Design and Development of a Lorentz Force-Based MRI-Driven Neuroendoscope

The introduction of neuroendoscopy, microneurosurgery, neuronavigation, and intraoperative imaging for surgical operations has made significant improvements over other traditionally invasive surgical techniques. The integration of magnetic resonance imaging (MRI)-driven surgical devices with intraoperative imaging and endoscopy can enable further advancements in surgical treatments and outcomes. This work proposes the design and development of an MRI-driven endoscope leveraging the high (3-7 T), external magnetic field of an MR scanner for heat-mitigated steering within the ventricular system of the brain. It also demonstrates the effectiveness of a Lorentz force-based grasper for diseased tissue manipulation and ablation. Feasibility studies show the neuroendoscope can be steered precisely within the lateral ventricle to locate a tumor using both MRI and endoscopic guidance. Results also indicate grasping forces as high as 31 mN are possible and power inputs as low as 0.69 mW can cause cancerous tissue ablation. These findings enable further developments of steerable devices using MR imaging integrated with endoscopic guidance for improved outcomes

Search full text options here 3 of 3 Heat-Mitigated Design and Lorentz Force-Based Steering of an MRI-Driven Microcatheter toward Minimally Invasive Surgery

Catheters integrated with microcoils for electromagnetic steering under the high, uniform magnetic field within magnetic resonance (MR) scanners (3-7 Tesla) have enabled an alternative approach for active catheter operations. Achieving larger ranges of tip motion for Lorentz force-based steering have previously been dependent on using high power coupled with active cooling, bulkier catheter designs, or introducing additional microcoil sets along the catheter. This work proposes an alternative approach using a heat-mitigated design and actuation strategy for a magnetic resonance imaging (MRI)-driven microcatheter. A quad-configuration microcoil (QCM) design is introduced, allowing miniaturization of existing MRI-driven, Lorentz force-based catheters down to 1-mm diameters with minimal power consumption (0.44 W). Heating concerns are experimentally validated using noninvasive MRI thermometry. The Cosserat model is implemented within an MR scanner and results demonstrate a desired tip range up to 110 degrees with 4 degrees error. The QCM is used to validate the proposed model and power-optimized steering algorithm using an MRI-compatible neurovascular phantom and ex vivo kidney tissue. The power-optimized tip orientation controller conserves as much as 25% power regardless of the catheter\u27s initial orientation. These results demonstrate the implementation of an MRI-driven, electromagnetic catheter steering platform for minimally invasive surgical applications without the need for camera feedback or manual advancement via guidewires. The incorporation of such system in clinics using the proposed design and actuation strategy can further improve the safety and reliability of future MRI-driven active catheter operations

Imaging Immune Response In vivo: Cytolytic Action of Genetically Altered T Cells Directed to Glioblastoma Multiforme

Purpose: Clinical trials have commenced to evaluate the feasibility of targeting malignant gliomas with genetically engineered CTLs delivered directly to the tumor bed in the central nervous system. The objective of this study is to determine a suite of magnetic resonance imaging (MRI) measurements using an orthotopic xenograft murine model that can noninvasively monitor immunologically mediated tumor regression and reactive changes in the surrounding brain parenchyma. Experimental Design: Our preclinical therapeutic platform is based on CTL genetic modification to express a membrane tethered interleukin-13 (IL-13) cytokine chimeric T-cell antigen receptor. This enables selective binding and signal transduction on encountering the glioma-restricted IL-13 α2 receptor (IL-13Rα2). We used MRI to visualize immune responses following adoptive transfer of IL-13Rα2-specific CD8^+ CTL clones. Results: Based on MRI measurements, several phases following IL-13Rα2-specific T-cell adoptive transfer could be distinguished, all of which correlated well with glioblastoma regression confirmed on histology. The first detectable changes, 24 hours post-treatment, were significantly increased T_2 relaxation times and strongly enhanced signal on T_1-weighted postcontrast images. In the next phase, the apparent diffusion coefficient was significantly increased at 2 and 3 days post-treatment. In the last phase, at day 3 after IL-13Rα2-specific T-cell injection, the volume of hyperintense signal on T_1-weighted postcontrast image was significantly decreased, whereas apparent diffusion coefficient remained elevated. Conclusions: The present study indicates the feasibility of MRI to visualize different phases of immune response when IL-13Rα2-specific CTLs are administered directly to the glioma tumor bed. This will further the aim of better predicting clinical outcome following immunotherapy

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases

Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons

Abstract Global cerebral ischemia results in oxygen and glucose deprivation (OGD) and consequent delayed cell death of vulnerable neurons, with hippocampal CA1 neurons more vulnerable than cortical neurons. Most AMPA receptors (AMPARs) are heteromeric complexes of subunits GluA1/GluA2 or GluA2/GluA3, and the presence of GluA2 renders AMPARs Ca2+-impermeable. In hippocampal CA1 neurons, OGD causes the synaptic expression of GluA2-lacking Ca2+-permeable AMPARs, contributing to toxic Ca2+ influx. The loss of synaptic GluA2 is caused by rapid trafficking of GluA2-containing AMPARs from the cell surface, followed by a delayed reduction in GluA2 mRNA expression. We show here that OGD causes endocytosis, lysosomal targeting and consequent degradation of GluA2- and GluA3-containing AMPARs, and that PICK1 is required for both OGD-induced GluA2 endocytosis and lysosomal sorting. Our results further suggest that GluA1-containing AMPARs resist OGD-induced endocytosis. OGD does not cause GluA2 endocytosis in cortical neurons, and we show that PICK1 binding to the endocytic adaptor AP2 is enhanced by OGD in hippocampal, but not cortical neurons. We propose that endocytosis of GluA2/3, caused by a hippocampal-specific increase in PICK1-AP2 interactions, followed by PICK1-dependent lysosomal targeting, are critical events in determining changes in AMPAR subunit composition in the response to ischaemia

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitorinduced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases