Evaluating Radioactive Analogs of Doxorubicin to Quantify ChemoFilter Binding and Whole-Body Positron Emission Tomography/Magnetic Resonance Imaging for Drug Biodistribution.

PURPOSE: To evaluate radiolabeled doxorubicin (Dox) analogs as tracers of baseline Dox biodistribution in vivo during hepatic intra-arterial chemotherapy and to assess the efficacy of ChemoFilter devices to bind Dox in vitro. MATERIALS AND METHODS: In an in vitro static experiment, [fluorine-18]N-succinimidyl 4-fluorobenzoate ([18F]SFB) and [fluorine-18]fluorobenzoyl-doxorubicin ([18F]FB-Dox) were added to a beaker containing a filter material (Dowex cation exchange resin, single-stranded DNA (ssDNA) resin, or sulfonated polymer coated mesh). In an in vitro flow model, [18F]FB-Dox was added into a Dox solution in phosphate-buffered saline, and the solution flowed via a syringe column containing the filter materials. In an in vitro flow experiment, using micro-positron emission tomography (PET), images were taken as [18F]SFB and [18F]FB-Dox moved through a phantom. For in vivo biodistribution testing, a catheter was placed into the common hepatic artery of a swine, and [18F]FB-Dox was infused over 30 seconds. A 10-minute dynamic image and three 20-minute static images were acquired using 3T PET/MR imaging. RESULTS: In the in vitro static experiment, [18F]FB-Dox demonstrated 76.7%, 88.0%, and 52.4% binding to the Dowex resin, ssDNA resin, and coated mesh, respectively. In the in vitro flow model, the first-pass binding of [18F]FB-Dox to the Dowex resin, ssDNA resin, and coated mesh was 76.7%, 74.2%, and 76.2%, respectively, and the total bound fraction was 80.9%, 84.6%, and 79.9%, respectively. In the in vitro flow experiment using micro-PET, the phantom demonstrated a greater amount of [18F]FB-Dox bound to both filter cartridges than of the control [18F]SFB. In in vivo biodistribution testing, the first 10 minutes depicted [18F]FB-Dox moving through the right upper quadrant of the abdomen. A region-of-interest analysis showed that the relative amount increased by 2.97 times in the gallbladder and 1.08 times in the kidney. The amount decreased by 0.74 times in the brain and 0.57 times in the heart. CONCLUSIONS: [18F]FB-Dox can be used to assess Dox binding to ChemoFilters as well as in vivo biodistribution. This sets the stage for the evaluation of ChemoFilter effectiveness in reducing systemic toxicity from intra-arterial chemotherapy.

Anatomic thermochromic tissue-mimicking phantom of the lumbar spine for pre-clinical evaluation of MR-guided focused ultrasound (MRgFUS) ablation of the facet joint.

OBJECTIVE: To develop a thermochromic tissue-mimicking phantom (TTMP) with an embedded 3D-printed bone mimic of the lumbar spine to evaluate MRgFUS ablation of the facet joint and medial branch nerve. MATERIALS AND METHODS: Multiple 3D-printed materials were selected and characterized by measurements of speed of sound and linear acoustic attenuation coefficient using a through-transmission technique. A 3D model of the lumbar spine was segmented from a de-identified CT scan, and 3D printed. The 3D-printed spine was embedded within a TTMP with thermochromic ink color change setpoint at 60 °C. Multiple high energy sonications were targeted to the facet joints and medial branch nerve anatomical location using an ExAblate MRgFUS system connected to a 3T MR scanner. The phantom was dissected to assess sonication targets and the surrounding structures for color change as compared to the expected region of ablation on MR-thermometry. RESULTS: The measured sound attenuation coefficient and speed of sound of gypsum was 240 Np/m-MHz and 2471 m/s, which is the closest to published values for cortical bone. Following sonication, dissection of the TTMP revealed good concordance between the regions of color change within the phantom and expected areas of ablation on MR-thermometry. No heat deposition was observed in critical areas, including the spinal canal and nerve roots from either color change or MRI. CONCLUSION: Ablated regions in the TTMP correlated well with expected ablations based on MR-thermometry. These findings demonstrate the utility of an anatomic spine phantom in evaluating MRgFUS sonication for facet joint and medial branch nerve ablations.

