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Background: Tissue hypoxia plays a critical role in the events leading to cell death in ischemic stroke. Despite promising results in preclinical and small clinical pilot studies, inhaled oxygen supplementation has not translated to improved outcomes in large clinical trials. Moreover, clinical observations suggest that indiscriminate oxygen supplementation can adversely affect outcome, highlighting the need to develop novel approaches to selectively deliver oxygen to affected regions. This study tested the hypothesis that intravenous delivery of a novel oxygen carrier (Omniox-Ischemic Stroke [OMX-IS]), which selectively releases oxygen into severely ischemic tissue, could delay infarct progression in an established canine thromboembolic large vessel occlusion stroke model that replicates key dynamics of human infarct evolution. Methods: After endovascular placement of an autologous clot into the middle cerebral artery, animals received OMX-IS treatment or placebo 45 to 60 minutes after stroke onset. Perfusion-weighted magnetic resonance imaging was performed to define infarct progression dynamics to stratify animals into fast versus slow stroke evolvers. Serial diffusion-weighted magnetic resonance imaging was performed for up to 5 hours to quantify infarct evolution. Histology was performed postmortem to confirm final infarct size. Results: In fast evolvers, OMX-IS therapy substantially slowed infarct progression (by ≈1 hour, P P P =0.09). The final normalized infarct volume also did not show a significant difference (0.93 versus 0.95, OMX-IS drug versus control, P =0.34). Postmortem histologically determined infarct volumes showed excellent concordance with the magnetic resonance imaging defined ischemic lesion volume (bias: 1.33% [95% CI, −15% to 18%). Conclusions: Intravenous delivery of a novel oxygen carrier is a promising approach to delay infarct progression after ischemic stroke, especially in treating patients with large vessel occlusion stroke who cannot undergo definitive reperfusion therapy within a timely fashion.

BackgroundThe micro-architectonics of the subarachnoid space (SAS) remain partially understood and largely ignored, likely the result of the inability to image these structures in vivo. We explored transvascular imaging with high-frequency optical coherence tomography (HF-OCT) to interrogate the SAS.MethodsIn vivo HF-OCT was performed in 10 dogs in both the posterior and anterior cerebral circulations. The conduit vessels used were the basilar, anterior spinal, and middle and anterior cerebral arteries through which the perivascular SAS was imaged. The HF-OCT imaging probe was introduced via a microcatheter and images were acquired using a contrast injection (3.5 mL/s) for blood clearance. Segmentation and three-dimensional rendering of HF-OCT images were performed to study the different configurations and porosity of the subarachnoid trabeculae (SAT) as a function of location.ResultsOf 13 acquisitions, three were excluded due to suboptimal image quality. Analysis of 15 locations from seven animals was performed showing six distinct configurations of arachnoid structures in the posterior circulation and middle cerebral artery, ranging from minimal presence of SAT to dense networks and membranes. Different locations showed predilection for specific arachnoid morphologies. At the basilar bifurcation, a thick, fenestrated membrane had a unique morphology. SAT average thickness was 100 µm and did not vary significantly based on location. Similarly, the porosity of the SAT averaged 91% and showed low variability.ConclusionWe have demonstrated the feasibility to image the structures of the SAS with transvascular HF-OCT. Future studies are planned to further map the SAT to increase our understanding of their function and possible impact on neurovascular pathologies.

Expansions of a G(4)C(2) repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient derived cells and C9ORF72 BAC transgenic mice, we have generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G(4)C(2) repeat containing transcripts and effectively suppress tissue levels of polyGP dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G(4)C(2) repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of CSF polyGP. This report provides insight into the impact of nucleic acid chemistry on toxicity and for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Further clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber’s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (βgal) using a self-immolative βgal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1−/−) correlates with βgal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With >1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field., Graphical abstract, We describe a bio-responsive contrast agent that informs on the biodistribution and durability of gene expression in the lysosomal storage disease, GM1 gangliosidosis. We illustrate the sensitivity of this contrast agent to detect β-galactosidase enzyme in the central nervous system and periphery of an AAV-GLB-1-treated mouse model of GM1.

BackgroundPreclinical testing of intracranial stents is currently performed in the peripheral circulation, and rarely in the basilar artery of the dog.ObjectiveTo test the feasibility of intracranial stenting in the middle cerebral artery (MCA) of the dog and explore the use of MRI to detect thromboembolic complications.MethodsSix purpose-bred cross-hound dogs were used for proof-of-concept stenting of both MCAs in each animal. Immediately following the procedure, the animals were imaged with MRI. MRI was repeated weekly for 1 month. After the final angiography at 30 days, the animals were euthanized for pathological assessment of the stents and the brain.ResultsWe successfully deployed 12 stents in the MCAs of all animals. We deployed three techniques for microcatheterization of the MCA—namely, directly through the internal carotid artery (ICA), using anastomotic arteries from the external carotid artery, or via the contralateral ICA through the anterior communicating artery. Two iatrogenic perforations of the ICA with formation of an arteriovenous fistula occurred, without clinical sequelae, which spontaneously resolved on follow-up. All animals tolerated the procedure and completed the follow-up surveillance. MRI revealed procedural thromboembolic induced areas of restricted diffusion, and only one instance of a delayed thromboembolic lesion during surveillance. At follow-up angiography, the devices were all patent.ConclusionWe describe a new preclinical model of intracranial stenting in the MCA. Such a model may prove useful for evaluating new surface modifications.

BackgroundHigh-frequency optical coherence tomography (HF-OCT) is an intravascular imaging method that allows for volumetric imaging of flow diverters in vivo.ObjectiveTo examine the hypothesis that a threshold for both volume and area of communicating malapposition can be predictive of early aneurysm occlusion.MethodsFifty-two rabbits underwent elastase aneurysm formation, followed by treatment with a flow diverter. At the time of implant, HF-OCT was acquired to study the rate and degree of communicating malapposition. Treated aneurysms were allowed to heal for either 90 or 180 days and euthanized following catheter angiography. Healing was dichotomized into aneurysm remnant or neck remnant/complete occlusion. Communicating malapposition was measured by HF-OCT using a semi-automatic algorithm able to detect any points where the flow diverter was more than 50 µm from the vessel wall. This was then summed across image slices to either a volume or area. Finally, a subsampled population was used to train a statistical classifier for the larger dataset.ResultsNo difference in occlusion rate was found between device type or follow-up time (p=0.28 and p=0.67, respectively). Both volume and area of malapposition were significantly lower in aneurysms with a good outcome (p3 or a normalized area less than 0.69 as quantified by HF-OCT was predictive of occlusion (pConclusionsHF-OCT allows for measurements of both volume and area of malapposition and, from these measurements, an accurate prediction for early aneurysm occlusion can be made.

