Publications by authors named "Robert M King"

31 Publications

Novel Oxygen Carrier Slows Infarct Growth in Large Vessel Occlusion Dog Model Based on Magnetic Resonance Imaging Analysis.

Stroke 2022 04 21;53(4):1363-1372. Epub 2022 Mar 21.

New England Center for Stroke Research, Department of Radiology (M.S., R.M.K., V.A., Z.V., A.K., J.K., C.R., M.J.G.), University of Massachusetts Medical School, Worcester.

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, <0.0001) and reduced the final normalized infarct volume as compared to controls (0.99 versus 0.88, control versus OMX-IS drug, <0.0001). Among slow evolvers, OMX-IS treatment delayed infarct progression by approximately 45 minutes; however, this did not reach statistical significance (=0.09). The final normalized infarct volume also did not show a significant difference (0.93 versus 0.95, OMX-IS drug versus control, =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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http://dx.doi.org/10.1161/STROKEAHA.121.036896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960363PMC
April 2022

Transvascular in vivo microscopy of the subarachnoid space.

J Neurointerv Surg 2022 May 3;14(5). Epub 2022 Feb 3.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA

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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http://dx.doi.org/10.1136/neurintsurg-2021-018544DOI Listing
May 2022

Biophysical targeting of high-risk cerebral aneurysms.

Bioeng Transl Med 2022 Jan 16;7(1):e10251. Epub 2021 Sep 16.

Department of Biomedical Engineering Technion Israel Institute of Technology Technion City, Haifa Israel.

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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http://dx.doi.org/10.1002/btm2.10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780020PMC
January 2022

Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide.

Nat Med 2022 01 23;28(1):117-124. Epub 2021 Dec 23.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Expansions of a GC 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 GC 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 GC 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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http://dx.doi.org/10.1038/s41591-021-01557-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861976PMC
January 2022

Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep.

JCI Insight 2021 12 22;6(24). Epub 2021 Dec 22.

RNA Therapeutics Institute and.

siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS.
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http://dx.doi.org/10.1172/jci.insight.152203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783676PMC
December 2021

Preclinical modeling of mechanical thrombectomy.

J Biomech 2022 01 8;130:110894. Epub 2021 Dec 8.

New England Center for Stroke Research, Department of Radiology University of Massachusetts 55 Lake Avenue North, SA 107-R, Worcester, MA 01655, United States. Electronic address:

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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http://dx.doi.org/10.1016/j.jbiomech.2021.110894DOI Listing
January 2022

Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis.

Mol Ther Methods Clin Dev 2021 Dec 26;23:128-134. Epub 2021 Aug 26.

Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.

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.
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http://dx.doi.org/10.1016/j.omtm.2021.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517204PMC
December 2021

Efficacy of beveled tip aspiration catheter in mechanical thrombectomy for acute ischemic stroke.

J Neurointerv Surg 2021 Sep 6;13(9):823-826. Epub 2020 Oct 6.

Neurosurgery, Prisma Health Upstate, Greenville, South Carolina, USA.

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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http://dx.doi.org/10.1136/neurintsurg-2020-016695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372385PMC
September 2021

In situ decellularization of a large animal saccular aneurysm model: sustained inflammation and active aneurysm wall remodeling.

J Neurointerv Surg 2021 Mar 5;13(3):267-271. Epub 2020 Oct 5.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

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.
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http://dx.doi.org/10.1136/neurintsurg-2020-016589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632232PMC
March 2021

High-resolution image-guided WEB aneurysm embolization by high-frequency optical coherence tomography.

J Neurointerv Surg 2021 Jul 28;13(7):669-673. Epub 2020 Sep 28.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

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.
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http://dx.doi.org/10.1136/neurintsurg-2020-016447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205185PMC
July 2021

A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy.

Nat Commun 2020 07 31;11(1):3851. Epub 2020 Jul 31.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

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.
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http://dx.doi.org/10.1038/s41467-020-17702-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395105PMC
July 2020

Longitudinal Monitoring of Flow-Diverting Stent Tissue Coverage After Implant in a Bifurcation Model Using Neurovascular High-Frequency Optical Coherence Tomography.

Neurosurgery 2020 11;87(6):1311-1319

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts.

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.
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http://dx.doi.org/10.1093/neuros/nyaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666887PMC
November 2020

Biomechanics and hemodynamics of stent-retrievers.