Wireless Resonant Circuits Printed Using Aerosol Jet Deposition for MRI Catheter Tracking.

Interventional magnetic resonance imaging (MRI) could allow for diagnosis and immediate treatment of ischemic stroke; however, such endovascular catheter-based procedures under MRI guidance are inherently difficult. One major challenge is tracking the tip of the catheter, as standard fabrication methods for building inductively coupled coil markers are rigid and bulky. Here, we report a new approach that uses aerosol jet deposition to three-dimensional (3-D) print an inductively coupled RF coil marker on a polymer catheter. Our approach enables lightweight conforming markers on polymer catheters and these low-profile markers allow the catheter to be more safely navigated in small caliber vessels. Prototype markers with an inductor with the geometry of a double helix are incorporated on catheters for in vitro studies, and we show that these markers exhibit good signal amplification. We report temperature measurements and, finally, demonstrate feasibility in a preliminary in vivo experiment. We provide material properties and electromagnetic simulation performance analysis. This paper presents fully aerosol jet-deposited and functional wireless resonant markers on polymer catheters for use in 3T clinical scanners.

Interventional magnetic resonance imaging guided carotid embolectomy using a novel resonant marker catheter: demonstration of preclinical feasibility.

To assess the visualization and efficacy of a wireless resonant circuit (wRC) catheter system for carotid artery occlusion and embolectomy under real-time MRI guidance in vivo, and to compare MR imaging modality with x-ray for analysis of qualitative physiological measures of blood flow at baseline and after embolectomy. The wRC catheter system was constructed using a MR compatible PEEK fiber braided catheter (Penumbra, Inc, Alameda, CA) with a single insulated longitudinal copper loop soldered to a printed circuit board embedded within the catheter wall. In concordance with IACUC protocol (AN103047), in vivo carotid artery navigation and embolectomy were performed in four farm pigs (40-45 kg) under real-time MRI at 1.5T. Industry standard clots were introduced in incremental amounts until adequate arterial occlusion was noted in a total of n=13 arteries. Baseline vasculature and restoration of blood flow were confirmed via MR and x-ray imaging, and graded by the Thrombolysis in Cerebral Infarction (TICI) scale. Wilcoxon signed-rank tests were used to analyze differences in recanalization status between DSA and MRA imaging. Successful recanalizations (TICI 2b/3) were compared to clinical rates reported in literature via binomial tests. The wRC catheter system was visible both on 5° sagittal bSSFP and coronal GRE sequence. Successful recanalization was demonstrated in 11 of 13 occluded arteries by DSA analysis and 8 of 13 by MRA. Recanalization rates based on DSA (0.85) and MRA (0.62) were not significantly different from the clinical rate of mechanical aspiration thrombectomy reported in literature. Lastly, a Wilcoxon signed rank test indicated no significant difference between TICI scores analyzed by DSA and MRA. With demonstrated compatibility and visualization under MRI, the wRC catheter system is effective for in vivo endovascular embolectomy, suggesting progress towards clinical endovascular interventional MRI.

Endovascular MR-guided Renal Embolization by Using a Magnetically Assisted Remote-controlled Catheter System.

Purpose To assess the feasibility of a magnetically assisted remote-controlled (MARC) catheter system under magnetic resonance (MR) imaging guidance for performing a simple endovascular procedure (ie, renal artery embolization) in vivo and to compare with x-ray guidance to determine the value of MR imaging guidance and the specific areas where the MARC system can be improved. Materials and Methods In concordance with the Institutional Animal Care and Use Committee protocol, in vivo renal artery navigation and embolization were tested in three farm pigs (mean weight 43 kg ± 2 [standard deviation]) under real-time MR imaging at 1.5 T. The MARC catheter device was constructed by using an intramural copper-braided catheter connected to a laser-lithographed saddle coil at the distal tip. Interventionalists controlled an in-room cart that delivered electrical current to deflect the catheter in the MR imager. Contralateral kidneys were similarly embolized under x-ray guidance by using standard clinical catheters and guidewires. Changes in renal artery flow and perfusion were measured before and after embolization by using velocity-encoded and perfusion MR imaging. Catheter navigation times, renal parenchymal perfusion, and renal artery flow rates were measured for MR-guided and x-ray-guided embolization procedures and are presented as means ± standard deviation in this pilot study. Results Embolization was successful in all six kidneys under both x-ray and MR imaging guidance. Mean catheterization time with MR guidance was 93 seconds ± 56, compared with 60 seconds ± 22 for x-ray guidance. Mean changes in perfusion rates were 4.9 au/sec ± 0.8 versus 4.6 au/sec ± 0.6, and mean changes in renal flow rate were 2.1 mL/min/g ± 0.2 versus 1.9 mL/min/g ± 0.2 with MR imaging and x-ray guidance, respectively. Conclusion The MARC catheter system is feasible for renal artery catheterization and embolization under real-time MR imaging in vivo, and quantitative physiologic measures under MR imaging guidance were similar to those measured under x-ray guidance, suggesting that the MARC catheter system could be used for endovascular procedures with interventional MR imaging. (©) RSNA, 2016.

