Publications by authors named "Matthew J Gounis"

122 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.121.036896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960363PMC
April 2022

Flow Diverter Reconstruction of Internal Carotid Artery (Loop) Dissections with or without Associated Pseudoaneurysms.

World Neurosurg 2022 Feb 22. Epub 2022 Feb 22.

Division of Neurointerventional Radiology, Department of Radiology and New England Center for Stroke Research, University of Massachusetts Medical Center, Worcester, Massachusetts, USA. Electronic address:

Objective: Endovascular treatment of cervical internal carotid artery (ICA) loop dissections in acute stroke interventions can be challenging. Flow diverters can effectively reconstruct vessel loops and treat the injured vessel and provide a safe conduit for intracranial catheterization.

Methods: We retrospectively reviewed our neurointerventional database and identified all patients with ICA loop dissections treated with flow diverters in the acute setting between August 2016 and September 2020. Patient demographics, procedural data, imaging follow-up results, and clinical outcome information were collected.

Results: Seven patients with a mean age of 62 years (range: 43-85 years) who underwent reconstruction of an ICA (loop) dissection with flow diverters were included. Four ICA dissections were treated with the Surpass Streamline flow diverter and 3 with the Pipeline embolization device. All cases were technically successful. All stroke cases achieved intracranial flow ≥thrombolysis in cerebral infarction 2B. Observed intracranial hemorrhages were all asymptomatic. All cases showed patent flow diverter(s) with or without (carotid) stent(s) on follow-up imaging. Semielectively treated patients did not show a change from baseline modified Rankin scale related to the procedure. Patients with acute stroke had a modified Rankin scale ≤2 in 4 of 5 cases (80%) at 3 months. Two patients died due to medical issues unrelated to the procedures. No patient showed new or recurrent symptoms.

Conclusion: Use of flow diverters, in some cases in conjunction with (carotid) stents, is an effective treatment option for cervical carotid artery (loop) dissections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2022.02.073DOI Listing
February 2022

Histological composition of retrieved emboli in acute ischemic stroke is independent of pre-thrombectomy alteplase use.

J Stroke Cerebrovasc Dis 2022 Apr 17;31(4):106376. Epub 2022 Feb 17.

Department of Neurosurgery, Baptist Medical Center, Jacksonville, Florida, USA.

Background And Purpose: Given recent evidence suggesting the clot composition may be associated with revascularization outcomes and stroke etiology, clot composition research has been a topic of growing interest. It is currently unclear what effect, if any, pre-thrombectomy thrombolysis has on clot composition. Understanding this association is important as it is a potential confounding variable in clot composition research. We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients who did and did not receive pre-treatment tPA to study the effect of tPA on clot composition.

Materials And Methods: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using Martius Scarlett Blue (MSB) staining and area of the clot was also measured on the gross photos. Student's t test was used for continuous variables and chi-squared test for categorical variables.

Results: A total of 1430 patients were included in this study. Mean age was 68.4±13.5 years. Overall rate of TICI 2c/3 was 67%. A total of 517 patients received tPA (36%) and 913 patients did not (64%). Mean RBC density for the tPA group was 42.97±22.62% compared to 42.80±23.18% for the non-tPA group (P=0.89). Mean WBC density for the tPA group was 3.74±2.60% compared to 3.42±2.21% for the non-tPA group (P=0.012). Mean fibrin density for the tPA group was 26.52±15.81% compared to 26.53±15.34% for the non-tPA group (P=0.98). Mean platelet density for the tPA group was 26.22±18.60% compared to 26.55±19.47% for the non-tPA group (P=0.75). tPA group also had significantly smaller clot area compared to non-tPA group.

Conclusions: Our study 1430 retrieved emboli and ischemic stroke patients shows no interaction between tPA administration and clot composition. These findings suggest that tPA does not result in any histological changes in clot composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2022.106376DOI Listing
April 2022

Comparison of Large Animal Models for Acute Ischemic Stroke: Which Model to Use?

Stroke 2022 04 15;53(4):1411-1422. Epub 2022 Feb 15.