Background Neurointerventionalists use in-vitro vascular models to train for worst-case scenarios and test new devices in a simulated use environment to predict clinical performance. According to the Food and Drug Administration (FDA), any neurovascular navigation device should be able to successfully navigate two 360-degree turns and two 180-degree turns at the distal portion of the anatomical model. Here, we present a device benchmarking vascular model that complies with FDA recommendations. Methods Our vascular model was assembled from quantitative characterization of 49 patients who underwent CT angiography either for acute ischemic stroke caused by large vessel occlusion or for aneurysm treatment. Following complete characterization of these data, the vascular segments were 3D reconstructed from CT angiograms of 6 selected patients that presented with challenging anatomy. The curvature and total rotational angle were calculated for each segment and the anatomical parts that complied with FDA recommendations were fused together into a single in-vitro model. Results The model was constructed containing two common carotid branches arising from a type two aortic arch and the dimensions of the overall model exceeded the recommendations of the FDA. Two experienced neurointerventionalists tested the model for navigation difficulty using several devices on an in-vitro perfusion system and concluded that the model provided a realistic, challenging scenario. Conclusions This model provides a first prototype designed according to FDA recommendations of cumulative angle while also integrating an aggregation of actual patient-specific anatomy. The availability of this clinically relevant benchmark model presents a potential standardized approach for neurovascular device testing.

BackgroundHigh-frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging technique capable of assessing device-vessel interactions at spatial resolution approaching 10 µm. We tested the hypothesis that adequately deployed Woven EndoBridge (WEB) devices as visualized by HF-OCT lead to higher aneurysm occlusion rates.MethodsIn a leporine model, elastase-induced aneurysms (n=24) were treated with the WEB device. HF-OCT and digital subtraction angiography (DSA) were performed following WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion (0-present, 1-absent) and malapposition (0-malapposed, 1-neck apposition >50%) were binary coded. A device was considered ‘adequately deployed’ by HF-OCT and DSA if apposed and non-protruding. Aneurysm healing on DSA was reported using the 4-point WEB occlusion score: A or B grades were considered positive outcome. Neointimal coverage was quantified on HF-OCT images at 12 weeks and compared with scanning electron microscopy (SEM).ResultsAdequate deployment on HF-OCT correlated with positive outcome (P=0.007), but no statistically significant relationship was found between good outcome and adequate deployment on DSA (P=0.289). Absence of protrusion on HF-OCT correlated with a positive outcome (P=0.006); however, malapposition alone had no significant relationship (P=0.19). HF-OCT showed a strong correlation with SEM for the assessment of areas of neointimal tissue (R²=0.96; PConclusionHF-OCT visualizes features that can determine adequate device deployment to prognosticate early aneurysm occlusion following WEB implantation and can be used to longitudinally monitor aneurysm healing progression.

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated., High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature.

Background Tissue growth over covered branches is a leading cause of delayed thrombotic complications after flow-diverter stenting (FDS). Due to insufficient resolution, no imaging modality is clinically available to monitor this phenomenon. Objective To evaluate high-frequency optical coherence tomography (HF-OCT), a novel intravascular imaging modality designed for the cerebrovascular anatomy with a resolution approaching 10 microns, to monitor tissue growth over FDS in an arterial bifurcation model. Methods FDS were deployed in a rabbit model (n = 6), covering the aortic bifurcation. The animals were divided in different groups, receiving dual antiplatelet therapy (DAPT) (n = 4), aspirin only (n = 1), and no treatment (n = 1). HF-OCT data were obtained in vivo at 3 different time points in each animal. For each cross-sectional image, metal and tissue coverage of the jailed ostium was quantified. Scanning electron microscopy images of harvested arteries were subsequently obtained. Results Good quality HF-OCT data sets were successfully acquired at implant and follow-up. A median value of 41 (range 21-55) cross-sectional images were analyzed per ostium for each time point. Between 0 and 30 d after implant, HF-OCT analysis showed a significantly higher ostium coverage when DAPT was not given. After 30 d, similar growth rates were found in the DAPT and in the aspirin group. At 60 d, a coverage of 90% was reached in all groups. Conclusion HF-OCT enables an accurate visualization of tissue growth over time on FDS struts. The use of FDS in bifurcation locations may induce a drastic reduction of the jailed-branch ostium area.

The implantation of flow diverters requires administration of dual anti-platelet therapy, posing the potential for complications. The p48MW HPC (phenox, Bochum, Germany) hydrophilic-coated flow diverting stent is designed to be anti-thrombotic, thus opening the potential for single anti-platelet therapy. We deploy a novel intravascular high-resolution imaging technique, high-frequency optical coherence tomography (HF-OCT), to study in an animal model the acute thrombus formation on coated p48MW devices versus uncoated control devices. Three pigs were implanted with 4 flow diverters each, two test hydrophilic-coated devices, and two control uncoated devices (p48MW). Each pig was treated with a different anti-platelet regime: no anti-platelet therapy, aspirin only, aspirin and clopidogrel. Twenty minutes after the flow diverter was implanted, an HF-OCT data set was acquired. Acute clot formed on the flow diverter at each covered side branch was measured from the HF-OCT slices. Factors considered to be important were the device type (pHPC versus bare metal), aspirin, clopidogrel, and vessel location. A linear model was constructed from the significant factors. Both coating (p

Localized delivery of diagnostic/therapeutic agents to cerebral aneurysms, lesions in brain arteries, may offer a new treatment paradigm. Since aneurysm rupture leading to subarachnoid hemorrhage is a devastating medical emergency with high mortality, the ability to noninvasively diagnose high‐risk aneurysms is of paramount importance. Moreover, treatment of unruptured aneurysms with invasive surgery or minimally invasive neurointerventional surgery poses relatively high risk and there is presently no medical treatment of aneurysms. Here, leveraging the endogenous biophysical properties of brain aneurysms, we develop particulate carriers designed to localize in aneurysm low‐shear flows as well as to adhere to a diseased vessel wall, a known characteristic of high‐risk aneurysms. We first show, in an in vitro model, flow guided targeting to aneurysms using micron‐sized (2 μm) particles, that exhibited enhanced targeting (>7 folds) to the aneurysm cavity while smaller nanoparticles (200 nm) showed no preferable accumulation. We then functionalize the microparticles with glycoprotein VI (GPVI), the main platelet receptor for collagen under low‐medium shear, and study their targeting in an in vitro reconstructed patient‐specific aneurysm that contained a disrupted endothelium at the cavity. Results in this model showed that GPVI microparticles localize at the injured aneurysm an order of magnitude (>9 folds) more than control particles. Finally, effective targeting to aneurysm sites was also demonstrated in an in vivo rabbit aneurysm model with a disrupted endothelium. Altogether, the presented biophysical strategy for targeted delivery may offer new treatment opportunities for cerebral aneurysms.