In Vitro Capture of Small Ferrous Particles with a Magnetic Filtration Device Designed for Intravascular Use with Intraarterial Chemotherapy: Proof-of-Concept Study.

PURPOSE: To establish that a magnetic device designed for intravascular use can bind small iron particles in physiologic flow models. MATERIALS AND METHODS: Uncoated iron oxide particles 50-100 nm and 1-5 µm in size were tested in a water flow chamber over a period of 10 minutes without a magnet (ie, control) and with large and small prototype magnets. These same particles and 1-µm carboxylic acid-coated iron oxide beads were likewise tested in a serum flow chamber model without a magnet (ie, control) and with the small prototype magnet. RESULTS: Particles were successfully captured from solution. Particle concentrations in solution decreased in all experiments (P < .05 vs matched control runs). At 10 minutes, concentrations were 98% (50-100-nm particles in water with a large magnet), 97% (50-100-nm particles in water with a small magnet), 99% (1-5-µm particles in water with a large magnet), 99% (1-5-µm particles in water with a small magnet), 95% (50-100-nm particles in serum with a small magnet), 92% (1-5-µm particles in serum with a small magnet), and 75% (1-µm coated beads in serum with a small magnet) lower compared with matched control runs. CONCLUSIONS: This study demonstrates the concept of magnetic capture of small iron oxide particles in physiologic flow models by using a small wire-mounted magnetic filter designed for intravascular use.

New-Generation Laser-lithographed Dual-Axis Magnetically Assisted Remote-controlled Endovascular Catheter for Interventional MR Imaging: In Vitro Multiplanar Navigation at 1.5 T and 3 T versus X-ray Fluoroscopy.

PURPOSE: To assess the feasibility of multiplanar vascular navigation with a new magnetically assisted remote-controlled (MARC) catheter with real-time magnetic resonance (MR) imaging at 1.5 T and 3 T and to compare it with standard x-ray guidance in simulated endovascular catheterization procedures. MATERIALS AND METHODS: A 1.6-mm-diameter custom clinical-grade microcatheter prototype with lithographed double-saddle coils at the distal tip was deflected with real-time MR imaging. Two inexperienced operators and two experienced operators catheterized anteroposterior (celiac, superior mesenteric, and inferior mesenteric arteries) and mediolateral (renal arteries) branch vessels in a cryogel abdominal aortic phantom. This was repeated with conventional x-ray fluoroscopy by using clinical catheters and guidewires. Mean procedure times and percentage success data were analyzed with linear mixed-effects regression. RESULTS: The MARC catheter tip was visible at 1.5 T and 3 T. Among inexperienced operators, MARC MR imaging guidance was not statistically different from x-ray guidance at 1.5 T (67% successful vessel selection turns with MR imaging vs 76% with x-ray guidance, P = .157) and at 3 T (75% successful turns with MR imaging vs 76% with x-ray guidance, P = .869). Experienced operators were more successful in catheterizing vessels with x-ray guidance (98% success within 60 seconds) than with 1.5-T (65%, P < .001) or 3-T (75%) MR imaging. Among inexperienced operators, mean procedure time was nearly equivalent by using MR imaging (31 seconds) and x-ray guidance (34 seconds, P = .436). Among experienced operators, catheterization was faster with x-ray guidance (20 seconds) compared with 1.5-T MR imaging (42 seconds, P < .001), but MARC guidance improved at 3 T (31 seconds). MARC MR imaging guidance at 3 T was not significantly different from x-ray guidance for the celiac (P = .755), superior mesenteric (P = .358), and inferior mesenteric (P = .065) arteries. CONCLUSION: Multiplanar navigation with a new MARC catheter with real-time MR imaging at 1.5 T and 3 T is feasible and comparable to x-ray guidance for anteroposterior vessels at 3 T in a vascular phantom.