J Cereb Blood Flow Metab 2020 12 19;40(12):2350-2365. Epub 2020 May 19.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

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.
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http://dx.doi.org/10.1177/0271678X20916002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820689PMC
December 2020

Acute Thrombus Burden on Coated Flow Diverters Assessed by High Frequency Optical Coherence Tomography.

Cardiovasc Intervent Radiol 2020 Aug 8;43(8):1218-1223. Epub 2020 May 8.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, 55 Lake Ave N, SA-107R, Worcester, MA, 01655, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1007/s00270-020-02482-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209672PMC
August 2020

A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna.

Mol Ther 2020 02 16;28(2):411-421. Epub 2019 Nov 16.

Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address:

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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http://dx.doi.org/10.1016/j.ymthe.2019.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002897PMC
February 2020

Infarct Evolution in a Large Animal Model of Middle Cerebral Artery Occlusion.

Transl Stroke Res 2020 06 3;11(3):468-480. Epub 2019 Sep 3.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.

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.
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http://dx.doi.org/10.1007/s12975-019-00732-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051891PMC
June 2020

A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system.

Nat Biotechnol 2019 08 2;37(8):884-894. Epub 2019 Aug 2.

RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.

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.
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http://dx.doi.org/10.1038/s41587-019-0205-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879195PMC
August 2019

Focal cooling of brain parenchyma in a transient large vessel occlusion model: proof-of-concept.

J Neurointerv Surg 2020 Feb 30;12(2):209-213. Epub 2019 Jul 30.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Introduction: The neuroprotective benefit of therapeutic hypothermia (TH) has been demonstrated, but systemic side effects and time required to achieve effective TH in acute ischemic stroke (AIS) care limits clinical use. We investigate rapid and localized cooling using a novel insulated catheter in an ischemia-reperfusion model.

Methods: In phase I (n=4), cold saline was delivered to the canine internal carotid artery via an insulated catheter. Temperature was measured using intracerebral thermocouples. The coolant flow rate was varied to meet a target temperature of 31-32°C in the hemisphere infused. In phase II (n=8), a temporary middle cerebral artery occlusion was created. Five dogs underwent localized TH at the optimal flow rate from phase I, and the remaining animals were untreated controls. Cooling was initiated 5 min before recanalization and continued for an additional 20 min following 45 min of occlusion duration. The outcome was infarct volume and neurological function.

Results: Ipsilateral tissue cooling rates were 2.2±2.5°C/min at a flow rate of 20-40 mL/min with an observed minimum of 23.8°C. Tissue cooling was localized to the ipsilateral side of the infusion with little impact on temperatures of the core or contralateral hemisphere of the brain. In phase II, animals tolerated TH with minimal systemic impact. Infarct volume in treated animals was 0.2±0.2 cm, which was smaller than in sham animals (3.8±1.0 cm) as well as six untreated historical control animals (4.0±2.8 cm) (p=0.013).

Conclusions: Proof-of-concept data show that localised brain TH can be quickly and safely achieved through a novel insulated catheter. The small infarct volumes suggest potential benefit for this approach.
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http://dx.doi.org/10.1136/neurintsurg-2019-015179DOI Listing
February 2020

A canine model of mechanical thrombectomy in stroke.

J Neurointerv Surg 2019 Dec 18;11(12):1243-1248. Epub 2019 May 18.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Purpose: To develop a preclinical model of stroke with a large vessel occlusion treated with mechanical thrombectomy.

Materials And Methods: An 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.

Results: Initial 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.

Conclusion: We 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.
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http://dx.doi.org/10.1136/neurintsurg-2019-014969DOI Listing
December 2019

High frequency optical coherence tomography assessment of homogenous neck coverage by intrasaccular devices predicts successful aneurysm occlusion.

J Neurointerv Surg 2019 Nov 29;11(11):1150-1154. Epub 2019 Apr 29.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: High frequency optical coherence tomography (HF-OCT) is a novel intravascular imaging technology developed for use in the cerebral vasculature. We hypothesize that HF-OCT characterization of intrasaccular device neck coverage can prognosticate exclusion of the aneurysm from the circulation.