Division of Experimental Cardiology, Department of Cardiology (A.T., J.B., D.J.D., H.M.M.v.B.), Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Translation of acute ischemic stroke research to the clinical setting remains limited over the last few decades with only one drug, recombinant tissue-type plasminogen activator, successfully completing the path from experimental study to clinical practice. To improve the selection of experimental treatments before testing in clinical studies, the use of large gyrencephalic animal models of acute ischemic stroke has been recommended. Currently, these models include, among others, dogs, swine, sheep, and nonhuman primates that closely emulate aspects of the human setting of brain ischemia and reperfusion. Species-specific characteristics, such as the cerebrovascular architecture or pathophysiology of thrombotic/ischemic processes, significantly influence the suitability of a model to address specific research questions. In this article, we review key characteristics of the main large animal models used in translational studies of acute ischemic stroke, regarding (1) anatomy and physiology of the cerebral vasculature, including brain morphology, coagulation characteristics, and immune function; (2) ischemic stroke modeling, including vessel occlusion approaches, reproducibility of infarct size, procedural complications, and functional outcome assessment; and (3) implementation aspects, including ethics, logistics, and costs. This review specifically aims to facilitate the selection of the appropriate large animal model for studies on acute ischemic stroke, based on specific research questions and large animal model characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.121.036050DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/btm2.10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780020PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

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

Quantification of clot spatial heterogeneity and its impact on thrombectomy.

J Neurointerv Surg 2021 Dec 15. Epub 2021 Dec 15.

Neurosurgery, Baptist Medical Center, Jacksonville, Florida, USA.

Background: Compositional and structural features of retrieved clots by thrombectomy can provide insight into improving the endovascular treatment of ischemic stroke. Currently, histological analysis is limited to quantification of compositions and qualitative description of the clot structure. We hypothesized that heterogeneous clots would be prone to poorer recanalization rates and performed a quantitative analysis to test this hypothesis.

Methods: We collected and did histology on clots retrieved by mechanical thrombectomy from 157 stroke cases (107 achieved first-pass effect (FPE) and 50 did not). Using an in-house algorithm, the scanned images were divided into grids (with sizes of 0.2, 0.3, 0.4, 0.5, and 0.6 mm) and the extent of non-uniformity of RBC distribution was computed using the proposed spatial heterogeneity index (SHI). Finally, we validated the clinical significance of clot heterogeneity using the Mann-Whitney test and an artificial neural network (ANN) model.

Results: For cases with FPE, SHI values were smaller (0.033 vs 0.039 for grid size of 0.4 mm, P=0.028) compared with those without. In comparison, the clot composition was not statistically different between those two groups. From the ANN model, clot heterogeneity was the most important factor, followed by fibrin content, thrombectomy techniques, red blood cell content, clot area, platelet content, etiology, and admission of intravenous tissue plasminogen activator (IV-tPA). No statistical difference of clot heterogeneity was found for different etiologies, thrombectomy techniques, and IV-tPA administration.

Conclusions: Clot heterogeneity can affect the clot response to thrombectomy devices and is associated with lower FPE. SHI can be a useful metric to quantify clot heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2021-018183DOI Listing
December 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Optical Coherence Tomography for Neurovascular Disorders.

Neuroscience 2021 10 12;474:134-144. Epub 2021 Jun 12.

University of Massachusetts Medical School, Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, United States. Electronic address:

Diagnosis of cerebrovascular disease includes vascular neuroimaging techniques such as computed tomography (CT) angiography, magnetic resonance (MR) angiography (with or without use of contrast agents) and catheter digital subtraction angiography (DSA). These techniques provide mostly information about the vessel lumen. Vessel wall imaging with MR seeks to characterize cerebrovascular pathology, but with resolution that is often insufficient for small lesions. Intravascular imaging techniques such as ultrasound and optical coherence tomography (OCT), used for over a decade in the peripheral circulation, is not amendable to routine deployment in the intracranial circulation due to vessel caliber and tortuosity. However, advances in OCT technology including the probe profile, stiffness and unique distal rotation solution, holds the promise for eventual translation of OCT into the clinical arena. As such, it is apropos to review this technology and present the rationale for utilization of OCT in the cerebrovasculature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2021.06.008DOI Listing
October 2021

Up around the bend: progress and promise of intravascular imaging in neurointerventional surgery.

J Neurointerv Surg 2021 Jun;13(6):495-496

Mechanical & Industrial Engineering, University of Toronto, Toronto, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2021-017707DOI Listing
June 2021

Histological evaluation of acute ischemic stroke thrombi may indicate the occurrence of vessel wall injury during mechanical thrombectomy.