Digital subtraction MR angiography roadmapping for magnetic steerable catheter tracking.

PURPOSE: To develop a high temporal resolution MR imaging technique that could be used with magnetically assisted remote control (MARC) endovascular catheters. MATERIALS AND METHODS: A technique is proposed based on selective intra-arterial injections of dilute MR contrast at the beginning of a fluoroscopic MR angiography acquisition. The initial bolus of contrast is used to establish a vascular roadmap upon which MARC catheters can be tracked. The contrast to noise ratio (CNR) of the achieved roadmap was assessed in phantoms and in a swine animal model. The ability of the technique to permit navigation of activated MARC catheters through arterial branch points was evaluated. RESULTS: The roadmapping mode proved effective in phantoms for tracking objects and achieved a CNR of 35.7 between the intra- and extra-vascular space. In vivo, the intra-arterial enhancement strategy produced roadmaps with a CNR of 42.0. The artifact produced by MARC catheter activation provided signal enhancement patterns on the roadmap that experienced interventionalists could track through vascular structures. CONCLUSION: A roadmapping approach with intra-arterial contrast-enhanced MR angiography is introduced for navigating the MARC catheter. The technique mitigates the artifact produced by the MARC catheter, greatly limits the required specific absorption rate, permits regular roadmap updates due to the low contrast agent requirements, and proved effective in the in vivo setting. Inc.

Magnetically assisted remote-controlled endovascular catheter for interventional MR imaging: in vitro navigation at 1.5 T versus X-ray fluoroscopy.

PURPOSE: To compare in vitro navigation of a magnetically assisted remote-controlled (MARC) catheter under real-time magnetic resonance (MR) imaging with manual navigation under MR imaging and standard x-ray guidance in endovascular catheterization procedures in an abdominal aortic phantom. MATERIALS AND METHODS: The 2-mm-diameter custom clinical-grade microcatheter prototype with a solenoid coil at the distal tip was deflected with a foot pedal actuator used to deliver 300 mA of positive or negative current. Investigators navigated the catheter into branch vessels in a custom cryogel abdominal aortic phantom. This was repeated under MR imaging guidance without magnetic assistance and under conventional x-ray fluoroscopy. MR experiments were performed at 1.5 T by using a balanced steady-state free precession sequence. The mean procedure times and percentage success data were determined and analyzed with a linear mixed-effects regression analysis. RESULTS: The catheter was clearly visible under real-time MR imaging. One hundred ninety-two (80%) of 240 turns were successfully completed with magnetically assisted guidance versus 144 (60%) of 240 turns with nonassisted guidance (P < .001) and 119 (74%) of 160 turns with standard x-ray guidance (P = .028). Overall mean procedure time was shorter with magnetically assisted than with nonassisted guidance under MR imaging (37 seconds ± 6 [standard error of the mean] vs 55 seconds ± 3, P < .001), and time was comparable between magnetically assisted and standard x-ray guidance (37 seconds ± 6 vs 44 seconds ± 3, P = .045). When stratified by angle of branch vessel, magnetic assistance was faster than nonassisted MR guidance at turns of 45°, 60°, and 75°. CONCLUSION: In this study, a MARC catheter for endovascular navigation under real-time MR imaging guidance was developed and tested. For catheterization of branch vessels arising at large angles, magnetically assisted catheterization was faster than manual catheterization under MR imaging guidance and was comparable to standard x-ray guidance.

Comparing deflection measurements of a magnetically steerable catheter using optical imaging and MRI.

