Advanced MRI Center: a 3 Tesla Magnetic Resonance system for preclinical, translational and clinical imaging studies

The Advanced MRI Center, located in the UMass Medical School building, is a research core facility providing the latest magnetic resonance imaging and spectroscopy capabilities to UMass scientists. It is equipped with a Philips Achieva 3.0T X-series whole-body scanner and radiofrequency coils for studying all organs of the human body, and small and large animals, such as mice, rats, rabbits, dogs, sheep and non-human primates. The center also includes a radiofrequency coil lab, a nurses’ station, two patient holding rooms and two patient changing rooms. The Center’s specialized techniques are able to elucidate functional, physiological and biochemical information from all organs of the body. The 3.0 Tesla system features the Quasar Dual gradient system with industry leading performance specifications, that allow high-level diffusion tensor imaging and functional MRI (fMRI) applications in humans, and high resolution imaging studies in small animal studies. A fMRI stimulus delivery system, a MRI compatible goggle set with eye tracking system, microphone and earphones are available for facilitating fMRI studies. Small animal monitoring and gating system and an MR compatible Anesthesia system with heater and ventilator option are also available. The 3.0T MR system is also equipped with a Multi-nuclear spectroscopy system, which provide the ability to perform 13C, 31P, 7Li, 23Na and other nuclei spectroscopy and imaging. Technical and clinical expertise for collaborative research is also provided

Effectiveness of mechanical endovascular thrombectomy in a model system of cerebrovascular occlusion

BACKGROUND AND PURPOSE: A number of thrombectomy devices are currently undergoing clinical evaluation; meanwhile, various novel devices are under investigation. The aims of this study were to quantify flow restoration and the particle size distribution of the effluent pursuant to MET in an in vitro occlusion model. MATERIALS AND METHODS: The model system was composed of 3 elements: an ICA/MCA replica, a clot model with mechanical properties similar to those of thrombi found in patients at risk of stroke, and a pulsatile flow loop. Different thrombectomy mechanisms including mechanical retrieval, aspiration, and waveguide induced cavitation were used. The efficacy end points were recanalization rate and amount of flow restoration. The risk of the embolic shower was assessed to evaluate device safety. RESULTS: The recanalization rates were the following: Merci, 67%; Solitaire, 100%; Penumbra, 83%; Enterprise, 17%; and the waveguide, 0%. In experiments in which recanalization was achieved, the amount of flow restoration for the Merci, Solitaire, and Enterprise devices was 100%, 92%, and 86%, respectively. The mean sizes of generated small and large clot fragments were between 23 and 37 and 215 and 285 mum, respectively, depending on the device used. The Merci device generated the fewest number of large fragments compared with the Penumbra system (P \u3c .05) and Solitaire (not significant). CONCLUSIONS: The risk of embolic shower was influenced by the mechanism of action for the thrombectomy device. Clinically reported recanalization rates for the Solitaire, Penumbra, and Merci devices were nearly identical in this model system, suggesting that this model may provide a predictive tool for preclinical evaluation of MET

Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles

Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method

Risk of distal embolization with stent retriever thrombectomy and ADAPT

BACKGROUND: There is a discrepancy in clinical outcomes and the achieved recanalization rates with stent retrievers in the endovascular treatment of ischemic stroke. It is our hypothesis that procedural release of embolic particulate may be one contributor to poor outcomes and is a modifiable risk. The goal of this study is to assess various treatment strategies that reduce the risk of distal emboli. METHODS: Mechanical thrombectomy was simulated in a vascular phantom with collateral circulation. Hard fragment-prone clots (HFC) and soft elastic clots (SECs) were used to generate middle cerebral artery (MCA) occlusions that were retrieved by the Solitaire FR devices through (1) an 8 Fr balloon guide catheter (BGC), (2) a 5 Fr distal access catheter at the proximal aspect of the clot in the MCA (Solumbra), or (3) a 6 Fr guide catheter with the tip at the cervical internal carotid artery (guide catheter, GC). Results from mechanical thrombectomy were compared with those from direct aspiration using the Penumbra 5MAX catheter. The primary endpoint was the size distribution of emboli to the distribution of the middle and anterior cerebral arteries. RESULTS: Solumbra was the most efficient method for reducing HFC fragments (p \u3c 0.05) while BGC was the best method for preventing SEC fragmentation (p \u3c 0.05). The risk of forming HFC distal emboli ( \u3e 1000 microm) was significantly increased using GC. A non-statistically significant benefit of direct aspiration was observed in several subgroups of emboli with size 50-1000 microm. However, compared with the stent-retriever mechanical thrombectomy techniques, direct aspiration significantly increased the risk of SEC fragmentation (microm) by at least twofold. CONCLUSIONS: The risk of distal embolization is affected by the catheterization technique and clot mechanics

A thromboembolic model for the efficacy and safety evaluation of combined mechanical and pharmacologic revascularization strategies

