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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<0.0001) and reduced the final normalized infarct volume as compared to controls (0.99 versus 0.88, control versus OMX-IS drug, P<0.0001). Among slow evolvers, OMX-IS treatment delayed infarct progression by approximately 45 minutes; however, this did not reach statistical significance (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.
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Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Cães , Humanos , Infarto , Imageamento por Ressonância Magnética/métodos , Oxigênio , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
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.
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Cisterna Magna/metabolismo , Dependovirus/genética , Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Transdução Genética , Animais , Catéteres , Sistema Nervoso Central/metabolismo , Genes Reporter , Terapia Genética , Vetores Genéticos/administração & dosagem , Humanos , Injeções Espinhais , Imageamento por Ressonância Magnética , Modelos Animais , Ovinos , Cirurgia Assistida por Computador , Tomografia Computadorizada por Raios X , Transgenes , Gravação em VídeoRESUMO
BACKGROUND: Therapeutic hypothermia has shown potential in cardiac intervention for years; however, its adoption into the neurovascular space has been limited. Studies have pointed to slow cooling and limited depth of hypothermia yielding negative outcomes. Here we present an insulated catheter that allows for consistent infusion of chilled saline directly to the brain. Direct delivery of cold saline allows a faster depth of hypothermia, which could have a benefit to the growth of ischemic lesions. METHODS: Ten canines were randomized to either receive selective brain cooling or no additional therapy. Eight animals were successfully enrolled (n = 4 per group). Each animal underwent a temporary middle cerebral artery occlusion (MCAO) for a total of 45â min. Five minutes prior to flow restoration, chilled saline was injected through the ipsilateral internal carotid artery using an insulated catheter to ensure delivery temperature. The treatment continued for 20â min, after which the animal was transferred to an MRI scanner for imaging. RESULTS: Of the 8 animals that were successfully enrolled in the study, 3 were able to survive to the 30-day endpoint with no differences between the cooled and control animals. There was no difference in the initial mean infarct size between the groups; however, animals that did not receive cooling had infarcts continuing to progress more rapidly after the MCAO was removed (13.8% vs 161.3%, p = 0.016, cooled vs control). CONCLUSIONS: Selective hypothermia was able to reduce the post-MCAO infarct progression in a canine model of temporary MCAO.
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Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.
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Artérias Cerebrais , Tomografia de Coerência Óptica , Tomografia de Coerência Óptica/métodos , Humanos , Artérias Cerebrais/diagnóstico por imagem , Microscopia/métodos , Miniaturização , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/métodosRESUMO
BACKGROUND: Flow diversion has become a standard treatment for cerebral aneurysms. However, major drawbacks include the need for dual antiplatelet therapy after implant and delayed complete occlusion of the aneurysm, which occurs when new tissue growth excludes the aneurysm from the parent artery. Biomimetic surface modifications such as the phosphorylcholine polymer (Shield surface modification) represent major advances in reducing thrombogenicity of these devices. However, in vitro studies have raised concerns that this modification may also delay endothelialization of flow diverters. METHODS: Bare metal Pipeline, Pipeline Shield, and Vantage with Shield devices were implanted in the common carotid arteries (CCAs) of 10 rabbits (two in the left CCA, one in the right CCA). Following implant and at 5, 10, 15, and 30 days, the devices were imaged with high-frequency optical coherence tomography and conventional angiography to evaluate tissue growth. At 30 days the devices were explanted and their endothelial growth was assessed with scanning electron microscopy (SEM) at five locations along their length using a semi-quantitative score. RESULTS: The average tissue growth thickness (ATGT) was not different between the three devices. Neointima was apparent at 5 days and all devices demonstrated similar ATGT at each time point. On SEM, no difference was found in the endothelium scores between the device types. CONCLUSION: In vivo, neither the Shield surface modification nor the device design (Vantage) altered the longitudinal healing of the flow diverter.
