Magnetic Resonance Imaging-Guided Focused Ultrasound Positioning System for Preclinical Studies in Small Animals.

OBJECTIVES: A positioning device compatible with magnetic resonance imaging (MRI) used for preclinical studies in small animals was developed that fits in MRI scanners up to 7 T. The positioning device was designed with two computer-controlled linear stages. METHODS: The positioning device was evaluated in an agar-based phantom, which mimics soft tissues, and in a rabbit. Experiments with this positioning device were performed in an MRI system using the agar-based phantom. The transducer used had a diameter of 50 mm, operated at 0.5 MHz, and focused energy at 60 mm. RESULTS: Magnetic resonance thermometry was used to assess the functionality of the device, which showed adequate deposition of thermal energy and sufficient positional accuracy in all axes. CONCLUSIONS: The proposed system fits in MRI scanners up to 7 T. Because of the size of the positioning device, at the moment, it can be used to perform preclinical studies on small animals such as mice, rats, and rabbits.

Acoustical properties of 3D printed thermoplastics.

With focused ultrasound (FUS) gaining popularity as a therapeutic modality for brain diseases, the need for skull phantoms that are suitable for evaluating FUS protocols is increasing. In the current study, the acoustical properties of several three-dimensional (3D) printed thermoplastic samples were evaluated to assess their suitability to mimic human skull and bone accurately. Samples were 3D printed using eight commercially available thermoplastic materials. The acoustic properties of the printed samples, including attenuation coefficient, speed of sound, and acoustic impedance, were investigated using transmission-through and pulse-echo techniques. The ultrasonic attenuation, estimated at a frequency of 1.1 MHz, varied from approximately 7 to 32 dB/cm. The frequency dependence of attenuation was described by a power law in the frequency range of 0.2-3.5 MHz, and the exponential index of frequency was found to vary from 1.30 to 2.24. The longitudinal velocity of 2.7 MHz sound waves was in the range of 1700-3050 m/s. The results demonstrate that thermoplastics could potentially be used for the 3D construction of high-quality skull phantoms.

A High Intensity Focused Ultrasound System for Veterinary Oncology Applications.

BACKGROUND: Magnetic resonance-guided focused ultrasound surgery is an incisionless energy-based thermal method that is used for ablating tumors in the veterinary clinic. AIMS AND OBJECTIVES: In this article we describe a prototype of a veterinary system compatible with magnetic resonance imaging intended for small-to-medium-sized companion animals that was developed and tested in vivo in adult rabbits. METHODS: Real-time monitoring of the ablation during the experiment was possible with MR thermometry. Experiments involved thermal monitoring of sonications applied in the thigh of the rabbits. A 38-mm diameter transducer operating at 2.6 MHz was used with a 60-mm-focal length. The robotic system employed 3 linear axes and one angular axis. For this study, only X and Y axis were enabled. Due to the target size limitations, motion in Z and Θ was not needed. The functionality of the positioning device was evaluated by means of MR thermometry, demonstrating sufficient heating and accurate motion in both axes of operation. RESULTS: The postmortem findings confirm the ability of the system to induce thermal ablations in vivo in the absence of adverse effects. CONCLUSIONS: The device is a reliable and affordable solution for companion animal hospitals, offering and additional tool for the veterinary oncology society.

Ultrasonic Attenuation of an Agar, Silicon Dioxide, and Evaporated Milk Gel Phantom.

BACKGROUND: It has been demonstrated that agar-based gel phantoms can emulate the acoustic parameters of real tissues and are the most commonly used tissue-mimicking materials for high-intensity focused ultrasound applications. The following study presents ultrasonic attenuation measurements of agar-based phantoms with different concentrations of additives (percent of agar, silicon dioxide and evaporated milk) in an effort of matching the material's acoustic property as close as possible to human tissues. METHODS: Nine different agar-based phantoms with various amounts of agar, silicon dioxide, and evaporated milk were prepared. Attenuation measurements of the samples were conducted using the through-transmission immersion techniques. RESULTS: The ultrasonic attenuation coefficient of the agar-based phantoms varied in the range of 0.30-1.49 dB/cm-MHz. The attenuation was found to increase in proportion to the concentration of agar and evaporated milk. Silicon dioxide was found to significantly contribute to the attenuation coefficient up to 4% weight to volume (w/v) concentration. CONCLUSION: The acoustic attenuation coefficient of agar-based phantoms can be adjusted according to the tissue of interest in the range of animal and human tissues by the proper selection of agar, silicon dioxide, and evaporated milk.