Mechanical thrombectomy for the treatment of ischemic stroke shows high rates of recanalization; however, some patients still have a poor clinical outcome. A proposed reason for this relates to the fact that the ischemic infarct growth differs significantly between patients. While some patients demonstrate rapid evolution of their infarct core (fast evolvers), others have substantial potentially salvageable penumbral tissue even hours after initial vessel occlusion (slow evolvers). We show that the dog middle cerebral artery occlusion model recapitulates this key aspect of human stroke rendering it a highly desirable model to develop novel multimodal treatments to improve clinical outcomes. Moreover, this model is well suited to develop novel image analysis techniques that allow for improved lesion evolution prediction; we provide proof-of-concept that MRI perfusion-based time-to-peak maps can be utilized to predict the rate of infarct growth as validated by apparent diffusion coefficient-derived lesion maps allowing reliable classification of dogs into fast versus slow evolvers enabling more robust study design for interventional research.\ud \ud

Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington’s disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders. A divalent siRNA architecture enables sustained silencing of gene expression in deep regions of the brain.

Introduction: The ADAPT technique uses large bore aspiration catheters for mechanical thrombectomy. Several aspiration catheters are now available. We report a bench-top exploration of a beveled-tip catheter, and our experience in treating large vessel occlusions using next-generation aspiration catheters. Methods: Twenty experiments were conducted with either a Sofia Plus or a Zoom71 using a vascular phantom in which a clot model was introduced. Rate of ingestion, complete recanalization after a single attempt, and pressure at the catheter tip for both devices were recorded. A retrospective analysis from a prospectively-maintained database was performed. Patient demographics, periprocedural metrics, discharge and 90-day modified Rankin Scales were collected. Patients were divided into two groups based on which aspiration catheter was used. Results: In our bench-top experiment, complete ingestion of the clot occurred in 90% of beveled tip and 20% of control device experiments (p=0.006). Our clinical data demonstrated no significant difference in age, gender, IV tPA administration, admission NIHSS, baseline mRS, or LVO location between the beveled tip and flat tip groups. With the beveled tip, TICI 2C or better recanalization was more frequent (93.2% vs 74.2%, p-value 0.017), stent retriever usage was lower (9.1% versus 29%, p-value 0.024), and patients had lower mRS on discharge (median 3 vs 4, p less than 0.001) and at 90 days (median 2 vs 4, p=0.008). Conclusion: The beveled tip design leads to more frequent clot ingestion in a bench top model, which may translate into a more efficacious thrombectomy device with improved outcomes.

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2’-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds.

Expansions of a G4C2 repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Proposed disease mechanisms include a gain of toxic functions of the G4C2 repeats, implying that selective reduction in levels of the repeat-containing transcripts would represent a treatment strategy for this disorder. In the present study, using C9-ALS/FTD patient derived cells and C9ORF72 BAC transgenic mice, we have generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G4C2 repeat containing transcripts in both the sense and anti-sense strands of C9ORF72 and effectively suppress tissue levels of polyGP dipeptides. In a single patient harboring mutant C9ORF72 with the G4C2 repeat expressions, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of CSF polyGP.

Introduction Animal models of saccular aneurysms are stable following creation, and do not actively remodel or rupture. Recently, rodent models of aneurysm wall remodeling and rupture have been described by surgical grafting of decellularized arterial tissue.1 We sought to 1) develop and apply a modified in situ decellularization approach, not require complex grafting procedures, in a large animal model of saccular aneurysms and 2) investigate modified aneurysmal expansion and inflammation using in vivo imaging. Methods 18 New Zealand White rabbits (3.0–3.5 kg) underwent standard elastinolysis aneurysm creation of the right common carotid artery. The animals were randomized 2:1 to receive isolated vessel SDS treatment (perfusion with 1% solution for 45 min) or nothing. Every two weeks until week 8, three of the rabbits (2 SDS+elastase, 1 elastase), were subjected to MR imaging,2 followed by contrast injection with stable macrocyclic gadolinium(III)-based contrast agent that has been shown to selectively enhance the areas of vessel wall myeloperoxidase (MPO) accumulation.3 4 The MRI was repeated at 3 hours post contrast injection and the enhancement ratio (ER) was calculated. All aneurysms were measured for size by digital subtraction angiography. Results Of the 17 rabbits included in the study, 11 were treated in situ with SDS following elastase incubation and 6 served as controls. One SDS-treated rabbit was excluded due to rupture of the carotid artery during recovery. During follow-up MR imaging the ER was greater than 1 for all SDS-treated animals, whereas the controls had an ER of greater than 1 only at the two-week timepoint (consistent with the expected healing process). Average ER for SDS-treated animals was 1.63±0.20, while control animals had an ER of 1.02±0.06 (p Conclusions During the 12 weeks post aneurysm creation, MPO-mediated MR signal enhancement was continuously detected within the wall of the aneurysm, and other than at 2 weeks, only in the SDS-treated animals. This novel modified large animal aneurysm model is expected to be useful for testing of new therapies that rely on not only the mechanical properties of the aneurysm but also the biological processes that make aneurysms vulnerable to rupture. References Stroke 2014;45:248–254. AJNR2015;36:146–52. Radiology 2009;252:696–703. Sci Rep 2018;8:7687. Disclosures R. King: None. J. Caroff: 1; C; FullBright. A. Leopardi: None. A. Bogdanov: None. M. Gounis: None.