Methods: Bifurcation and sidewall aneurysms were made in six dogs. Seven aneurysms were treated with next generation intrasaccular devices (NGID) and four with traditional platinum coils. HF-OCT was performed to interrogate gaps in the neck coverage, coil herniation, or acute thrombus formation. Animals were re-imaged at 7, 30, 90, and 180 days following aneurysm embolization. An automated image processing method segmented the devices at the neck of the aneurysm and quantified neck coverage. The largest coverage gap was used to predict aneurysm occlusion at 180 days.

Results: No difference was found in occlusion rates between the coil and NGID groups (P=0.45). Successful segmentation of the NGID construct was achieved in all cases. A coverage gap >1 mm was found to predict failed aneurysm occlusion (P=0.047). This threshold was able to predict all cases of failed occlusion. The average number of devices needed to treat the aneurysm was lower in the NGID group (1.9 vs 6.75, P=0.009). HF-OCT showed strong agreement with scanning electron microscopy (bias 0.0024 mm (95% CI -0.0279, 0.0327)).

Conclusions: HF-OCT enables precise and accurate measurement of coverage gaps at the neck of aneurysms treated with intrasaccular devices in vivo. We provide in vivo evidence that uniform aneurysm neck coverage by intrasaccular devices is critical for aneurysm occlusion.
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http://dx.doi.org/10.1136/neurintsurg-2019-014843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204215PMC
November 2019

Complete clot ingestion with cyclical ADAPT increases first-pass recanalization and reduces distal embolization.

J Neurointerv Surg 2019 Sep 4;11(9):931-936. Epub 2019 Feb 4.

Department of Radiology, New England Center for Stroke Research, Division of Neuroimaging and Intervention, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: Evidence is mounting that first-pass complete recanalization during mechanical thrombectomy is associated with better clinical outcomes in patients presenting with an emergent large vessel occlusion. We hypothesize that aspiration achieving complete clot ingestion results in higher first-pass successful recanalization with quantitative reduction in distal emboli.

Methods: A patient-specific cerebrovascular replica was connected to a flow loop. Occlusion of the middle cerebral artery was achieved with clot analogs. Independent variables were the diameter of the aspiration catheter (0.054-0.088in) and aspiration pattern (static versus cyclical). Outcome measures were the first-pass rates of complete clot ingestion, the extent of recanalization, and the particle-size distribution of distal emboli.

Results: All aspiration catheters were successfully navigated to the occlusion. Complete clot ingestion during aspiration thrombectomy resulted in first-pass complete recanalization in every experiment, only achieved in 21% of experiments with partial ingestion (P<0.0001). Aspiration through the large bore 0.088in device resulted in the highest rates of complete clot ingestion (90%). Cyclical aspiration (18-29 inHg, 0.5 Hz) significantly increased the rate of complete clot ingestion (OR21 [1.6, 266]; P=0.04). In all experiments, complete clot ingestion resulted in fewer and smaller distal emboli.

Conclusions: Complete clot ingestion results in fewer distal emboli and the highest rates of first-pass complete recanalization. The rate of complete ingestion during aspiration thrombectomy is a function of both the inner diameter of the aspiration catheter and use of cyclical aspiration.
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http://dx.doi.org/10.1136/neurintsurg-2018-014625DOI Listing
September 2019

The occurrence of neointimal hyperplasia after flow-diverter implantation is associated with cardiovascular risks factors and the stent design.

J Neurointerv Surg 2019 Jun 10;11(6):610-613. Epub 2018 Nov 10.

Department of Interventional Neuroradiology, NEURI Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Background: Neo-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 Methods: All 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).

Results: From 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 (<12 months), NIH was more frequently associated with the use of the SILK stent (68%) rather than the PED (38%): P<0.02. At long-term follow-up, the NIH rate in the total population dropped from 55% to 26% with no more significant difference between the two stents. The complete occlusion rate as seen in early follow-up was higher in the SILK group with 76% vs 65% but without statistical significance (P=0.4).

Conclusion: NIH 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.
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http://dx.doi.org/10.1136/neurintsurg-2018-014441DOI Listing
June 2019

Microcatheter navigation through the clot: does size matter?

J Neurointerv Surg 2019 Mar 3;11(3):271-274. Epub 2018 Sep 3.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: Despite high recanalization rates achieved with endovascular treatment of acute ischemic strokes, around 50% of eligible patients will not achieve a good outcome. Parameters that may determine patient outcomes include: time from puncture to recanalization, the collateral status, the anesthesia regimen, blood pressure management, and distal emboli. Characterization of distal emboli generated during mechanical thrombectomy has been performed in previous studies.

