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AimsIntracranial aneurysms are treated with a variety of endovascular devices including coils, stents, and flow diverters. The mechanisms by which these devices result in aneurysm occlusion and subsequent healing have been the subject of significant research using various animal models. The murine Helsinki aneurysm model is a sidewall aneurysm created by the end-to-side anastomosis of a donor aortic graft onto the abdominal aorta of a recipient animal. The aim of this systematic review is to assess the efficacy of different endovascular devices for the treatment of the Helsinki model aneurysm.MethodsWe performed a systematic review of Pubmed in accordance with PRISMA guidelines, yielding eight studies detailing the results of endovascular treatment of this preclinical aneurysm model. Studies were included if they provided rates of complete aneurysm occlusion after treatment.ResultsIn these studies, aneurysms were treated with coiling (n=81, 7 studies), stenting (n=67, 3 studies), stent-coiling (n=13, 1 study), and flow diversion (n=49, 2 studies). The results of each individual study are discussed with the goal of providing a measure of the relative efficacy of different endovascular devices for the treatment of this particular model aneurysm. We also pay special attention to insights into the mechanisms underlying aneurysm healing after different forms of endovascular therapy.ConclusionThe data presented here may be useful to investigators attempting to demonstrate superiority of novel endovascular devices relative to previous device iterations using this preclinical model.

The use of flow diverters is a rapidly growing endovascular approach for the treatment of intracranial aneurysms. All FDA-approved flow diverters are composed of nitinol or cobalt-chromium, which will remain in the patient for the duration of their life. Bioresorbable flow diverters have been proposed by several independent investigators as the next generation of flow diverting devices. These devices aim to serve their transient function of occluding and healing the aneurysm prior to being safely resorbed by the body, eliminating complications associated with the permanent presence of conventional flow diverters. Theoretical advantages of bioresorbable flow diverters include (1) reduction in device-induced thrombosis; (2) reduction in chronic inflammation and device-induced stenosis; (3) reduction in side branch occlusion; (4) restoration of physiological vasomotor function; (5) reduction in imaging artifacts; and (6) use in pediatric applications. Advances made in the similar bioresorbable coronary stenting field highlight some of these advantages and demonstrate the feasibility and safety of bioresorbable endovascular devices in the clinic. The current work aims to review the progress of bioresorbable flow diverters, identify opportunities for further investigation, and ultimately stimulate the advancement of this technology.

BackgroundPlatelets and von Willebrand factor (vWF) are key components of acute ischemic stroke (AIS) emboli. We aimed to investigate the CD42b (platelets)/vWF expression, its association with stroke etiology and the impact these components may have on the clinical/procedural parameters.MethodsCD42b/vWF immunostaining was performed on 288 emboli collected as part of the multicenter STRIP Registry. CD42b/VWF expression and distribution were evaluated. Student’s t-test and χ2test were performed as appropriate.ResultsThe mean CD42b and VWF content in clots was 44.3% and 21.9%, respectively. There was a positive correlation between platelets and vWF (r=0.64, pConclusionsThe vWF level and CD42b/vWF distribution pattern in emboli were correlated with AIS etiology and revascularization outcome. Platelet content was associated with response to thrombolysis.

BackgroundPreclinical testing platforms that accurately replicate complex human cerebral vasculature are critical to advance neurointerventional knowledge, tools, and techniques. Here, we introduced and validated a human “live cadaveric” head-and-neck neurovascular model optimized for proximal and distal vascular occlusion and recanalization techniques.MethodsHuman cadaveric head-and-neck specimens were cannulated bilaterally in the jugular veins, carotid, and vertebral arteries. Specimens were then coupled with modular glass models of the aorta and extracranial carotid arteries, as well as radial and femoral access ports. Intracranial physiological flow was simulated using a flow-delivery system and blood-mimicking fluid. Baseline anatomy, histological, and mechanical properties of cerebral arteries were compared with those of fresh specimens. Radiopaque clot analogs were embolized to replicate proximal and distal arterial occlusions, followed by thrombectomy. Experienced interventionalists scored the model on different aspects.ResultsCompared with counterpart fresh human arteries, formalin-fixed arteries showed similar mechanical properties, including maximum stretch, increased tensile strength/stiffness, and friction coefficients were also not significantly different. On histology, minimal endothelial damage was noted in arteries after 3 months of light fixation, otherwise the arterial wall maintained the structural integrity. Contrast angiographies showed no micro- or macro-vasculature obstruction. Proximal and distal occlusions created within the middle cerebral arteries were consistently obtained and successfully recanalized. Additionally, interventionists scored the model highly realistic, indicating great similarity to patients’ vasculature.ConclusionsThe human “live cadaveric” neurovascular model accurately replicates the anatomy, mechanics, and hemodynamics of cerebral vasculature and allows the performance of neurointerventional procedures equivalent to those done in patients.