Amyloid ß Plaque Reduction With Antibodies Crossing the Blood-Brain Barrier, Which Was Opened in 3 Sessions of Focused Ultrasound in a Rabbit Model.

OBJECTIVES: The main objective of this study was to remove amyloid ß plaques by applying multiple sessions of focused ultrasound (US)-induced blood-brain barrier (BBB) opening using microbubbles with and without delivery of antibodies in a rabbit model. METHODS: The animal model was achieved by feeding a high-cholesterol diet to rabbits for 4 months. Fifty-two New Zealand White rabbits were divided into treatment groups: untreated control, high-cholesterol diet only, antibodies only, focused US only, and focused US and antibodies. Three sessions of focused US were administered to the treatment groups. RESULTS: It was shown that with this animal model, the plaques were 30 µm in diameter. By increasing the number of sessions, the number of plaques decreased (both for focused US only and focused US and antibodies). Without the application of focused US, the average number of plaques dropped from 200/cm2 (before treatment) to 170/cm2 (after treatment). The effect of treatment with focused US with antibodies was more drastic. With 3 BBB opening sessions, the average number of plaques was reduced from 200 to 78/cm2 . CONCLUSIONS: This feasibility study had demonstrated that by opening the BBB, it will be possible to deliver exogenous antibodies to the brain, thus eliminating amyloid ß plaques. More importantly with repeated opening of the BBB (3 times in this study), the reduction in the number of plaques was increased.

Preclinical robotic device for magnetic resonance imaging guided focussed ultrasound.

BACKGROUND: A robotic device featuring three motion axes was manufactured for preclinical research on focussed ultrasound (FUS). The device comprises a 2.75 MHz single element ultrasonic transducer and is guided by Magnetic Resonance Imaging (MRI). METHODS: The compatibility of the device with the MRI was evaluated by estimating the influence on the signal-to-noise ratio (SNR). The efficacy of the transducer in generating ablative temperatures was evaluated in phantoms and excised porcine tissue. RESULTS: System's activation in the MRI scanner reduced the SNR to an acceptable level without compromising the image quality. The transducer demonstrated efficient heating ability as proved by MR thermometry. Discrete and overlapping thermal lesions were inflicted in excised tissue. CONCLUSIONS: The FUS system was proven effective for FUS thermal applications in the MRI setting. It can thus be used for multiple preclinical applications of the emerging MRI-guided FUS technology. The device can be scaled-up for human use with minor modifications.

Phantom-based assessment of motion and needle targeting accuracy of robotic devices for magnetic resonance imaging-guided needle biopsy.

BACKGROUND: The current study proposes simple methods for assessing the performance of robotic devices intended for Magnetic Resonance Imaging (MRI)-guided needle biopsy. METHODS: In-house made agar-based breast phantoms containing biopsy targets served as the main tool in the evaluation process of an MRI compatible positioning device comprising a needle navigator. The motion accuracy of mechanical stages was assessed by calliper measurements. Laboratory evaluation of needle targeting included a repeatability phantom test and a laser-based method. The accuracy and repeatability of needle targeting was also assessed by MRI. RESULTS: The maximum error of linear motion for steps up to 10 mm was 0.1 mm. Needle navigation relative to the phantom and alignment with the various biopsy targets were performed successfully in both the laboratory and MRI settings. The proposed biopsy phantoms offered tissue-like signal in MRI and good haptic feedback during needle insertion. CONCLUSIONS: The proposed methods could be valuable in the process of validating the accuracy of MRI-guided biopsy robotic devices in both laboratory and real environments.

Robotic device for transcranial focussed ultrasound applications in small animal models.

BACKGROUND: Focussed Ultrasound (FUS) combined with microbubbles (MBs) was proven a promising modality for non-invasive blood brain barrier disruption (BBBD). Herein, two devices for FUS-mediated BBBD in rodents are presented. METHODS: A two-axes robotic device was manufactured for navigating a single element FUS transducer of 1 MHz relative to the brain of rodents. A second more compact device featuring a single motorized vertical axis was also developed. Their performance was assessed in terms of motion accuracy, MRI compatibility and trans-skull BBBD in wild type mice using MBs in synergy with pulsed FUS. RESULTS: Successful BBBD was evidenced by the Evans Blue dye method, as well as by Fibronectin and Fibrinogen immunostaining. BBB permeability was enhanced when the applied acoustic intensity was increased. CONCLUSIONS: The proposed devices constitute a cost-effective and ergonomic solution for FUS-mediated BBBD in small animal models. Further experimentation is needed to examine the repeatability of results and optimise the therapeutic protocol.