Introduction Neuroprotective strategies represent a significant opportunity to delay infarct progression in patients suffering a Large Vessel Occlusion (LVO), allowing more time for treatment by mechanical thrombectomy. Oxygen carrier therapy has the potential to deliver oxygen to hypoxic tissues, allowing for a longer window of treatment before cell death. Methods Twenty-three dogs were used in this study, with an additional 14 historical controls. Autologous clot was injected into the left MCA, confirmed on DSA, and the dog was transferred to a 3T MRI. In order to determine infarct evolution rate, Perfusion Weighted Imaging was performed and relative Time to Peak (rTTP) maps were generated.1 Based on the initial infarct evolution pathway (slow or rapid progressors), animals were randomized to either receive oxygen carrier or vehicle control. Regardless of evolution pathway, or treatment group, IV bolus was given 45 minutes after clot placement. Following bolus, diffusion weighted imaging (DWI) was performed every 30 minutes to assess infarct evolution. After 5 hours, dogs were removed from the MR, euthanized and the brain was explanted for histological processing. To calculate the true infarct volume, apparent diffusion coefficient (ADC) was calculated from the DWI images, and a threshold value of 0.533 × 10-3 mm2/s was used to differentiate infarct. The predicted final infarct size was taken from rTTP maps as the area with greater than 4.5s delay and used to normalize infarct volume. Results Of the 23 dogs used in the active group, 5 were excluded due to spontaneous recanalization or lack of sufficient infarct on DWI. From the included 18 dogs, 11 were identified as rapid progressors, and 7 as slow. The figure shows the average infarct growth rate for the four groups, showing the oxygen carrier increasing the time needed for the infarct to reach 50% of its expected size by approximately 45 minutes in the rapid group, and 30 minutes in the slow. Overall the final infarct size was reduced in both the rapid and slow groups, 0.99 vs 0.87 control versus treatment, and 0.97 vs 0.92 control versus treatment, respectively (p Conclusions Oxygen carrier therapy shows promise to slow down the infarct growth after an LVO, allowing for more time to perform mechanical thrombectomy. Not only was the time to 50% infarct increased, but after 5 hours, the infarct in the oxygen carrier groups still showed an area of penumbra. Reference Transl Stroke Res. 2019 Sep 3. Disclosures R. King: None. M. Shazeeb: None. J. Kolstad: None. C. Raskett: None. J. Winger: 5; C; Omniox Inc. L. Kelly: 5; C; Omniox Inc. Z. Vardar: None. A. Kraitem: None. V. Anagnostakou: None. A. Krtolica: 5; C; Omniox Inc. N. Henninger: 1; C; K08NS091499. M. Gounis: None.

Introduction High Frequency Optical Coherence Tomography (HF-OCT)1 is an intra-vascular imaging technique to assess device-vessel interactions and neointimal tissue growth at unprecedented spatial resolution (~10µm). In this study, we tested the hypothesis that an adequately deployed (as visualized by HF-OCT) Woven EndoBridge (WEB, Microvention, Aliso Viejo, CA) will lead to a higher aneurysm occlusion rate at 12-week follow-up in an animal model of aneurysms. Methods Elastase-induced rabbit aneurysms (n=24) were treated with the WEB device. HF-OCT (Vis-M; Gentuity LLC, Sudbury MA) and DSA were performed after WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion and malapposition were binary coded (0- present, 1- absent; 0- malapposed, 1- neck apposition >50%), respectively, on HF-OCT and DSA. A device was considered adequately deployed if it was scored as 1 on both metrics. Aneurysm healing on DSA was interpreted using the 4-point WEB occlusion score (WOS)2; with A-B considered a positive outcome. HF-OCT images acquired at 12 weeks were analyzed and neointimal coverage quantified. Scanning electron microscopy (SEM) was performed of the explanted specimens. Results Discrepancy between HF-OCT and DSA was found: HF-OCT classified as adequately deployed a total of 5 cases, whereas 8 cases were classified as adequately deployed by DSA images. Acceptable WOS grade at 12 weeks was seen in 21% of cases (n=5): 80% of those cases (n=4) were classified as adequately deployed based by HF-OCT; whereas only 60% of those cases (n=3) classified adequate by DSA. A significant interaction between adequate deployment on HF-OCT and positive outcome was confirmed (p=0.007). However, there was no statistically significant relationship between good outcome and adequate deployment based on DSA images (p=0.289). Based on HF-OCT images, the absence of the protrusion was related with a positive outcome (p=0.006); however, malapposition had no significant interaction with positive outcome (p=0.19). The area of neointimal tissue quantified by HF-OCT showed a strong correlation with SEM assessment (R²=0.96; p Conclusion HF-OCT may be valuable prognosticate adequate aneurysm occlusion with the WEB and can be used to monitor aneurysm healing longitudinally. Absence of protrusion was associated with subsequent aneurysm occlusion; however, malapposition alone did not show an effect on the rate of aneurysm healing. Reference Stroke. 2018:Nov29:STROKEAHA118022315 2. AJNR 2014;35:432–8. Disclosures Z. Vardar: None. R. King: None. A. Kraitem: None. E. Langan: None. L. Peterson: None. B. Duncan: None. C. Raskett: None. V. Anagnostakou: None. M. Gounis: None. A. Puri: None. G. Ughi: None.

Background The new generation of intrasaccular flow disruptors offers several potential advantages in aneurysm treatment.1 2 However, questions regarding risks for thromboembolic complications3 4 and long-term treatment durability remain. We study the safety and effectiveness of three Galaxy Therapeutics Seal© intrasaccular prototypes: A, B, and C (Galaxy Therapeutics LLC, Brookfield, WI). Methods Aneurysms were created in thirteen rabbits and one of 3 Seal devices were implanted. High frequency optical coherence tomography (HF-OCT) and Digital Subtraction Angiography (DSA) was performed 4- and 12-weeks post-implant. After 12 weeks, the parent vessel and the aneurysm were explanted for histological analysis. One rabbit developed symptoms consistent with a lumbar spine injury and was euthanized and explanted at day 56. Results 12-week DSA and OCT images demonstrated 8 animals had a satisfactory aneurysm occlusion (group 1: complete blood flow disruption or contrast filling in marker recess) and 4 into group 2 (residual neck or aneurysm). The percentage of neointimal coverage of the device at four-weeks was greater for group 1 (78±22.6%) than for group 2 (37 ±4.7%) (p=0.006) which persisted at 12-weeks (87.5± 14% vs. 41±3.1% respectively; p=0.004). There was no statistical difference between groups 1 and 2 in either baseline neck gap areas (0.8±0.64 mm2 vs. 2.6±1.42 mm2, respectively; p=0.808) nor in baseline neck gap volumes (26±26 mm3 vs. 113.11±134.17 mm3, respectively; p=0.361). Representative examples of pathology are shown in the figure 1. Conclusion Preliminary evidence in this preclinical study highlight advantages of a new generation of intrasaccular aneurysm embolization technology in terms of flexibility and optimization of healing features, particularly in the A and C cohorts. References Radiology 2014;273:194–201. J Neurointerv Surg 2019;11:1150–1154. World Neurosurg 2018;109:e183–e193. J Neurointerv Surg 2018;10:553–559. Disclosures A. Kraitem: None. M. Gounis: 1; C; Research grant to institution to fund experiments by Galaxy Therapeutics. Z. Vardar: None. R. King: None. E. Langan: None. T. Wolfe: 4; C; Founder, Galaxy Therapeutics. A. Badruddin: 4; C; Founder, Galaxy Therapeutics. E. Periera: 4; C; Founder, Galaxy Therapeutics. B. Follmer: 5; C; Galaxy Therapeutics. A. Rosqueta: 5; C; Galaxy Therapeutics. O. Zaidat: 4; C; Founder, Galaxy Therapeutics.