OBJECTIVE Despite advancement of thrombectomy technologies for large-vessel occlusion (LVO) stroke and increased user experience, complete recanalization rates linger around 50%, and one-third of patients who have undergone successful recanalization still experience poor neurological outcomes. To enhance the understanding of the biomechanics and failure modes, the authors conducted an experimental analysis of the interaction of emboli/artery/devices in the first human brain test platform for LVO stroke described to date. METHODS In 12 fresh human brains, 105 LVOs were recreated by embolizing engineered emboli analogs and recanalization was attempted using aspiration catheters and/or stent retrievers. The complex mechanical interaction between diverse emboli (elastic, stiff, and fragment prone), arteries (anterior and posterior circulation), and thrombectomy devices were observed, analyzed, and categorized. The authors systematically evaluated the recanalization process through failure modes and effects analysis, and they identified where and how thrombectomy devices fail and the impact of device failure. RESULTS The first-pass effect (34%), successful (71%), and complete (60%) recanalization rates in this model were consistent with those in the literature. Failure mode analysis of 184 passes with thrombectomy devices revealed the following. 1) Devices loaded the emboli with tensile forces leading to elongation and intravascular fragmentation. 2) In the presence of anterograde flow, small fragments embolize to the microcirculation and large fragments result in recurrent vessel occlusion. 3) Multiple passes are required due to recurrent (15%) and residual (73%) occlusions, or both (12%). 4) Residual emboli remained in small branching and perforating arteries in cases of alleged complete recanalization (28%). 5) Vacuum caused arterial collapse at physiological pressures (27%). 6) Device withdrawal caused arterial traction (41%), and severe traction provoked avulsion of perforating and small branching arteries. CONCLUSIONS Biomechanically superior thrombectomy technologies should prevent unrestrained tensional load on emboli, minimize intraluminal embolus fragmentation and release, improve device/embolus integration, recanalize small branching and perforating arteries, prevent arterial collapse, and minimize traction.

BackgroundCompositional and structural features of retrieved clots by thrombectomy can provide insight into improving the endovascular treatment of ischemic stroke. Currently, histological analysis is limited to quantification of compositions and qualitative description of the clot structure. We hypothesized that heterogeneous clots would be prone to poorer recanalization rates and performed a quantitative analysis to test this hypothesis.MethodsWe collected and did histology on clots retrieved by mechanical thrombectomy from 157 stroke cases (107 achieved first-pass effect (FPE) and 50 did not). Using an in-house algorithm, the scanned images were divided into grids (with sizes of 0.2, 0.3, 0.4, 0.5, and 0.6 mm) and the extent of non-uniformity of RBC distribution was computed using the proposed spatial heterogeneity index (SHI). Finally, we validated the clinical significance of clot heterogeneity using the Mann–Whitney test and an artificial neural network (ANN) model.ResultsFor cases with FPE, SHI values were smaller (0.033 vs 0.039 for grid size of 0.4 mm, P=0.028) compared with those without. In comparison, the clot composition was not statistically different between those two groups. From the ANN model, clot heterogeneity was the most important factor, followed by fibrin content, thrombectomy techniques, red blood cell content, clot area, platelet content, etiology, and admission of intravenous tissue plasminogen activator (IV-tPA). No statistical difference of clot heterogeneity was found for different etiologies, thrombectomy techniques, and IV-tPA administration.ConclusionsClot heterogeneity can affect the clot response to thrombectomy devices and is associated with lower FPE. SHI can be a useful metric to quantify clot heterogeneity.