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BACKGROUND: Preclinical testing of intracranial stents is currently performed in the peripheral circulation, and rarely in the basilar artery of the dog. OBJECTIVE: To 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. METHODS: Six 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. RESULTS: We 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. CONCLUSION: We describe a new preclinical model of intracranial stenting in the MCA. Such a model may prove useful for evaluating new surface modifications.
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OBJECTIVES: Inflammation plays a key role in driving brain aneurysmal instability and rupture, but clinical tools to noninvasively differentiate between inflamed and stable aneurysms are lacking. We hypothesize that imaging oxidative changes in the aneurysmal microenvironment driven by myeloid inflammatory cells may represent a noninvasive biomarker to evaluate rupture risk. In this study, we performed initial evaluation of the oxidatively activated probe Fe-PyC3A as a tool for magnetic resonance imaging (MRI) of inflammation in a rabbit model of saccular aneurysm. MATERIALS AND METHODS: The difference in longitudinal relaxivity ( r1 ) in reduced and oxidized states of Fe-PyC3A was measured in water and blood plasma phantoms at 3 T. A rabbit saccular aneurysm model was created by endovascular intervention/elastinolysis with subsequent decellularization in situ. Rabbits were imaged at 4 weeks (n = 4) or 12 weeks (n = 4) after aneurysmal induction, when luminal levels of inflammation reflected by the presence of myeloperoxidase positive cells are relatively high and low, respectively, using a 3 T clinical scanner. Both groups were imaged dynamically using a 2-dimensional T1-weighted fast field echo pulse MRI sequence before and up to 4 minutes postinjection of Fe-PyC3A. Dynamic imaging was then repeated after an injection of gadobutrol (0.1 mmol/kg) as negative control probe. Rabbits from the 12-week aneurysm group were also imaged before and 20 minutes and 3 hours after injection of Fe-PyC3A using an axial respiratory gated turbo-spin echo (TSE) pulse sequence with motion-sensitized driven equilibrium (MSDE) preparation. The MSDE/TSE imaging was repeated before, immediately after dynamic acquisition (20 minutes postinjection), and 3 hours after injection of gadobutrol. Aneurysmal enhancement ratios (ERs) were calculated by dividing the postinjection aneurysm versus skeletal muscle contrast ratio by the preinjection contrast ratio. After imaging, the aneurysms were excised and inflammatory infiltrate was characterized by fluorometric detection of myeloperoxidase activity and calprotectin immunostaining, respectively. RESULTS: In vitro relaxometry showed that oxidation of Fe-PyC3A by hydrogen peroxide resulted in a 15-fold increase of r1 at 3 T. Relaxometry in the presence of blood plasma showed no more than a 10% increase of r1 , indicating the absence of strong interaction of Fe-PyC3A with plasma proteins. Dynamic imaging with Fe-PyC3A generated little signal enhancement within the blood pool or adjacent muscle but did generate a transient increase in aneurysmal ER that was significantly greater 4 weeks versus 12 weeks after aneurysm induction (1.6 ± 0.30 vs 1.2 ± 0.03, P < 0.05). Dynamic imaging with gadobutrol generated strong aneurysmal enhancement, but also strong enhancement of the blood and muscle resulting in smaller relative ER change. In the 12-week group of rabbits, MSDE/TSE imaging showed that ER values measured immediately after dynamic MRI (20 minutes postinjection) were significantly higher ( P < 0.05) in the case of Fe-PyC3A (1.25 ± 0.06) than for gadobutrol injection (1.03 ± 0.03). Immunohistochemical corroboration using anticalprotectin antibody showed that leukocyte infiltration into the vessel walls and luminal thrombi was significantly higher in the 4-week group versus 12-week aneurysms (123 ± 37 vs 18 ± 7 cells/mm 2 , P < 0.05). CONCLUSIONS: Magnetic resonance imaging using Fe-PyC3A injection in dynamic or delayed acquisition modes was shown to generate a higher magnetic resonance signal enhancement in aneurysms that exhibit higher degree of inflammation. The results of our pilot experiments support further evaluation of MRI using Fe-PyC3A as a noninvasive marker of aneurysmal inflammation.