PURPOSE: Magnetic resonance imaging (MRI) is an emerging modality for interventional radiology, giving clinicians another tool for minimally invasive image-guided interventional procedures. Difficulties associated with endovascular catheter navigation using MRI guidance led to the development of a magnetically steerable catheter. The focus of this study was to mechanically characterize deflections of two different prototypes of the magnetically steerable catheter in vitro to better understand their efficacy. METHODS: A mathematical model for deflection of the magnetically steerable catheter is formulated based on the principle that at equilibrium the mechanical and magnetic torques are equal to each other. Furthermore, two different image based methods for empirically measuring the catheter deflection angle are presented. The first, referred to as the absolute tip method, measures the angle of the line that is tangential to the catheter tip. The second, referred to the base to tip method, is an approximation that is used when it is not possible to measure the angle of the tangent line. Optical images of the catheter deflection are analyzed using the absolute tip method to quantitatively validate the predicted deflections from the mathematical model. Optical images of the catheter deflection are also analyzed using the base to tip method to quantitatively determine the differences between the absolute tip and base to tip methods. Finally, the optical images are compared to MR images using the base to tip method to determine the accuracy of measuring the catheter deflection using MR. RESULTS: The optical catheter deflection angles measured for both catheter prototypes using the absolute tip method fit very well to the mathematical model (R(2) = 0.91 and 0.86 for each prototype, respectively). It was found that the angles measured using the base to tip method were consistently smaller than those measured using the absolute tip method. The deflection angles measured using optical data did not demonstrate a significant difference from the angles measured using MR image data when compared using the base to tip method. CONCLUSIONS: This study validates the theoretical description of the magnetically steerable catheter, while also giving insight into different methods and modalities for measuring the deflection angles of the prototype catheters. These results can be used to mechanically model future iterations of the design. Quantifying the difference between the different methods for measuring catheter deflection will be important when making deflection measurements in future studies. Finally, MR images can be used to reliably measure deflection angles since there is no significant difference between the MR and optical measurements.

System architecture for a magnetically guided endovascular microcatheter.

Magnetic resonance imaging (MRI) guided minimally invasive interventions are an emerging technology. We developed a microcatheter that utilizes micro-electromagnets manufactured on the distal tip, in combination with the magnetic field of a MRI scanner, to perform microcatheter steering during endovascular surgery. The aim of this study was to evaluate a user control system for operating, steering and monitoring this magnetically guided microcatheter. The magnetically-assisted remote control (MARC) microcatheter was magnetically steered within a phantom in the bore of a 1.5 T MRI scanner. Controls mounted in an interventional MRI suite, along with a graphical user interface at the MRI console, were developed with communication enabled via MRI compatible hardware modules. Microcatheter tip deflection measurements were performed by evaluating MRI steady-state free precession (SSFP) images and compared to models derived from magnetic moment interactions and composite beam mechanics. The magnitude and direction of microcatheter deflections were controlled with user hand, foot, and software controls. Data from two different techniques for measuring the microcatheter tip location within a 1.5 T MRI scanner showed correlation of magnetic deflections to our model (R(2): 0.88) with a region of linear response (R(2): 0.98). Image processing tools were successful in autolocating the in vivo microcatheter tip within MRI SSFP images. Our system showed good correlation to response curves and introduced low amounts of MRI noise artifact. The center of the artifact created by the energized microcatheter solenoid was a reliable marker for determining the degree of microcatheter deflection and auto-locating the in vivo microcatheter tip.

Safety of retained microcatheters: an evaluation of radiofrequency heating in endovascular microcatheters with nitinol, tungsten, and polyetheretherketone braiding at 1.5 T and 3 T.

