.2 After 21 days, animals were randomly implanted with: Pipeline Embolization Device (PED; n=20); Pipeline Embolization Device with Shield technology (SHIELD; n=20); or, Flow Reduction Endoluminal Device (FRED; n=10). Five days prior to implantation, 10 animals from each group began dual antiplatelet therapy (DAPT; aspirin/clopidogrel 10 mg/kg each) which was continued daily until the 30 day terminal endpoint. All animals were used for statistical analysis in this study since the influence of DAPT yielded no significant impact on rates of aneurysm occlusion. All animals underwent post-deployment OCT to assess device/vessel apposition. At 30 days, DSA and OCT were acquired to assess aneurysm healing. The incidence of CM was assessed on a binary scoring system: 0 CM present; 1 CM absent. Aneurysm healing on DSA was measured using a previously developed 5-point scale3 – a score of 3 or 4 (neck remnant or complete occlusion) was considered a positive outcome. Separately, the presence of malapposition distal to the aneurysm neck was measured on a similar binary scale: 0- malapposition seen distal to aneurysm; 1 – no malapposition observed. A Fisher’s exact test was used to show significance. Abstract O-013 Figure 1 (A) OCT slice of aneurysm neck showing no communicating malapposition – final DSA occlusion score=4; (B) OCT slice of aneurysm neck showing communicating malapposition (arrow) – final occlusion score=1 Results Overall positive aneurysm outcome at 30 days was seen in 50% of cases (n=25), with no CM seen in 80% of those cases (n=20). Significant interaction between no CM and positive outcome was confirmed by a Fisher exact test, p=0.0014. When malapposition incidence along the parent artery distal to the aneurysm was compared to positive outcome, no significant interaction was found, p=0.776. Conclusion OCT shows potential in serving as an indicator of poor outcome in the presence of CM during device implant. From these data, absence of communicating malapposition is strongly associated with early aneurysm occlusion, whereas malapposition distal to the aneurysm showed no effect on rates of aneurysm healing. References . AJNR 2016;37(11):2087–91. 2. AJR. 2000;174:349–354. . AJNR 2012;33(10):2004–9. Disclosures R. King: None. O. Brooks: None. E. Langan: None. M. Marosfoi: None. F. Clarençon: None. T. Tamaura: None. J. Wainwright: 5; C; Medtronic Neurovascular. M. Gounis: 1; C; Medtronic Neurovascular. A. Puri: 1; C; Medtronic Neurovascular.

O-012 Acute clot formation on the surface of flow diverters can be reduced by using phosphoryl-choline surface modification

Introduction/Purpose Major ipsilateral ischemic stroke have been reported to range between 1.6%–4.3%1,2 after flow diverter treatment. Patient-specific contributors to peri-procedural thromboembolic complications remain under investigation. Beyond understanding and correcting patient-specific factors, we seek device technology to decrease these unpredictable complications. By using high resolution intravascular imaging tool (optical coherence tomography – OCT) we sought to determine the rate of acute micro-clot formation on the surface of different flow diverters. Furthermore, we assessed the consequences of angioplasty (after FD implant) with respect to acute clot formation. We hypothesize that a new generation phosphoryl-choline surface modified flow diverter may reduce acute clot formation on the surface of the device. Materials and methods Thirty elastase induced aneurysms were created in rabbits and treated with 3 different types of flow diverters. Classic Pipeline (C-PED), Pipeline-Flex with Shield Technology (S-PED) and FRED devices were implanted in 10 animals in each group. Four days prior to implant animals received dual anti-platelet therapy (DAPT: 10 mg/kg aspirin and clopidogrel) and that was continued until the end of the study (30 days). OCT (Dragonfly, St Jude) was used to assess the acute clot formation on the surface of devices, after deployment, and repeated 20 min after angioplasty (Figure). Thrombus formation was analyzed and scored by looking at 3 different locations along the implant. In addition, clot formation at the origins of covered side branches (OSB) was separately scored. Results At the origin of side branches, the S-PED showed a significantly less amount of clot formation both pre- and post-angioplasty (10% and 20%, versus C-PED: 40% and 60% and FRED: 60% and 90%, respectively, p=0.0065). At the 3 other locations (OSB not included): the distal end of the device, proximal end (including the level of the aneurysm) and the location between the aneurysm and the vertebral artery there was no difference in clot formation between the 3 devices immediately after deployment. However, following angioplasty of the devices, a decrease of clot formation was seen only in the S-PED group versus an increase as expected with the other devices (S-PED: 20% decrease, C-PED: 30% increase, FRED: 20% increase). Abstract O-012 Figure 1 Presence of clot formation at the origin of the internal thoracic artery (*) and diffuse clot along the surface of the device (**) Conclusion Our preliminary study supported our hypothesis that using phosphoryl-choline surface modified flow diverter can be useful to decrease the occurrence of micro-clot formation, especially post-angioplasty. Importantly, S-PED reduced clot formation at the origin of covered side-branches. References . AJNR 2015;36:98–107. . J. Neurosurg 2016;1–6. Disclosures M. Marosfoi: None. F. Clarençon: None. E. Langan: None. R. King: None. O. Brooks: None. T. Tamura: None. M. Gounis: 1; C; Medtronic Neurovascular. A. Puri: 1; C; Medtronic Neurovascular.