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Aneurisma Intracraniano , Peroxidase , Animais , Coelhos , Meios de Contraste/química , Ferro , Imageamento por Ressonância Magnética/métodos , Inflamação/diagnóstico por imagem , OxirreduçãoRESUMO
BACKGROUND: High-frequency optical coherence tomography (HF-OCT) is an intravascular imaging method that allows for volumetric imaging of flow diverters in vivo. OBJECTIVE: To examine the hypothesis that a threshold for both volume and area of communicating malapposition can be predictive of early aneurysm occlusion. METHODS: Fifty-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. RESULTS: No 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 (p<0.001, both). From the statistical model, a volume of less than 0.56 mm3 or a normalized area less than 0.69 as quantified by HF-OCT was predictive of occlusion (p<0.001, each). CONCLUSIONS: HF-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.
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Procedimentos Endovasculares , Aneurisma Intracraniano , Animais , Coelhos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/terapia , Tomografia de Coerência Óptica/métodos , Stents , Procedimentos Endovasculares/métodos , Angiografia Cerebral/métodos , Resultado do TratamentoRESUMO
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.
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BACKGROUND: Intrasaccular flow-disrupting devices are a safe and effective treatment strategy for intracranial aneurysms. We utilized high-frequency optical coherence tomography (HF-OCT) and digital subtraction angiography (DSA) to evaluate SEAL Arc, a new intrasaccular device, and compare the findings with the well-established Woven EndoBridge (WEB) device in an animal model of saccular aneurysms. METHODS: In a rabbit model, elastase-induced aneurysms were treated with SEAL Arc (n=11) devices. HF-OCT and DSA were performed after implant and repeated after 12 weeks. Device protrusion and malapposition were assessed at implant time and scored on a binary system. Aneurysm occlusion was assessed at 12 weeks with the WEB Occlusion Scale and dichotomized to complete (A and B) or incomplete (C and D) occlusion. The percentage of neointimal coverage after 12 weeks was quantified using HF-OCT. We compared these data to previously published historical controls treated with the gold-standard WEB device (n=24) in the same model. RESULTS: Aneurysm size and device placement were not significantly different between the two groups. Complete occlusion was demonstrated in 80% of the SEAL Arc devices, which compared favorably to the 21% of the aneurysms treated with WEB devices (P=0.002). Neointimal coverage across SEAL Arc devices was 86±15% compared with 49±27% for WEB (P=0.001). Protruding devices had significantly less neointimal coverage (P<0.001) as did incompletely occluded aneurysms (P<0.001). Histologically, all aneurysms treated with SEAL Arc devices were completely healed. CONCLUSION: Complete early aneurysm occlusion was frequently observed in the SEAL Arc treated aneurysms, with significant neointimal coverage after 12 weeks.
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BACKGROUND: Flow diverters carry the risk of thromboembolic complications (TEC). We tested a coating with covalently bound heparin that activates antithrombin to address TEC by locally downregulating the coagulation cascade. We hypothesized that the neuroimaging evidence of TEC would be reduced by the coating. METHODS: 16 dogs were implanted with overlapping flow diverters in the basilar artery, separated into two groups: heparin-coated (n=9) and uncoated (n=7). Following implantation, high-frequency optical coherence tomography (HF-OCT) was acquired to quantify acute thrombus (AT) formation on the flow diverters. MRI was performed postoperatively and repeated at 1, 2, 3, 4, and 8 weeks, consisting of T1-weighted imaging, time-0f-flight (ToF), diffusion weighted imaging (DWI), susceptibility weighted imaging (SWI), and fluid attenuated inversion recovery (FLAIR) sequences. Neurological examinations were performed throughout the 8-week duration of the study. RESULTS: The mean AT volume on coated devices was lower than uncoated (0.014 vs 0.018 mm3); however, this was not significant (P=0.3). The mean number of foci of magnetic susceptibility artifacts (MSAs) on SWI was significantly different between the uncoated and coated groups at the 1-week follow-up (P<0.02), and remained statistically different throughout the duration of the study. The AT volume showed a direct linear correlation with the MSA count and 80% of the variance in the MSA could be explained by the AT volume (P<0.001). Pathological analysis showed evidence of ischemic injury at locations of MSA. CONCLUSIONS: Heparin-coated flow diverters significantly reduced the number of new MSAs after 1 week follow-up, showing the potential to reduce TEC.