ObjectiveTo investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation.Methods18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks. Every 2 weeks, three of the rabbits (two elastase + SDS, one control) underwent MRI, followed by contrast injection with myeloperoxidase (MPO)-sensing contrast agent. MRI was repeated 3 hours after contrast injection and the enhancement ratio (ER) was calculated. Following MRI, aneurysms were explanted and subjected to immunohistopathology.ResultsDuring follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (pConclusionsIn situ decellularization of a large animal model of saccular aneurysms reproduces features of unstable aneurysms, such as chronic inflammation (up to 12 weeks) and active aneurysm wall remodeling, leading to continued growth over 8 weeks.

In 2015, multiple randomized clinical trials showed an unparalleled treatment benefit of stent-retriever thrombectomy as compared to standard medical therapy for the treatment of a large artery occlusion causing acute ischemic stroke. A short time later, the HERMES collaborators presented the patient-level pooled analysis of five randomized clinical trials, establishing class 1, level of evidence A for stent-retriever thrombectomy, in combination with intravenous thrombolysis when indicated to treat ischemic stroke. In the years following, evidence continues to mount for expanded use of this therapy for a broader category of patients. The enabling technology that changed the tide to support endovascular treatment of acute ischemic stroke is the stent-retriever. This review summarizes the history of intra-arterial treatment of stroke, introduces the biomechanics of embolus extraction with stent-retrievers, describes technical aspects of the intervention, provides a description of hemodynamic implications of stent-retriever embolectomy, and proposes future directions for a more comprehensive, multi-modal endovascular approach for the treatment of acute ischemic stroke.

Introduction: Optical coherence tomography (OCT) has played an important role in the diagnosis and treatment guidance in coronary artery disease. However, existing OCT systems are not suitable for routine neurovascular applications due to the size and tortuosity of the arteries. Hypothesis: We seek to demonstrate a prototype high-frequency OCT (HF-OCT) capable of high-resolution imaging in simulated cerebrovascular anatomy. Methods: A low-profile HF-OCT system was constructed with an image resolution approaching 10μm. Using an in vitro, patient-specific model of the circle of Willis with circulating porcine blood, we characterized the delivery of the device and ability to image in a tortuous path. Also, human cadaver intracranial atherosclerosis plaques were imaged with HF-OCT and assessed by an expert imager. Finally, neurovascular devices were implanted in 8 pigs (Fig 1) and HF-OCT imaging was compared with gold-standard DSA and CT. Results: In the phantom, optimal blood clearance was achieved through an intermediate catheter (5 Fr Navien) with infusion of contrast at 5 ml/s in the internal carotid and basilar artery, and 3 ml/sec in the MCA. The in vivo study demonstrated that both malapposition of devices or thrombus formation along the device surface could be reliably diagnosed among 3 reviewers (Fleiss’s kappa of 0.87 and 0.9, respectively). This agreement was superior to DSA and CT. Imaging in tortuous swine brachial showed in all cases imaging free of artifacts, uniform illumination and ability to visualize vessel wall layers. Plaque types including ‘lipid pools’, fibrotic, and calcific tissue from cadaver specimens of ICAD could be adequately depicted by HF-OCT. Conclusion: In vitro, in vivo and ex vivo characterization of a novel HF-OCT device has shown it is capable of imaging in the tortuous intracranial vascular anatomy. This technology has to potential to aid in the diagnosis of cerebrovascular disease and guide optimal endovascular treatment.

The implantation of flow diverters requires administration of dual anti-platelet therapy, posing the potential for complications. The p48MW HPC (phenox, Bochüm, Germany) hydrophilic-coated flow diverting stent is designed to be anti-thrombotic, thus opening the potential for single anti-platelet therapy. We deploy a novel intravascular high-resolution imaging technique, high-frequency optical coherence tomography (HF-OCT), to study in an animal model the acute thrombus formation on coated p48MW devices versus uncoated control devices.Three pigs were implanted with 4 flow diverters each, two test hydrophilic-coated devices, and two control uncoated devices (p48MW). Each pig was treated with a different anti-platelet regime: no anti-platelet therapy, aspirin only, aspirin and clopidogrel. Twenty minutes after the flow diverter was implanted, an HF-OCT data set was acquired. Acute clot formed on the flow diverter at each covered side branch was measured from the HF-OCT slices. Factors considered to be important were the device type (pHPC versus bare metal), aspirin, clopidogrel, and vessel location. A linear model was constructed from the significant factors.Both coating (p 0.001) and aspirin (p = 0.003) were significantly related to reduction in clot burden, leading to an approximate 100-fold and 50-fold reduction in clot, respectively.This study shows the power of HF-OCT not only in the detection of clot but also the quantification of clot burden. In an animal model, the pHPC-coated p48MW significantly reduced acute thrombus formation over jailed side branches as compared to the bare metal p48MW that was nearly eliminated when combined with aspirin administration.