Robotic system for top to bottom MRgFUS therapy of multiple cancer types.

BACKGROUND: A robotic system for Magnetic Resonance guided Focussed Ultrasound (MRgFUS) therapy of tumours in the breast, bone, thyroid, and abdomen was developed. METHODS: A special C-shaped structure was designed to be attached to the table of conventional magnetic resonance imaging (MRI) systems carrying 4 computer-controlled motion stages dedicated to positioning a 2.75 MHz spherically focussed transducer relative to a patient placed in the supine position. The developed system was evaluated for its MRI compatibility and heating abilities in agar-based phantoms and freshly excised tissue. RESULTS: Compatibility of the system with a clinical high-field MRI scanner was demonstrated. FUS heating in the phantom was successfully monitored by magnetic resonance thermometry without any evidence of magnetically induced phenomena. Cigar-shaped discrete lesions and well-defined areas of overlapping lesions were inflicted in excised tissue by robotic movement along grid patterns. CONCLUSIONS: The developed MRgFUS robotic system was proven safe and efficient by ex-vivo feasibility studies.

Focused ultrasound phantom model for blood brain barrier disruption.

In this paper a high intensity focused ultrasound (FUS) phantom model was developed, in order to be used in experiments for Blood Brain Barrier (BBB) disruption. The target was to create a phantom model that represents the disruption of the BBB during ultrasound application. An appropriate experimental setup was created bearing a single element transducer with diameter 50 mm and geometric focus 100 mm operating at 0.5 MHz. It included a set of tubes and a connector with multiple 0.4 mm openings, through which a suitable liquid is being circulated with a pump. The lesions were sealed with a thin homogenous layer of wax, preventing a liquid leakage. The system was tested successfully with FUS and a liquid leakage was achieved after FUS application. This set up is the first phantom model that has the potential to be utilized as a cost-effective solution for performing experiments for BBB disruption, without the need of using animal models.

Experimental evaluation of the near-field and far-field heating of focused ultrasound using the thermal dose concept.

BACKGROUND: Conventional motion algorithms utilized during High Intensity Focused Ultrasound (HIFU) procedures usually sonicate successive tissue cells, thereby inducing excess deposition of thermal dose in the pre-focal region. Long delays (~60 s) are used to reduce the heating around the focal region. In the present study the experimental evaluation of six motion algorithms so as to examine the required delay and algorithm for which the pre-focal (near-field) and post-focal (far-field) heating can be reduced using thermal dose estimations is presented. MATERIALS AND METHODS: A single element spherically focused transducer operating at 1.1 MHz and focusing beam at 9 cm, was utilized for sonication on a 400 mm2 area of an agar-based phantom. Movement of the transducer was performed with each algorithm, using 0-60 s (10 s step) delays between sonications. Temperatures were recorded at both near and far-field regions and thermal dose calculations were implemented. RESULTS: With the algorithms used in the present study, a delay of 50-60 s was required to reduce heating in the near-field region. A 30 s delay induced a safe thermal dose in the far-field region using all algorithms except sequential which still required 60 s delay. CONCLUSIONS: The study verified the conservative need for 60 s delay for the sequential plan treatment. Nevertheless, present findings suggest that prolonged treatment times can be significantly reduced in homogeneous tissues by selection of the optimized nonlinear algorithm and delay.

Characterization of a soft tissue-mimicking agar/wood powder material for MRgFUS applications.