BACKGROUND AND PURPOSE: The persistent challenges in thrombectomy for large-vessel occlusion, such as suboptimal complete recanalization and first-pass effect imply an insufficient understanding of the artery-clot-device interaction. In this study, we present a thrombectomy model using fresh human brains, which can capture the artery-clot-device interaction through concurrent transmural and angiographic visualizations. MATERIALS AND METHODS: Fresh nonfrozen whole adult human brains were collected and connected to a customized pump system tuned to deliver saline flow at a physiologic flow rate and pressure. Angiography was performed to verify the flow in the anterior-posterior and vertebrobasilar circulations and collaterals. Large-vessel occlusion was simulated by embolizing a radiopaque clot analog. Thrombectomy was tested, and the artery-clot-device interactions were recorded by transmural and angiographic videos. RESULTS: Baseline cerebral angiography revealed excellent penetration of contrast in the anterior-posterior and vertebrobasilar circulations without notable arterial cutoffs and with robust collaterals. Small branches (

Background and aim First pass effect (FPE) is defined as achieving a complete recanalization with a single thrombectomy device pass. Although clinically desired, FPE is reached in less than 30% of thrombectomy procedures. Multiple device passes are often necessary to achieve successful or complete recanalization. We performed a systematic review and meta-analysis to determine the recanalization rate after each pass of mechanical thrombectomy and its association with good neurological outcome. Methods A literature search was performed for studies reporting the number of device passes required for either successful (mTICI 2b or higher) or complete (mTICI 2c or higher) recanalization. Using random-effect meta-analysis, we evaluated the likelihood of recanalization and good neurological outcome (measured with the modified Rankin Score Results Thirteen studies comprising 4197 patients were included. Among cases with failed first pass, 24% of them achieved final complete recanalization and 45% of them achieved final successful recanalization. Independently to the total number of previously failed attempts, the likelihood of achieving successful recanalization was 30% per pass, and the likelihood to achieve complete recanalization was about 20% per pass. The likelihood of good neurological outcome in patients with final successful recanalization decreased after each device pass: 55% after the first pass, 48% after the second pass, 42% after the third pass, 36% after the fourth pass, and 26% for 5 passes or more. Conclusion Each pass is associated with a stable likelihood of recanalization but a decreased likelihood of good neurological outcome.

BackgroundSeveral animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine.ObjectiveTo investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots.MethodsAs part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells).ResultsMT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material.Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1–4] vs 1 [1–3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI.ConclusionsHistological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.

BACKGROUND AND PURPOSE: Previous studies have successfully created blood clot analogs for in vitro endovascular device testing using animal blood of various species. Blood components vary greatly among species; therefore, creating clot analogs from human blood is likely a more accurate representation of thrombi formed in the human vasculature. MATERIALS AND METHODS: Following approval from the Mayo Clinic institutional review board, human whole-blood and platelet donations were obtained from the blood transfusion service. Twelve clot analogs were created by combining different ratios of red blood cells + buffy coat, plasma, and platelets. Thrombin and calcium chloride were added to stimulate coagulation. Clot composition was assessed using histologic and immunohistochemical staining. To assess the similarities of mechanical properties to patient clots, 3 types of clot analogs (soft, elastic, and stiff) were selected for in vitro thrombectomy testing. RESULTS: The range of histopathologic compositions produced is representative of clots removed during thrombectomy procedures. The red blood cell composition ranged from 8.9% to 91.4%, and fibrin composition ranged from 3.1% to 53.4%. Platelets (CD42b) and von Willebrand Factor ranged from 0.5% to 47.1% and 1.0% to 63.4%, respectively. The soft clots had the highest first-pass effect and successful revascularization rates followed by the elastic and stiff clots. Distal embolization events were observed when clot ingestion could not be achieved, requiring device pullback. The incidence rate of distal embolization was the highest for the stiff clots due to the weak clot/device integration. CONCLUSIONS: Red blood cell–rich, fibrin-rich, and platelet-rich clot analogs that mimic clots retrieved from patients with acute ischemic stroke were created in vitro. Differing retrieval outcomes were confirmed using in vitro thrombectomy testing in a subset of clots. This work was supported by the National Institutes of Health grant No. R01 NS105853, the European Regional Development Fund and Science Foundation Ireland grant No. 13/RC/2073, and Enterprise Ireland (IP20190865). peer-reviewed

Preclinical testing platforms have been instrumental in the research and development of thrombectomy devices. However, there is no single model which fully captures the complexity of cerebrovascular anatomy, physiology, and the dynamic artery-clot-device interaction. This article provides a critical review of phantoms, in-vivo animal, and human cadaveric models used for thrombectomy testing and provides insights into the strengths and limitations of each platform. Articles published in the past 10 years that reported thrombectomy testing platforms were identified. Characteristics of each test platform, such as intracranial anatomy, artery tortuosity, vessel friction, flow conditions, device-vessel interaction, and visualization, were captured and benchmarked against human cerebral vessels involved in large-vessel occlusion stroke. Thrombectomy phantoms have been constructed from silicone, direct 3D-printed polymers, and glass. These phantoms represent oversimplified patient-specific cerebrovascular geometry but enable adequate visualization of devices and clots under appropriate flow conditions. They do not realistically mimic the artery-clot interaction. For the animal models, arteries from swine, canines, and rabbits have been reported. These models can reasonably replicate the artery-clot-device interaction and have the unique value of evaluating the safety of thrombectomy devices. However, the vasculature geometries are substantially less complex and flow conditions are different from human cerebral arteries. Cadaveric models are the most accurate vascular representations but with limited access and challenges in reproducibility of testing conditions. Multiple test platforms should be likely used for comprehensive evaluation of thrombectomy devices. Interpretation of the testing results should take into consideration platform-specific limitations.