Mechanical thrombectomy to treat large vessel occlusions (LVO) causing a stroke is one of the most effective treatments in medicine, with a number needed to treat to improve clinical outcomes as low as 2.6. As the name implies, it is a mechanical solution to a blocked artery and modeling these mechanics preclinically for device design, regulatory clearance and high-fidelity physician training made clinical applications possible. In vitro simulation of LVO is extensively used to characterize device performance in representative vascular anatomies with physiologically accurate hemodynamics. Embolus analogues, validated against clots extracted from patients, provide a realistic simulated use experience. In vitro experimentation produces quantitative results such as particle analysis of distal emboli generated during the procedure, as well as pressure and flow throughout the experiment. Animal modeling, used mostly for regulatory review, allows estimation of device safety. Other than one recent development, nearly all animal modeling does not incorporate the desired target organ, the brain, but rather is performed in the extracranial circulation. Computational modeling of the procedure remains at the earliest stages but represents an enormous opportunity to rapidly characterize and iterate new thrombectomy concepts as well as optimize procedure workflow. No preclinical model is a perfect surrogate; however, models available can answer important questions during device development and have to date been successful in delivering efficacious and safe devices producing excellent clinical outcomes. This review reflects on the developments of preclinical modeling of mechanical thrombectomy with particular focus on clinical translation, as well as articulate existing gaps requiring additional research.

BackgroundNeo-intimal hyperplasia (NIH) is frequently observed after flow-diverter stent (FDS) implantation. Although mostly asymptomatic, this vascular response can sometimes lead to delayed ischemic strokes. This study intended to evaluate the factors potentially influencing the rates of NIH following FDS treatment.Material and MethodsAll aneurysm treatments performed with a Pipeline embolization device (PED) or a SILK stent from May 2011 to May 2015 were collected in a prospectively maintained database. Patient demographics, clinical, and angiographic outcomes including both digital subtraction angiography and C-arm cone-beam CT were registered. Two blind reviewers rated the presence of NIH on a binary scale (present/absent).ResultsFrom 148 patients, 63 datasets were available for analysis. Inter-reader agreement was excellent (Kappa=0.88). NIH was positively correlated with smoking, dyslipidemia, and high blood pressure, but not with aneurysm characteristics. At early follow-up (ConclusionNIH is a dual-vessel reaction after FDS implant. When planning a treatment in locations at risk of ischemic complications if severe NIH would occur, then the stent design should be considered. However, minimal NIH might also be needed as it is involved in aneurysm healing. Before treatment patients should be recommended best medical management of their cardiovascular risks factors to prevent an excessive NIH reaction.

BackgroundDespite 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.ObjectiveTo further investigate the risk of distal embolization associated with microcatheter navigation across the clot.MethodsA 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.ResultsThe use of Pro18 and XT-27 resulted in a significant reduction of visible particles (size ≥500 µm) as compared with the 3MAX catheter (P0.05). 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 (ConclusionsThe 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.

PurposeThromboembolic 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).MethodsElastase-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.ResultsFollowing angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (pConclusionIn the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.

Background and purposeCurrently, there is neither a standard protocol for vessel wall MR imaging of intracranial atherosclerotic disease (ICAD) nor a gold standard phantom to compare MR sequences. In this study, a plaque phantom is developed and characterized that provides a platform for establishing a uniform imaging approach for ICAD.Materials and methodsA patient specific injection mold was 3D printed to construct a geometrically accurate ICAD phantom. Polyvinyl alcohol hydrogel was infused into the core shell mold to form the stenotic artery. The ICAD phantom incorporated materials mimicking a stenotic vessel and plaque components, including fibrous cap and lipid core. Two phantoms were scanned using high resolution cone beam CT and compared with four different 3 T MRI systems across eight different sites over a period of 18 months. Inter-phantom variability was assessed by lumen dimensions and contrast to noise ratio (CNR).ResultsQuantitative evaluation of the minimum lumen radius in the stenosis showed that the radius was on average 0.80 mm (95% CI 0.77 to 0.82 mm) in model 1 and 0.77 mm (95% CI 0.74 to 0.81 mm) in model 2. The highest CNRs were observed for comparisons between lipid and vessel wall. To evaluate manufacturing reproducibility, the CNR variability between the two models had an average absolute difference of 4.31 (95% CI 3.82 to 5.78). Variation in CNR between the images from the same scanner separated by 7 months was 2.5–6.2, showing reproducible phantom durability.ConclusionsA plaque phantom composed of a stenotic vessel wall and plaque components was successfully constructed for multicenter high resolution MRI standardization.

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

Introduction High frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging modality designed for cerebrovascular anatomy. With a spatial resolution approaching 10 µm, HF-OCT can visualize the interaction between the vessel wall and neurovascular devices in great detail.1, 2 In this study, we sought to evaluate its use to monitor tissue growth over flow diverter stents (FDS) in an arterial bifurcation rabbit model. Materials and methods Six FDS (Pipeline Embolization devices) were deployed in 6 animals, covering the iliac bifurcation. Four animals were treated with double antiplatelet therapy (10 mg/kg aspirin and clopidogrel), 1 with aspirin (10 mg/kg) and 1 was not given any treatment. HF-OCT data were obtained at three different time points per each animal (at implant for all animals then 14 and 60 or 7 and 30 days). For each ostium section, manual segmentation was performed to quantify the percentage of the ostium surface covered by metal and tissue (figure 1A). Results Good quality HF-OCT data sets were successfully acquired in all cases. An average of 35 sections (with a spacing between sections of approximately 70 µm) were analyzed per ostium for each time point. Between 0 and 30 days after implant, HF-OCT analysis showed a significantly higher ostium coverage when DAPT was not given. After 30 days, similar growth rates were found in the DAPT and in the aspirin group (Figure 1B). At 60 days a high 90% coverage rate was reached in both groups. Conclusions HF-OCT enables an accurate visualization of tissue growth over time on FDS struts. HF-OCT imaging can contribute in the pre-clinical evaluation of novel neurovascular devices and, in the near-future, it could potentially contribute to a personalized care, helping the physicians in determining and modulating the ideal antiplatelet regimen for each patient. References Chen C-J, Kumar JS, Chen SH, et al. Optical coherence tomography: future applications in cerebrovascular imaging. Stroke 2018. Gounis MJ, Ughi GJ, Marősfoi M, et al. Intravascular optical coherence tomography for neurointerventional surgery. Stroke 2018. Disclosures J. Caroff: None. G. J. Ughi: 4; C; Gentuity LLC. 5; C; Employee of Gentuity LLC. R. King: None. M. Marosfoi: None. E. Langan: None. M. Gounis: None.