Objective: To further investigate the risk of distal embolization associated with microcatheter navigation across the clot.

Methods: A contrast-enhanced clot analog was used in an in vitro model that mimicked a middle cerebral artery occlusion within a complete circle of Willis vascular replica. The clot was crossed with one of the following microcatheters: Pro18, XT-27 or 3MAX. The emboli generated during the procedure were collected and measured.

Results: The use of Pro18 and XT-27 resulted in a significant reduction of visible particles (size ≥500 µm) as compared with the 3MAX catheter (P<0.003). For the size range between 8 and 200 µm, there was a trend for Pro18 to generate fewer particles (-18%) than XT-27 but without statistical significance (P>0.05). In comparison with previously published data, acquired under the same conditions, it was found that the clot crossing maneuver accounts approximately for 12% of the total number of small emboli (<200 µm) induced during a stent retriever-mediated mechanical thrombectomy procedure via a balloon guide catheter.

Conclusions: The clot crossing maneuver has a significant effect on the total number of small particles induced during mechanical thrombectomy. Smaller microcatheter sizes should be favored when possible.
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http://dx.doi.org/10.1136/neurintsurg-2018-014105DOI Listing
March 2019

Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia.

J Neurointerv Surg 2018 Nov 6;10(11):1097-1101. Epub 2018 Mar 6.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: Optical coherence tomography (OCT) is a high-resolution, intra-vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED).

Methods: In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline - cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations.

Results: OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED.

Conclusion: OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates.
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http://dx.doi.org/10.1136/neurintsurg-2018-013776DOI Listing
November 2018

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

J Neurointerv Surg 2018 Jul 10;10(7):693-697. Epub 2017 Nov 10.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: Optical coherence tomography (OCT) is a high resolution intravascular imaging method that allows visualization of flow diverter struts and the vessel wall. In this study, malapposition of the flow diverter that continues into the neck of the aneurysm, named communicating malapposition (CM), was investigated as a potential factor for delayed aneurysm healing.

Methods: 40 New Zealand White rabbits underwent elastase induced aneurysm creation, and were subsequently assigned to one of four treatment groups based on flow diverter type and administration of antiplatelet therapy. All animals underwent post device deployment balloon angioplasty and subsequent OCT to assess device/vessel apposition. The incidence of CM seen on OCT was assessed with a binary scoring system: 0-CM present; 1-CM absent. At 30 days, DSA was acquired to assess aneurysm healing. Aneurysm healing on terminal DSA was measured using a previously developed 5 point scale, with a score of 3 or 4 considered a positive outcome.

Results: All animals were grouped into a single cohort for analysis as no difference in the rate of CM or healing was seen in the four treatment groups. Significant interaction between the absence of CM and a positive outcome was confirmed by Fisher exact test (P=0.0034). Angioplasty was shown to treat 33% of the cases of CM seen at implant, and these treated cases overwhelmingly had a positive outcome (P<0.001).

Conclusion: The use of OCT to assess CM of flow diverters has been shown to be predictive of the 30 day healing rate of an animal model of aneurysms.
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http://dx.doi.org/10.1136/neurintsurg-2017-013502DOI Listing
July 2018

Novel Distal Emboli Protection Technology: The EmboTrap.

Interv Neurol 2017 Oct 16;6(3-4):268-276. Epub 2017 Sep 16.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts, Worcester, Massachusetts, USA.

Background: Over the course of the thrombectomy procedure, clot fragments may become dislodged and lead to downstream emboli due to manipulation of an endovascular device. The EmboTrap thrombectomy system features an inner stent channel with an outer stent trap design that may potentially reduce the risk of distal clot fragmentation during clot removal. We tested the hypothesis that distal emboli to both the same and new territory generated during mechanical thrombectomy are a function of device design.

Methods: EmboTrap and Solitaire thrombectomy were conducted in an in vitro model system that mimicked a middle-cerebral artery (MCA) occlusion within a complete circle of Willis vascular replica and a contrast-enhanced clot analog. Emboli generated during the procedure with a size >1,000 μm were collected and measured with calipers. The Coulter principle was used to characterize emboli with a size between 200 and 1,000 µm.