BackgroundEmbolization of the middle meningeal artery (MMA) is a promising minimally invasive technique that is gaining traction in the treatment of chronic subdural hematoma. Unfortunately, the human meninges and associated arteries are significantly larger than those of conventional laboratory animals, making the development of a clinically relevant animal model for testing of embolization agents elusive.ObjectiveTo introduce the posterior intercostal artery (PIA) model in swine and provide anatomical, angiographic, histological, and procedural data to validate its relevance in modeling the human MMA.MethodsIn human cadaveric specimens, 3D angiograms of the internal maxillary arteries (n=6) were obtained and the dura with MMA were harvested and histologically processed. Angiographic and histologic data of the human MMA were compared with the swine PIA (three animals). Then, embolization of the PIA (n=48 arteries) was conducted with liquid embolization agent (Onyx, Medtronic), and angiographic and histological results were assessed acutely (four animals) and after 30 days (two animals).ResultsThe human MMA has equivalent diameter, length, branching pattern, 3D trajectory, and wall structure to those of swine PIAs. Each swine has 12 to 14 PIAs (6–7 per side) suitable for acute or chronic embolization, which can be performed with high fidelity using the same devices, agents, and techniques currently used to embolize the MMA. The arterial wall structure and the acute and chronic histological findings in PIAs after embolization are comparable to those of humans.ConclusionsThis PIA model in swine could be used for research and development; objective benchmarking of agents, devices, and techniques; and in the training of neurointerventionalists.

BackgroundTransvenous embolization is emerging as a promising treatment for cerebrospinal fluid-venous fistulas (CVF) associated with spontaneous intracranial hypotension (SIH).ObjectiveTo perform an independent validation of the efficacy and safety of the procedure and describe the procedural techniques used at our institution.MethodsA retrospective review was performed including consecutive patients with SIH who had undergone CVF embolization with 3-month clinical and imaging follow-up. Clinical evaluation included the Patient Global Impression of Change (PGIC) Scale and six-item Headache Impact Test (HIT-6). Bern SIH score was used for imaging evaluation on brain MRI. Post-treatment changes in scores were assessed by Wilcoxon signed rank test. Procedural technical details, including use of upper-extremity access and dual-microcatheter pressure cooker technique, were recorded.Results18 patients (13 female, median age 60 years) were included. 17 (94%) procedures were performed with upper-extremity access and 12 (67%) using dual-microcatheter pressure cooker technique. After embolization, 16 (89%) patients reported much or very much improved at follow-up PGIC; median (IQR) HIT-6 score improved from 68 (62–72) to 36 (36–38) and Bern SIH score improved from 8 (6–8) to 3 (1.5–3.5),pvalues pvalues >0.05).ConclusionTransvenous embolization is independently validated as a highly effective and safe treatment for CVF and is feasible using upper-extremity venous access. Dual-microcatheter and balloon/coil pressure cooker techniques may be used to optimize distribution of embolic material and potentially, treatment efficacy.

Background and purpose Delayed time to recanalization is associated with reduced recanalization success of mechanical thrombectomy (MT) and thrombolysis in acute ischemic stroke (AIS). The reasons for this are unclear. We hypothesized that alterations in thrombus structure and composition could be responsible for this. Methods Retrieved thrombi from AIS patients who underwent MT less than 8 h from symptom onset to groin puncture (SOGP) were evaluated. Patients were divided into early (≤4 h.) vs delayed (> 4 h) groups based SOGP timing. Thrombi were histologically analysed using Martius Scarlett Blue and immunohistochemistry staining for von Willebrand Factor (vWF), anti-citrullinated H3 (H3Cit; NETs [neutrophil extracellular traps] marker). We used inferential statistics including, t-test, artificial neural network (ANN) to interpret the data. Results A total of 137 thrombi were collected. The overall average percentage of red blood cells (RBC), white blood cells (WBC), platelet, fibrin, H3Cit, and vWF components in thrombi was 45.83%, 3.58%, 22.23%, 28.27%, 19.97% and 16.23% respectively. Delayed group had higher WBCs, (p = 0.02), fibrin (p = 0.02), H3Cit (p = 0.04) and vWF (p = 0.03) thrombus fractions compared to early group. Based on ANN model, the most important factors for predicting the number of passes required for successful recanalization are fibrin and RBC contents of the thrombus followed by vWF and H3Cit contents. Conclusions Longer time to recanalization was associated with increased WBCs, fibrin, H3Cit and vWF fractions of thrombi reflecting possible in situ maturation of thrombus components. Increased fibrin, NETs and vWF composition may reduce likelihood of revascularization by altering thrombus mechanical properties.