BACKGROUND AND PURPOSE: Recanalization strategies mediated by intra-arterial fibrinolytic therapy in combination with mechanical clot disruption may be a more effective treatment approach than either therapy used alone. There are few preclinical animal models to evaluate these strategies. Here we report on a model to simultaneously evaluate both of these treatment approaches. METHODS: Allogeneic clot was injected through the 6 F guide catheter after creating \u3e50% luminal stenosis of the common carotid arteries of New Zealand White rabbits. The stenosis was released after 1 h, allowing sufficient time for clot-vessel wall interaction. Occlusion was confirmed and each vessel was assigned to receive either balloon angioplasty alone, intra-arterial tissue plasminogen activator (tPA, Alteplase, Genentech, San Francisco, California, USA), tPA delivery through prototype balloon infusion wire (NIT Therapeutics, Pittsburgh, Pennsylvania, USA), partial stent deployment or partial stent deployment with locally delivered tPA. The negative control received no treatment. RESULTS: In vivo revascularization Thrombolysis in Cerebral Infarction (TICI) score revealed that the balloon infusion wire achieved a stable and higher revascularization score of TICI 2B, with a lower dose of tPA in comparison with other treatment strategies. All treatment strategies resulted in endothelial denudation and exposure of the internal elastic lamina. CONCLUSIONS: The proposed animal model permits reliable and consistent thromboembolic occlusion of the target vasculature and allows for an assessment of both pharmacologic and mechanical revascularization strategies for acute ischemic stroke

Role of Balloon Guide Catheter in Modern Endovascular Thrombectomy

Proximal flow control achieved with a balloon guide catheter (BGC) during endovascular treatment of acute ischemic stroke is reviewed in this article. In clinical practice, BGCs offer a multi-faceted approach for clot retrieval by creating proximal flow arrest, reducing embolic burden, and shortening procedure time. Evaluation of frontline thrombectomy procedures with BGCs revealed advantages of combined use over the conventional guide catheter (CGC), notably in the significant reduction of distal emboli to both the affected and previously unaffected territories. Recently, new measures of early and complete reperfusion at first thrombectomy pass have been identified as independent predictors of improved outcomes, which were consistently demonstrated with use of BGC as a safe and effective option to minimize number of passes during intervention. Prior randomized controlled trials reported the positive correlation between BGC-treated patients and a lower risk of mortality as well as shortened procedure time. While BGC use is more common in stent retriever-mediated mechanical thrombectomy, preliminary data has shown the potential benefit of device application during contact aspiration thrombectomy to achieve successful recanalization. However, the question of which major endovascular strategy reigns superior as a frontline remains to be answered. Along with clinical case assessments, BGC performance during in-vitro simulation was analyzed to further understand mechanisms for optimization of thrombectomy technique

Porcine brachial artery tortuosity for in vivo evaluation of neuroendovascular devices

We report a novel model of arterial tortuosity in the porcine brachial artery for testing of endovascular devices in the flexed forelimb position. This provides an ideal vascular territory for an in vivo assessment of guidewires, microcatheters, and endovascular implants because it closely mimics the challenging curvature at the carotid siphon

Frameless multimodal image guidance of localized convection-enhanced delivery of therapeutics in the brain

INTRODUCTION: Convection-enhanced delivery (CED) has been shown to be an effective method of administering macromolecular compounds into the brain that are unable to cross the blood-brain barrier. Because the administration is highly localized, accurate cannula placement by minimally invasive surgery is an important requisite. This paper reports on the use of an angiographic c-arm system which enables truly frameless multimodal image guidance during CED surgery. METHODS: A microcannula was placed into the striatum of five sheep under real-time fluoroscopic guidance using imaging data previously acquired by cone beam computed tomography (CBCT) and MRI, enabling three-dimensional navigation. After introduction of the cannula, high resolution CBCT was performed and registered with MRI to confirm the position of the cannula tip and to make adjustments as necessary. Adeno-associated viral vector-10, designed to deliver small-hairpin micro RNA (shRNAmir), was mixed with 2.0 mM gadolinium (Gd) and infused at a rate of 3 mul/min for a total of 100 mul. Upon completion, the animals were transferred to an MR scanner to assess the approximate distribution by measuring the volume of spread of Gd. RESULTS: The cannula was successfully introduced under multimodal image guidance. High resolution CBCT enabled validation of the cannula position and Gd-enhanced MRI after CED confirmed localized administration of the therapy. CONCLUSION: A microcannula for CED was introduced into the striatum of five sheep under multimodal image guidance. The non-alloy 300 mum diameter cannula tip was well visualized using CBCT, enabling confirmation of the position of the end of the tip in the area of interest

Infarct evolution in a large animal model of middle cerebral artery occlusion

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

Biophysical targeting of high-risk cerebral aneurysms

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 mum) particles, that exhibited enhanced targeting ( \u3e 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 ( \u3e 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