J Neurointerv Surg 2022 Apr 11;14(4):356-361. Epub 2021 May 11.

Department of Neurology, Grady Memorial Hospital, Atlanta, Georgia, USA.

Background: Several animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine.

Objective: To investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots.

Methods: As part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells).

Results: MT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material.Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1-4] vs 1 [1-3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI.

Conclusions: Histological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2021-017310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581068PMC
April 2022

Per pass analysis of thrombus composition retrieved by mechanical thrombectomy.

Interv Neuroradiol 2021 Dec 7;27(6):815-820. Epub 2021 Apr 7.

Departments of Radiology and Neurosurgery, Northwestern University, Chicago, IL, USA.

Background And Aim: Mechanical thrombectomy (MT) for large vessel occlusion often requires multiple passes to retrieve the entire thrombus load. In this multi-institutional study we sought to examine the composition of thrombus fragments retrieved with each pass during MT.

Methods: Patients who required multiple passes during thrombectomy were included. Histopathological evaluation of thrombus fragments retrieved from each pass was performed using Martius Scarlet Blue staining and the composition of each thrombus component including RBC, fibrin and platelet was determined using image analysis software.

Results: 154 patients underwent MT and 868 passes was performed which resulted in 263 thrombus fragments retrieval. The analysis of thrombus components per pass showed higher RBC, lower fibrin and platelet composition in the pass 1 and 2 when compared to pass 3 and passes 4 or more combined (P values <0.05). There were no significant differences between thrombus fragments retrieved in pass 1 and pass 2 in terms of RBC, WBC, fibrin, and platelet composition (P values >0.05). Similarly, when each composition of thrombus fragments retrieved in pass 3 and passes 4 or more combined were compared with each other, no significant difference was noted (P values >0.05).

Conclusion: Our findings confirm that thrombus fragments retrieved with each pass differed significantly in histological content. Fragments in the first passes were associated with lower fibrin and platelet composition compared to fragments retrieved in passes three and four or higher. Also, thrombus fragments retrieved after failed pass were associated with higher fibrin and platelet components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/15910199211009119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673903PMC
December 2021

Association between clot composition and stroke origin in mechanical thrombectomy patients: analysis of the Stroke Thromboembolism Registry of Imaging and Pathology.

J Neurointerv Surg 2021 Jul 15;13(7):594-598. Epub 2021 Mar 15.

Neurosurgery, Baptist Medical Center Jacksonville, Jacksonville, Florida, USA.

Background: We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients to study the association between histological composition and stroke etiology METHODS: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using martius scarlet blue (MSB) staining, and quantification for red blood cells (RBCs), white blood cells (WBCs), fibrin and platelets was performed using Orbit Image Software. A Wilcoxon test was used for continuous variables and χ test for categorical variables.

Results: 1350 patients were included in this study. The overall rate of Thrombolysis In Cerebral Infarction (TICI) 2c/3 was 68%. 501 patients received tissue plasminogen activator (tPA) (37%). 267 patients (20%) had a large artery atherosclerosis (LAA) source, 662 (49%) a cardioembolic (CE) source, 301 (22%) were cryptogenic, and the remainder had other identifiable sources including hypercoagulable state or dissection. LAA thrombi had a higher mean RBC density (46±23% vs 42±22%, p=0.01) and a lower platelet density (24±18% vs 27±18%, p=0.03) than CE thrombi. Clots from dissection patients had the highest mean RBC density (50±24%) while clots from patients with a hypercoagulable state had the lowest mean RBC density (26±21%).

Conclusions: Our study found statistically significant but clinically insignificant differences between clots of CE and LAA etiologies. Future studies should emphasize molecular, proteomic and immunohistochemical characteristics to determine links between clot composition and etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2020-017167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069417PMC
July 2021

Modelling the impact of clot fragmentation on the microcirculation after thrombectomy.

PLoS Comput Biol 2021 03 12;17(3):e1008515. Epub 2021 Mar 12.

Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom.

Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this 'no-reperfusion' phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters-permeability and coupling coefficients-are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1008515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990195PMC
March 2021

Preventing Inadvertent Foreign Body Injection in Angiography.

Radiology 2021 05 9;299(2):460-467. Epub 2021 Mar 9.