Introduction Thrombectomy has rates of successful recanalization of nearly 85%1; however, many patients may not be eligible or not have a successful outcome following recanalization if the infarct evolves prior to arriving to the angiosuite. Neuroprotection that ‘freezes’ the penumbra to allow a longer window to receive treatment has become the next critical topic in stroke care2. The canine temporary large vessel occlusion model has been recently developed to allow for assessment of neuroprotectants. A limitation of this model is the rate of stroke evolution tends towards one of two pathways: fast evolution, where more than half the total infarct volume is present within 90 minutes; and slow evolution, where less than half the final volume occurs within 90 minutes. Here we present a novel analysis of MR based Time-to-Peak (TTP) maps, derived from perfusion-weighted MRI (PW-MRI), to classify the canine stroke evolution based on the first PW-MRI. Methods Fourteen dogs were retrospectively analyzed for patterns of stroke evolution. An autologous clot was injected into the MCA in order to cause an occlusion. Once the occlusion was confirmed, the animal was moved to the MRI scanner. MRI protocol included Time of Flight (ToF), Diffusion weighted (DWI) and perfusion weighted (PWI) imaging. For PWI 0.2mmol/kg gadopentetate dimeglumine was injected IV. To calculate the true volume of stroke, ADC maps were generated from the DWI images. The TTP maps were normalized relative to the unaffected contralateral half of the brain. The TTP map was registered to the DWI images to only account for voxels within the stroke volume. Finally, all voxels of the TTP map within the ADC lesion were binned into one of four categories: slight delay (4–8s), moderate delay (9–13s), long delay (14–18s) and extended delay (≥19s). Results Using the DWI evolution as the ground truth, the canines were categorized into two groups of fast and slow evolvers (figure 1A). The binned TTP maps in the slight delay and extended delay groups also accurately predicted the evolution pathway in classifying all the canines in this study (figure 1B, p Conclusions The ability to predict the rate of stoke evolution, at the point of first MRI, will allow for a better understanding of new therapeutics. Here we have shown that by analyzing the degree of delay from the TTP map, the rate of evolution of the stroke can be predicted. References Acute Stroke. Stroke 2017;48:1588–1593. Stroke. 2011;42:3265-3270. Disclosures R. King: None. O. Brooks: None. M. Gounis: None. M. Shazeeb: None.

Introduction The use of flow diverters has emerged as an effective treatment of aneurysm. One of the major limitations of flow diverters is the need to put patients on dual anti-platelet therapy (DAPT). The exposure of bare metal struts leads to platelet activation. A method to assess the degree of neointimal tissue ingrowth over the surface of the device could permit patient-specific tailoring of DAPT. Currently, the standard of follow-up for flow diverter patients is digital subtraction angiography (DSA); however, it has been previously reported DSA appearance of complete aneurysm occlusion is not always reliable with continued aneurysm growth.1 There have been reported cases of very delayed complications after DAPT has been stopped,2 although rare, such complications can be catastrophic. High Frequency Optical Coherence Tomography (HF-OCT) is a novel intravascular imaging technique designed for use in cerebrovascular anatomy with a spatial resolution approaching 10 microns. In this study, we sought to compare HF-OCT with state-of-the-art DSA for the in vivo evaluation of complete aneurysm occlusion. Methods Flow diverters were implanted in 15 rabbits, at least 21 days after a standard elastase aneurysm creation. Six of the rabbits were imaged at 15 days post implant, including both DSA and HF-OCT to assess healing of the aneurysm. The remaining 9 rabbits were allowed to heal for 60 days, at which point they also received HF-OCT. Finally, the rabbits were euthanized, perfused with formalin, and the aneurysms were explanted for histological analysis. Results Fifteen days following implant, one aneurysm was seen to be fully occluded on DSA, but HF-OCT demonstrated an aneurysm remnant, and the struts remained uncovered (figure 1D-E). At 60 days post-implant, another aneurysm appeared fully healed on DSA, yet HF-OCT demonstrated that the aneurysm remained in communication with the parent artery (figure 1A-B). This observation was later confirmed on SEM (figure C). Conclusions Preliminary evidence is presented showing that DSA alone is insufficient to confirm complete aneurysm occlusion. HF-OCT may reliably show parent artery remodeling and inform patient-specific decisions regarding duration of DAPT. References AJNR June 2012;33(6):1150–1155. J Neurosurg 2016;125:929–935. Disclosures R. King: None. M. Marsofoi: None. E. Langan: None. M. Shazeeb: None. G. Ughi: 4; C; Gentuity LLC. 5; C; Gentuity LLC. C. Raskett: None. A. Puri: None. M. Gounis: None.

Introduction The development of High Frequency OCT1 (HF-OCT) allows for higher resolution intra-arterial imaging, such that vascular remodeling in response to stents and next generation intrasaccular devices (NGID) can be interrogated. We hypothesize that imperfections or gaps in the neck coverage of an aneurysm after treatment with a NGID will be predictive of failed aneurysm occlusion. Materials and methods Two aneurysms were made in each of six dogs, one sidewall aneurysm on the distal right common carotid artery (CCA), and a bifurcation aneurysm proximally at the apex of an anastomosis between the left and right CCAs. One aneurysm was excluded due to thrombosis at the time of treatment. Each aneurysm was treated with either detachable coils, or NGID, with a 7:4 randomization NGID:COIL. At implant, HF-OCT was obtained after each aneurysm was successfully packed. At 180 days, animals were assessed for final aneurysm occlusion by DSA. Separately, the HF-OCT data sets were automatically segmented such that gaps in the coverage of the aneurysm neck could be identified and used to predict if the aneurysm occlusion at 180 days. Results The overall rate of occlusion was not seen to be different between the NGID and COIL group (p=0.45) on the Raymond-Roy scale.2 All of the NGID constructs were successfully segmented, and the associated larges gap in the neck coverage for each was determined. A gap in the NGID construct at the level of the neck greater than 1 mm2 predicted failed aneurysm occlusion at 180-days (p = 0.047). This threshold correctly classified all aneurysms. Conclusions HF-OCT allows not only for the imaging and segmentation of intra-arterial devices in vivo, but showed great potential as a robust diagnostic tool. Preliminary evidence collected in this study showed that HF-OCT can prognosticate aneurysm treatment success at the time of treatment. References Stroke. 2018:Nov29:STROKEAHA118022315 Stroke. 2003;34(6):1398–1403. Disclosures R. King: None. M. Marosfoi: None. J. Caroff: None. G. Ughi: 4; C; Gentuity LLC. 5; C; Gentuity LLC. D. Groth: None. M. Gounis: None. A. Puri: None.