Results: EmboTrap thrombectomy resulted in a significant reduction in the risk of large emboli (>1,000 μm) formation as compared to first-generation stent retriever thrombectomy ( = 0.031, Fisher exact test). The majority of emboli >1,000 μm (∼80%) were found in the MCA, regardless of device type. There was no significant difference between the EmboTrap and Solitaire in 200 to 1,000 μm emboli formation ( = 0.89, Mann-Whitney test). When combining all emboli in the most dangerous range (>200 μm), EmboTrap offered a size reduction of emboli ( = 0.022).

Conclusion: The risk of distal embolization can be altered with improved stent retriever design. When encountering fragment-prone clots, EmboTrap thrombectomy may lower the risk of distal embolization.
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http://dx.doi.org/10.1159/000480668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662987PMC
October 2017

Acute thrombus formation on phosphorilcholine surface modified flow diverters.

J Neurointerv Surg 2018 Apr 8;10(4):406-411. Epub 2017 Jul 8.

New England Center for Stroke Research, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Purpose: Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED).

Methods: Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent.

Results: Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p<0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198).

Conclusion: In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.
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http://dx.doi.org/10.1136/neurintsurg-2017-013175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869458PMC
April 2018

Development of a high resolution MRI intracranial atherosclerosis imaging phantom.

J Neurointerv Surg 2018 Feb 9;10(2):143-149. Epub 2017 Mar 9.

Departments of Neurology and Radiology, Medical University of South Carolina, Charleston, South Carolina, USA.

Background And Purpose: Currently, 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 Methods: A 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).

Results: Quantitative 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.

Conclusions: A plaque phantom composed of a stenotic vessel wall and plaque components was successfully constructed for multicenter high resolution MRI standardization.
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http://dx.doi.org/10.1136/neurintsurg-2016-012974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028932PMC
February 2018

Quantitative assessment of device-clot interaction for stent retriever thrombectomy.

J Neurointerv Surg 2016 Dec 1;8(12):1278-1282. Epub 2016 Feb 1.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Purpose: Rapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device-clot interaction as a potential mechanism for efficient embolectomy.

Methods: Two different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF).

Results: The CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004-0.007).

Conclusions: This study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot-device integration increased in both clot models by waiting 5 min.
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http://dx.doi.org/10.1136/neurintsurg-2015-012209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5136713PMC
December 2016

Grading of Regional Apposition after Flow-Diverter Treatment (GRAFT): a comparative evaluation of VasoCT and intravascular OCT.

J Neurointerv Surg 2016 Aug 28;8(8):847-52. Epub 2015 Jul 28.

Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Background: Poor vessel wall apposition of flow diverter (FD) stents poses risks for stroke-related complications when treating intracranial aneurysms, necessitating long-term surveillance imaging. To facilitate quantitative evaluation of deployed devices, a novel algorithm is presented that generates intuitive two-dimensional representations of wall apposition from either high-resolution contrast-enhanced cone-beam CT (VasoCT) or intravascular optical coherence tomography (OCT) images.

Methods: VasoCT and OCT images were obtained after FD implant (n=8 aneurysms) in an experimental sidewall aneurysm model in canines. Surface models of the vessel wall and FD device were extracted, and the distance between them was presented on a two-dimensional flattened map. Maps and cross-sections at potential locations of malapposition detected on VasoCT-based maps were compared. The performance of OCT-based apposition detection was evaluated on manually labeled cross-sections using logistic regression against a thresholded (≥0.25 mm) apposition measure.

Results: VasoCT and OCT acquisitions yielded similar Grading of Regional Apposition after Flow-Diverter Treatment (GRAFT) apposition maps. GRAFT maps from VasoCT highlighted 16 potential locations of malapposition, of which two were found to represent malapposed device struts. Logistic regression showed that OCT could detect malapposition with a sensitivity of 98% and a specificity of 81%.

Conclusions: GRAFT delivered quantitative and visually convenient representations of potential FD malapposition and occasional acute thrombus formation. A powerful combination for future neuroendovascular applications is foreseen with the superior resolution delivered by intravascular OCT.
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http://dx.doi.org/10.1136/neurintsurg-2015-011843DOI Listing
August 2016
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