From the Department of Neuroradiology, University Hospital RWTH Aachen, Neuroradiologie, Universitätsklinikum Aachen, Pauwelsstr 30, 52074 Aachen, Germany (O.N., T.S., M.W.); and New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Mass (A.K., R.A., M.J.G.).

Background Inadvertent injection of foreign material during angiography, particularly neuroangiography, should be avoided to reduce the risk of embolic complications. Woven gauze and cotton fabrics have been identified as sources of inadvertent foreign body embolization. Purpose To find the source of particles that contaminate injections on an angiography table and to identify measures for their reduction. Materials and Methods The number and size of particles on an angiographic supply table at a tertiary stroke center were analyzed by using the Coulter principle in September 2019. Seven conditions (saline directly drawn from its bag, from a small metal cup, from a small plastic cup, from a large plastic bowl, from a large plastic bowl with a guidewire and its sheath, from a large plastic bowl with a stack of woven gauze, and from a large plastic bowl with a large cotton towel) were tested at different time intervals (0, 30, and 60 minutes). Each container was filled with saline, and particle count was analyzed immediately after unpackaging, after rinsing with saline, and after introduction of foreign material; tests were used for statistical comparisons. Results Freshly unpacked basins can be contaminated with many submillimetric particles (range, 4.4-25.1 particles per milliliter on average, depending on basin). Cotton towels and woven gauze placed in rinsed basins resulted in a significant increase in particles (from 1.5 particles per milliliter ± 0.4 [standard deviation] to 64.4 particles per milliliter ± 4.1 and 257.1 particles per milliliter ± 11.6, respectively; < .001). Rinsing basins with saline significantly reduced the number of particles ( ≤ .03). Drawing saline directly from bags through intravenous lines yielded the lowest number of particles (0.1 particles per milliliter). Conclusion To decrease the risk for foreign body embolization, it is best to rinse all basins before use, draw saline and contrast agents directly from the respective bags and bottles through intravenous lines, and avoid cotton towels and woven gauze in basins and on the angiography table altogether whenever possible. © RSNA, 2021 See also the editorial by Nikolic in this issue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2021200207DOI Listing
May 2021

Distal radial artery (Snuffbox) access for intracranial aneurysm treatment using the Woven EndoBridge (WEB) device.

J Clin Neurosci 2020 Nov 20;81:310-315. Epub 2020 Oct 20.

Division of Neurointerventional Radiology, Department of Radiology, University of Massachusetts Medical Center, Worcester, MA 01655, USA. Electronic address:

Preliminary experience with distal radial artery (dRA) access for diagnostic cerebral angiography and some neurointerventional procedures has proved to be promising with good technical results and a reliable safety profile. Vascular access via the dRA may further improve minimally invasive treatment of intracranial aneurysms. Between July 2019 and June 2020 we identified 11 patients (9 females) with a mean age of 63.5 years who underwent WEB device placement for treatment of their intracranial aneurysm via the dRA approach. The mean aneurysm size (largest diameter) was 6.7 mm. One patient required conversion to femoral access due to severe brachial artery fibromuscular dysplasia. Placement of the WEB device was successful in all other cases via dRA approach. In all but one case, a low profile triaxial catheter system with the 6F Benchmark guide catheter (Penumbra) and 5F Sofia distal access catheter (Microvention) were used. No access related complications were observed. The combination of the intrasaccular WEB device and dRA access represents an ideal approach which offers operators a low risk vascular access and high procedural success by maintaining the ability to precisely place and manipulate the device using low-profile catheter systems. At the same time, this approach offers patients the most minimally invasive experience currently available for treatment of intracranial aneurysms with quick postprocedural recovery, minimal restrictions and low risk for access site complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jocn.2020.10.006DOI Listing
November 2020

Quantitative Characterization of Recanalization and Distal Emboli with a Novel Thrombectomy Device.

Cardiovasc Intervent Radiol 2021 Feb 11;44(2):318-324. Epub 2020 Nov 11.

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

Purpose: The first-pass effect during mechanical thrombectomy improves clinical outcomes regardless of first-line treatment approach, but current success rates for complete clot capture with one attempt are still less than 40%. We hypothesize that the ThrombX retriever (ThrombX Medical Inc.) can better engage challenging clot models during retrieval throughout tortuous vasculature in comparison with a standard stent retriever without increasing distal emboli.