BACKGROUND: The use of ethylene-vinyl alcohol copolymer for liquid embolization of cranial vascular lesions has resulted in microcatheter fragments entrapped in patients following endovascular procedures. Undergoing subsequent diagnostic MRI examinations poses a safety concern due to the possibility of radiofrequency heating of the metallic braid incorporated into the microcatheter. Heating of nitinol, tungsten, and polyetheretherketone (PEEK) braided microcatheters was assessed and compared using a phantom model. METHODS: Microcatheters coupled with fluoroptic temperature probes were embedded in a polyacrylamide gel within a head and torso phantom. Experiments were performed at 1.5 T and 3 T, analyzing the effects of different catheter immersion lengths, specific absorption rate (SAR) levels, short clinical scans, long clinical scans, and microcatheter fragment lengths. RESULTS: The maximal increase in temperature for the nitinol braided microcatheter during a 15 min scan was 3.06°C using the T1 fast spin echo sequence at 1.5 T and 0.45°C using the balanced steady state free precession sequence at 3 T. The same scans for fragment lengths of 9, 18, 36, and 72 cm produced maximal temperature rises of 0.68, 0.80, 1.70, and 1.07°C at 1.5 T, respectively. The temperature changes at 3 T for these fragment lengths were 0.66, 0.83, 1.07, and 0.72°C, respectively. The tungsten and PEEK braided microcatheters did not demonstrate heating. CONCLUSIONS: Substantial heating of nitinol braided microcatheters occurred and was a function of SAR level and geometric considerations. SAR and time limitations on MR scanning are proposed for patients with this microcatheter entrapped in their vasculature. In contrast, tungsten and PEEK braided microcatheters showed potential safe use in MRI.

Development and Validation of Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin: Preclinical Study.

To develop a novel endovascular chemotherapy filter (CF) able to remove excess drug from the blood during intra-arterial chemotherapy delivery (IAC), thus preventing systemic toxicities and thereby enabling higher dose IAC. A flow circuit containing 2.5 mL of ion-exchange resin was constructed. Phosphate-buffered saline (PBS) containing 50 mg doxorubicin (Dox) was placed in the flow model with the hypothesis that doxorubicin would bind rapidly to resin. To simulate IAC, 50 mg of doxorubicin was infused over 10 min into the flow model containing resin. Similar testing was repeated with porcine serum. Doxorubicin concentrations were measured over 60 min and compared to controls (without resin). Single-pass experiments were also performed. Based on these experiments, an 18F CF was constructed with resin in its tip. In a pilot porcine study, the device was deployed under fluoroscopy. A control hepatic doxorubicin IAC model (no CF placed) was developed in another animal. A second CF device was created with a resin membrane and tested in the infrarenal inferior vena cava (IVC) of a swine. In the PBS model, resin bound 76% of doxorubicin in 10 min, and 92% in 30 min (P < 0.001). During IAC simulation, 64% of doxorubicin bound in 10 min and 96% in 60 min (P < 0.001). On average, 51% of doxorubicin concentration was reduced during each pass in single pass studies. In porcine serum, 52% of doxorubicin bound in 10 min, and 80% in 30 min (P < 0.05). CF device placement and administration of IAC were successful in three animals. No clot was present on the resin within the CF following the in vivo study. The infrarenal IVC swine study demonstrated promising results with up to 85% reduction in peak concentration by the CF device. An endovascular CF device was developed and shown feasible in vitro. An in vivo model was established with promising results supporting high-capacity rapid doxorubicin filtration from the blood that can be further evaluated in future studies.

Magnetic catheter manipulation in the interventional MR imaging environment.

PURPOSE: To evaluate deflection capability of a prototype endovascular catheter, which is remotely magnetically steerable, for use in the interventional magnetic resonance (MR) imaging environment. MATERIALS AND METHODS: Copper coils were mounted on the tips of commercially available 2.3-3.0-F microcatheters. The coils were fabricated in a novel manner by plasma vapor deposition of a copper layer followed by laser lithography of the layer into coils. Orthogonal helical (ie, solenoid) and saddle-shaped (ie, Helmholtz) coils were mounted on a single catheter tip. Microcatheters were tested in water bath phantoms in a 1.5-T clinical MR scanner, with variable simultaneous currents applied to the coils. Catheter tip deflection was imaged in the axial plane by using a "real-time" steady-state free precession MR imaging sequence. Degree of deflection and catheter tip orientation were measured for each current application. RESULTS: The catheter tip was clearly visible in the longitudinal and axial planes. Magnetic field artifacts were visible when the orthogonal coils at the catheter tip were energized. Variable amounts of current applied to a single coil demonstrated consistent catheter deflection in all water bath experiments. Changing current polarity reversed the observed direction of deflection, whereas current applied to two different coils resulted in deflection represented by the composite vector of individual coil activations. Microcatheter navigation through the vascular phantom was successful through control of applied current to one or more coils. CONCLUSIONS: Controlled catheter deflection is possible with laser lithographed multiaxis coil-tipped catheters in the MR imaging environment.