Introduction The use of stents in the treatment of wide neck aneurysms, and more recently the adoption of flow diverters, are important tools for the treatment of aneurysms.1 One major complication of such implants is thromboembolism, requiring the use of dual anti-platelet therapy (DAPT). However, due to variable response and inherent risks of DAPT, new stents are being developed with anti-thrombogenic coatings with the goal to reduce or eliminate the need for DAPT. Methods A novel hydrophilic polymer coating (HPC) applied to a nitinol substrate has been shown to resist platelet aggregation in vitro.2 We sought to demonstrate preliminary evidence to confirm this observation in vivo. Three pigs were used with different regimens: no antiplatelet medication (NAPT), 81 mg aspirin (SAPT), and 81 mg aspirin with 75 mg Clopidogrel (DAPT). Two control and two coated devices were implanted in each animal. High Frequency Optical Coherence Tomography (HF-OCT), with a spatial resolution approaching 10 microns, was used to study acute thrombus formation along the surface of the device. HF-OCT acquisitions were acquired 20 minutes following device implant. Specifically, the total clot volume on each side branch opening (SBO) was segmented with manual input by a blinded user. Statistical analyses were performed to determine the relative benefit of the HPC coating and the antiplatelet regiment for prevention of platelet aggregation, a linear model was constructed to interrogate the relative importance. Results The figure 1 shows one section from each device type. It was found that device type and aspirin where significantly correlated with thrombus volume over SBOs. Mean thrombus volume per mm2 of SBO for coated versus control devices was 0.00033 mm versus 0.087 mm, respectively (p = 0.005). Mean clot per SBO was 0.004 mm versus 0.15 mm in animals receiving aspirin versus NAPT (p Conclusions This preliminary evidence shows the dramatic effect that the coating can have on the acute thrombus formation. Further, this novel HF-OCT technology allows for quantitative measurements of the amount of thrombus formed on the surface of a flow diverter, not just the presence. Finally, this study shows the possibility that the combined effect of aspirin and this new coating may be sufficient antiplatelet therapy. References Neurosurgery 2017;80:40–48. CardioVasc Intervent Radiol 2018;41:1779–1785. Disclosures R. King: None. E. Langan: None. M. Marosfoi: None. G. Ughi: 4; C; Gentuity LLC. 5; C; Gentuity LLC. C. Raskett: None. M. Gounis: 2; C; Phenox

Introduction Intravascular optical coherence tomography (OCT) has an established role in the diagnosis and image guided treatment of coronary artery disease. However, due to the profile and design of the catheter, these devices are not suitable for routine application in neurointerventional surgery. We aim to demonstrate that new generation high frequency OCT (HF-OCT) can image stents and flow diverters used to treat intracranial aneurysms with acceptable workflow deployed in neurointerventional surgery. Materials and methods An HF-OCT prototype was built (Gentuity, Sudbury MA) that is compatible with standard microcatheters (0.017’). An in vitro flow loop consisting of a patient-specific vascular replica and using porcine blood as a working fluid was deployed to test contrast infusion protocols necessary to remove blood from the target vascular section. Subsequently, eight pigs were implanted bilaterally with flow diverters and stents. The presence of acute platelet aggregation on the surface of the devices and malapposition of the device to the vessel wall was assessed by 3 raters reviewing digital subtraction angiography (DSA), high resolution cone beam CT (CBCT), and HF-OCT. Finally, using the tortuous porcine brachial artery, HF-OCT was performed, and image quality assessed. Results In the in vitro experiment, the optimized contrast infusion protocol was delivery of contrast through the intermediate catheter (0.058’ Navien, Medtronic Neurovascular, Irvine CA) delivering the HF-OCT device at a rate of 5 ml/s for 20–25 ml of contrast. This protocol resulted in complete clearing of highly attenuating erythrocytes for an optically clear field. In the pig study, the agreement by the reviewers (Fleiss kappa) regarding clot formation at 3 distinct locations along the flow diverter was 0.49, 0.67 and 0.90 for DSA, CBCT and HF-OCT, respectively. The agreement for diagnosing malapposition at these locations was 0.18, 0.67 and 0.87 for DSA, CBCT, and HF-OCT, respectively. In the porcine tortuosity model, in all cases, navigation and imaging was performed with uniform illumination and free from artifact. Conclusion An HF-OCT device has been built that is compatible with neurointerventional surgery workflow and cerebrovascular anatomy. Preclinical data demonstrate consistent improvement to diagnose acute platelet aggregation and malapposition of flow diverters as compared to existing imaging modalities (figure 1). Disclosures A. Puri: 1; C; NIH. M. Marosfoi: None. G. Ughi: 4; C; Gentuity. 5; C; Gentuity. R. King: None. E. Langan: None. J. Chueh: None. M. Gounis: 1; C; NIH.

PurposeTo develop a preclinical model of stroke with a large vessel occlusion treated with mechanical thrombectomy.Materials and methodsAn ischemic stroke model was created in dogs by the introduction of an autologous clot into the middle cerebral artery (MCA). A microcatheter was navigated to the clot and a stent retriever thrombectomy was performed with the goal to achieve Thrombolysis in Cerebral Ischemia (TICI) 2b/3 reperfusion. Perfusion and diffusion MRI was acquired after clot placement and following thrombectomy to monitor the progression of restricted diffusion as well as changes in ischemia as a result of mechanical thrombectomy. Post-mortem histology was done to confirm MCA territory infarct volume.ResultsInitial MCA occlusion with TICI 0 flow was documented in all six hound-cross dogs entered into the study. TICI 2b/3 revascularization was achieved with one thrombectomy pass in four of six animals (67%). Intra-procedural events including clot autolysis leading to spontaneous revascularization (n=1) and unresolved vasospasm (n=1) accounted for thrombectomy failure. In one case, iatrogenic trauma during microcatheter navigation resulted in a direct arteriovenous fistula at the level of the cavernous carotid. Analysis of MRI indicated that a volume of tissue from the initial perfusion deficit was spared with reperfusion following thrombectomy, and there was also a volume of tissue that infarcted between MRI and ultimate recanalization.ConclusionWe describe a large animal stroke model in which mechanical thrombectomy can be performed. This model may facilitate, in a preclinical setting, optimization of complex multimodal stroke treatment paradigms for clinical translation.