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Background: Infarct volume measured from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices is critical to in vivo stroke models. In this study, we developed an interactive, tunable, software that automatically computes whole-brain infarct metrics from serial TTC-stained brain sections. Methods: Three rat ischemic stroke cohorts were used in this study (Total n = 91 rats; Cohort 1 n = 21, Cohort 2 n = 40, Cohort 3 n = 30). For each, brains were serially-sliced, stained with TTC and scanned on both anterior and posterior sides. Ground truth annotation and infarct morphometric analysis (e.g., brain-Vbrain, infarct-Vinfarct, and non-infarct-Vnon-infarct volumes) were completed by domain experts. We used Cohort 1 for brain and infarct segmentation model development (n = 3 training cases with 36 slices [18 anterior and posterior faces], n = 18 testing cases with 218 slices [109 anterior and posterior faces]), as well as infarct morphometrics automation. The infarct quantification pipeline and pre-trained model were packaged as a standalone software and applied to Cohort 2, an internal validation dataset. Finally, software and model trainability were tested as a use-case with Cohort 3, a dataset from a separate institute. Results: Both high segmentation and statistically significant quantification performance (correlation between manual and software) were observed across all datasets. Segmentation performance: Cohort 1 brain accuracy = 0.95/f1-score = 0.90, infarct accuracy = 0.96/f1-score = 0.89; Cohort 2 brain accuracy = 0.97/f1-score = 0.90, infarct accuracy = 0.97/f1-score = 0.80; Cohort 3 brain accuracy = 0.96/f1-score = 0.92, infarct accuracy = 0.95/f1-score = 0.82. Infarct quantification (cohort average): Vbrain (ρ = 0.87, p < 0.001), Vinfarct (0.92, p < 0.001), Vnon-infarct (0.80, p < 0.001), %infarct (0.87, p = 0.001), and infarct:non-infact ratio (ρ = 0.92, p < 0.001). Conclusion: Tectonic Infarct Analysis software offers a robust and adaptable approach for rapid TTC-based stroke assessment.
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BACKGROUND: Diagnosing and treating acute ischemic stroke patients within a narrow timeframe is challenging. Time needed to access the occluded vessel and initiate thrombectomy is dictated by the availability of information regarding vascular anatomy and trajectory. Absence of such information potentially impacts device selection, procedure success, and stroke outcomes. While the cervical vessels allow neurointerventionalists to navigate devices to the occlusion site, procedures are often encumbered due to tortuous pathways. The purpose of this retrospective study was to determine how neurointerventionalists consider the physical nature of carotid segments when evaluating a procedure's difficulty. METHODS: Seven neurointerventionalists reviewed 3D reconstructions of CT angiograms of left and right carotid arteries from 49 subjects and rated the perceived procedural difficulty on a three-point scale (easy, medium, difficult) to reach the targeted M1. Twenty-two vessel metrics were quantified by dividing the carotids into 5 segments and measuring the radius of curvature, tortuosity, vessel radius, and vessel length of each segment. RESULTS: The tortuosity and length of the arch-cervical and cervical regions significantly impacted difficulty ratings. Additionally, two-way interaction between the radius of curvature and tortuosity on the arch-cervical region was significant (p < 0.0001) wherein, for example, at a given arch-cervical tortuosity, an increased radius of curvature reduced the perceived case difficulty. CONCLUSIONS: Examining the vessel metrics and providing detailed vascular data tailored to patient characteristics may result in better procedure preparation, facilitate faster vessel access time, and improve thrombectomy outcomes. Additionally, documenting these correlations can enhance device design to ensure they suitably function under various vessel conditions.