Introduction: Suction catheters and stent retrievers are based on the classical paradigm of “en bloc” removal of emboli by generation of tensile forces by vacuum or device withdrawal. However, in this process emboli elongate and fracture leading to fragmentation. Fragments can migrate downstream or remain impacted in the arterial wall resulting in a residual occlusion. Hypothesis: Clot ingestion is biomechanically superior to “en bloc” removal and leads to higher recanalization rates with less complications. Methods: To test this hypothesis, we present a hybrid test bed consisting of pressurized human brains which was developed and validated for large vessel occlusion (LVO) and revascularization. We fabricated 3 types of representative embolus analogs (EAs) (elastic, fragment-prone and stiff) and recreated 105 LVO in twenty-four fresh human brains with the vasculature connected to an hydraulic system to mimic physiological flow and pressures. Recanalization was attempted in 61 LVO cases by Direct Aspiration (DA) using an 068 catheter and in 44 LVO cases combining Stent Retriever with Aspiration (SR+A). Rates of successful recanalization (SR, Grade 2b or higher) and complete recanalization (CR, Grade 2c or higher) were measured. Up to 4 attempts were done before declaring a failure (Grade 2a or lower). Results: DA resulted in 90% of SR, 79% of CR, 61% of first pass SR and 49% of first pass CR. SR+A resulted in 34% of SR, 34% of CR, 23% of first pass SR and 14% of first pass CR. Elastic EA were associated with 88% of SR, 85% of CR, 61% of first pass SR and 52% of first pass CR. Stiff EAs were associated with 64% of SR, 64% of CR, 36% of first pass SR and 36% of first pass CR. Fragment-prone EAs were associated with 64% of SR, 40% of CR, 38% of first pass SR and 21% of first pass CR. Conclusion: Clot ingestion is biomechanically superior to “en bloc” removal and leads to the highest rates of SR, CR and first pass recanalization. DA achieves higher recanalization rates than SR+A. Elastic clots are associated with the highest rates or recanalization, followed by stiff clots and finally by fragment-prone clots.

BackgroundFirst pass effect (FPE) in mechanical thrombectomy is thought to be associated with good clinical outcomes.ObjectiveTo determine FPE rates as a function of thrombectomy technique and to compare clinical outcomes between patients with and without FPE.MethodsIn July 2020, a literature search on FPE (defined as modified Thrombolysis in Cerebral Infarction (TICI) 2c–3 after a single pass) and modified FPE (mFPE, defined as TICI 2b–3 after a single pass) and mechanical thrombectomy for stroke was performed. Using a random-effects meta-analysis, we evaluated the following outcomes for both FPE and mFPE: overall rates, rates by thrombectomy technique, rates of good neurologic outcome (modified Rankin Scale score ≤2 at day 90), mortality, and symptomatic intracerebral hemorrhage (sICH) rate.ResultsSixty-seven studies comprising 16 870 patients were included. Overall rates of FPE and mFPE were 28% and 45%, respectively. Thrombectomy techniques shared similar FPE (p=0.17) and mFPE (p=0.20) rates. Higher odds of good neurologic outcome were found when we compared FPE with non-FPE (56% vs 41%, OR=1.78) and mFPE with non-mFPE (57% vs 44%, OR=1.73). FPE had a lower mortality rate (17% vs 25%, OR=0.62) than non-FPE. FPE and mFPE were not associated with lower sICH rate compared with non-FPE and non-mFPE (4% vs 18%, OR=0.41 for FPE; 5% vs 7%, OR=0.98 for mFPE).ConclusionsOur findings suggest that approximately one-third of patients achieve FPE and around half of patients achieve mFPE, with equivalent results throughout thrombectomy techniques. FPE and mFPE are associated with better clinical outcomes.