Materials And Methods: Thrombectomy testing with the new retriever as compared to the Solitaire stent retriever was simulated in a vascular replica with hard and soft clot analogs to create a challenging occlusive burden. Parameters included analysis of distal emboli generated per clot type, along with the degree of recanalization (complete, partial or none) by retrieval device verified by angiography.

Results: The ThrombX device exhibited significantly higher rates of first-pass efficacy (90%) during hard clot retrieval in comparison with the control device (20%) (p < 0.009), while use of both techniques during soft clot retrieval resulted in equivalent recanalization. The soft clot model generated higher numbers of large emboli (>200 μm) across both device groups (p = 0.0147), and no significant differences in numbers of distal emboli were noted between the ThrombX and Solitaire techniques.

Conclusions: Irrespective of clot composition, use of the ThrombX retriever demonstrated high rates of complete recanalization at first pass in comparison with a state-of-the-art stent retriever and proved to be superior in the hard clot model. Preliminary data suggest that risk of distal embolization associated with the ThrombX system is comparable to that of the control device.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00270-020-02683-3DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

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

Distal radial artery (snuffbox) access for carotid artery stenting - Technical pearls and procedural set-up.

Interv Neuroradiol 2021 Apr 13;27(2):241-248. Epub 2020 Sep 13.

Division of Neurointerventional Radiology, Department of Radiology, University of Massachusetts Medical Center, Worcester, MA, USA.

Purpose: To report use of distal radial artery (dRA) access for carotid artery stenting (CAS) and to discuss procedural setup and technical considerations for a successful intervention.

Methods: A retrospective review of our prospective neurointerventional database of CAS was conducted between May 2019 and March 2020. All CAS cases via dRA in the anatomical snuffbox were identified. Patient demographics, clinical information, procedural and radiographic data was collected.

Results: 22 CAS procedures in 20 patients via dRA were identified. Patients' mean age was 69.4 years (range 53-87 years). 3 patients were female. Mean radial artery diameter was 2.1 mm (range 1.6-2.8 mm). dRA access was achieved in all cases. Conversion to femoral access was required in 2 cases (9.1%) due to persistent radial artery vasospasm resulting in patient discomfort despite multiple additional doses of intraarterial vasodilators and added intravenous sedation as well as tortuous vessel anatomy and limited support of the catheters in a type 3 aortic arch for left CAS.

Conclusion: Our preliminary experience with dRA access for CAS suggests this approach to be feasible and safe for patients. Technical considerations are important and preprocedural planning is necessary for a successful intervention. Catheter systems and devices specifically designed for radial access are needed to enable more interventionalists to safely perform neurointerventional procedures via wrist access.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1591019920959537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050532PMC
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

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

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model.

Hum Gene Ther 2020 06 29;31(11-12):617-625. Epub 2020 May 29.

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

Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 μL) and rates (0.5-5 μL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for ∼1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 μL (2 × the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 μL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 μL/min at a volume ∼1/3 of the thalamus (400-600 μL) appears to be well tolerated in sheep both clinically and histopathologically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/hum.2019.288DOI Listing
June 2020

Introduction: History and Development of Flow Diverter Technology and Evolution.

Neurosurgery 2020 01;86(Suppl 1):S3-S10

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

The introduction of flow diverter technology to the field of neurointervention has revolutionized the treatment of intracranial aneurysms. The therapy approach has shifted from intrasaccular aneurysm treatment to exclusion of the aneurysm from the blood circulation with remodeling of the parent artery. Previously, "difficult"-to-treat aneurysms including fusiform and blister aneurysms, but also aneurysms arising from a diseased vessel segment, can now be safely and permanently treated with flow diverters.  A little over a decade ago, after extensive bench testing and refinement of the flow diverter concept, the device was eventually available for clinical use and today it has become a standard treatment for intracranial aneurysms. Currently, United States Food and Drug Administration (FDA)-approved flow diverters are the Pipeline Embolization Device (Medtronic) and the Surpass Streamline Flow Diverter (Stryker).  The devices can either be delivered or deployed via a standard femoral artery approach or a radial artery approach. Other considerations for catheter setup and device deployment strategies depending on aneurysm location or vessel anatomy are described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyz307DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

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