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Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estudos Retrospectivos , Imageamento Tridimensional , Trombectomia/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Resultado do Tratamento , Procedimentos Endovasculares/métodosRESUMO
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.
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Embolia , Embolia Intracraniana , Acidente Vascular Cerebral , Animais , Humanos , Acidente Vascular Cerebral/terapia , Trombectomia , Resultado do TratamentoRESUMO
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.
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BACKGROUND: The 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. METHODS: In 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. RESULTS: Of 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. CONCLUSION: We 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.
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Espaço Subaracnóideo , Tomografia de Coerência Óptica , Animais , Cães , Humanos , Microscopia Intravital , Microcirurgia/métodos , Espaço Subaracnóideo/anatomia & histologia , Espaço Subaracnóideo/diagnóstico por imagem , Tomografia de Coerência Óptica/métodosRESUMO
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. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G4C2 repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G4C2 repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of cerebrospinal fluid poly(GP). This report provides insight into the effect of nucleic acid chemistry on toxicity and, to our knowledge, for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Additional clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations.
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Proteína C9orf72/genética , Mutação , Oligonucleotídeos Antissenso/genética , Animais , Proteína C9orf72/metabolismo , Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/metabolismoRESUMO
BACKGROUND: Direct aspiration thrombectomy techniques use large bore aspiration catheters for mechanical thrombectomy. Several aspiration catheters are now available. We report a bench top exploration of a novel beveled tip catheter and our experience in treating large vessel occlusions (LVOs) using next-generation aspiration catheters. METHODS: A retrospective analysis from a prospectively maintained database comparing the bevel shaped tip aspiration catheter versus non-beveled tip catheters was performed. Patient demographics, periprocedural metrics, and discharge and 90-day modified Rankin Scale (mRS) scores were collected. Patients were divided into two groups based on which aspiration catheter was used. RESULTS: Our data showed no significant difference in age, gender, IV tissue plasminogen activator administration, admission NIH Stroke Scale score, baseline mRS, or LVO location between the beveled tip and flat tip groups. With the beveled tip, Thrombolysis in Cerebral Infarction (TICI) 2C or better recanalization was more frequent overall (93.2% vs 74.2%, p=0.017), stent retriever usage was lower (9.1% vs 29%, p=0.024), and patients had lower mRS on discharge (median 3 vs 4, p<0.001) and at 90 days (median 2 vs 4, p=0.008). CONCLUSION: Patients who underwent mechanical thrombectomy with the beveled tip catheter had a higher proportion of TICI 2C or better and had a significantly lower mRS score on discharge and at 90 days.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/cirurgia , Catéteres , Humanos , Estudos Retrospectivos , Stents , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia , Ativador de Plasminogênio Tecidual , Resultado do TratamentoRESUMO
BACKGROUND: High-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. METHODS: In 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). RESULTS: Adequate 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; P<0.001). More neointimal coverage of 78%±32% was found on 'adequate deployment' cases versus 31%±24% for the 'inadequate deployment' cases (P=0.001). CONCLUSION: HF-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.
Assuntos
Angiografia Digital/métodos , Embolização Terapêutica/métodos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/terapia , Stents Metálicos Autoexpansíveis , Tomografia de Coerência Óptica/métodos , Animais , Embolização Terapêutica/instrumentação , Aneurisma Intracraniano/induzido quimicamente , Masculino , Elastase Pancreática/toxicidade , Coelhos , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation. METHODS: 18 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. RESULTS: During follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (p<0.001). The width of SDS-treated aneurysms increased significantly in comparison with the elastase aneurysms (47% vs 20%, p<0.001). Image analysis of thin sections showed infiltration of MPO-positive cells in decellularized aneurysms and surroundings through the 12-week observation period while control tissue had 5-6 times fewer cells present 2 weeks after aneurysm creation. Immunohistochemistry demonstrated the presence of MPO-positive cells surrounding decellularized lesions at early time points. MPO-positive cells were found in the adventitia and in the thrombi adherent to the aneurysm wall at later time points. CONCLUSIONS: In 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.