This study describes the development and characterization of an agar-based soft tissue-mimicking material (TMM) doped with wood powder destined for fabricating MRgFUS applications. The main objective of the following work was to investigate the suitability of wood powder as an inexpensive alternative in replacing other added materials that have been suggested in previous studies for controlling the ultrasonic properties of TMMs. The characterization procedure involved a series of experiments designed to estimate the acoustic (attenuation coefficient, absorption coefficient, propagation speed, and impedance), thermal (conductivity, diffusivity, specific heat capacity), and MR properties (T1 and T2 relaxation times) of the wood-powder doped material. The developed TMM (2% w/v agar and 4% w/v wood powder) as expected demonstrated compatibility with MRI scanner following images artifacts evaluation. The acoustic attenuation coefficient of the proposed material was measured over the frequency range of 1.1-3 MHz and found to be nearly proportional to frequency. The measured attenuation coefficient was 0.48 dB/cm at 1 MHz which was well within the range of soft tissue. Temperatures over 37 °C proved to increase marginally the attenuation coefficient. Following the transient thermoelectric method, the acoustic absorption coefficient was estimated at 0.34 dB/cm-MHz. The estimated propagation speed (1487 m/s) was within the range of soft tissue at room temperature, while it significantly increased with higher temperature. The material possessed an acoustic impedance of 1.58 MRayl which was found to be comparable to the corresponding value of muscle tissue. The thermal conductivity of the material was estimated at 0.51 W/m K. The measured relaxation times T1 (844 ms) and T2 (66 ms) were within the range of values found in the literature for soft tissue. The phantom was tested for its suitability for evaluating MRgFUS thermal protocols. High acoustic energy was applied, and temperature change was recorded using thermocouples and MR thermometry. MR thermal maps were acquired using single-shot Echo Planar Imaging (EPI) gradient echo sequence. The TMM matched adequately the acoustic and thermal properties of human tissues and through a series of experiments, it was proven that wood concentration enhances acoustic absorption. Experiments using MR thermometry demonstrated the usefulness of this phantom to evaluate ultrasonic thermal protocols by monitoring peak temperatures in real-time. Thermal lesions formed above a thermal dose were observed in high-resolution MR images and visually in dissections of the proposed TMM.

Robotic system for magnetic resonance guided focused ultrasound ablation of abdominal cancer.

BACKGROUND: A prototype robotic system that uses magnetic resonance guided focused ultrasound (MRgFUS) technology is presented. It features three degrees of freedom (DOF) and is intended for thermal ablation of abdominal cancer. METHODS: The device is equipped with three identical transducers being offset between them, thus focussing at different depths in tissue. The efficacy and safety of the system in ablating rabbit liver and kidney was assessed, both in laboratory and magnetic resonance imaging (MRI) conditions. RESULTS: Despite these organs' challenging location, in situ coagulative necrosis of a tissue area was achieved. Heating of abdominal organs in rabbit was successfully monitored with MR thermometry. CONCLUSIONS: The MRgFUS system was proven successful in creating lesions in the abdominal area of rabbits. The outcomes of the study are promising for future translation of the technology to the clinic.

Magnetic resonance image-guided focused ultrasound robotic system for transrectal prostate cancer therapy.

BACKGROUND: A magnetic resonance image (MRI) guided robotic device for focussed ultrasound therapy of prostate cancer (PC) was developed. The device offers movement in 5 degrees of freedom (DOF) and uses a single-element transducer that operates at 3.2 MHz, has a diameter of 25 mm and focuses at 45 mm. METHODS: The MRI compatibility of the system was evaluated in a 1.5 T scanner. The ability of the transducer to create lesions was evaluated in laboratory and MRI settings, on ex vivo pork tissue and in vivo rabbit thigh tissue. RESULTS: Cavitational and thermal lesions were created on the excised pork tissue. In vivo experiments proved the efficacy of the system in ablating muscle tissue without damaging intervening areas. CONCLUSIONS: The MRI compatible robotic system can be placed on the table of any commercial MRI scanner up to 7 T. The device has the ability of future use for transrectal focal therapy of PC with the patient in supine position.

Simple methods to test the accuracy of MRgFUS robotic systems.

BACKGROUND: Robotic-assisted diagnostic and therapeutic modalities require a highly accurate performance to be certified for clinical application. In this paper, three simple methods for assessing the accuracy of motion of magnetic resonance-guided focused ultrasound (MRgFUS) robotic systems are presented. METHODS: The accuracy of motion of a 4 degrees of freedom robotic system intended for preclinical use of MRgFUS was evaluated by calliper-based and magnetic resonance imaging (MRI) methods, as well as visually by performing multiple ablations on a plastic film. RESULTS: The benchtop results confirmed a highly accurate motion in all axes of operation. The spatial positioning errors estimated by MRI evaluation were defined by the size of the imaging pixels. Lesions arrangement in discrete and overlapping patterns confirmed satisfactory alignment of motion trajectories. CONCLUSIONS: We believe the methods presented here should serve as a standard for evaluating the accuracy of motion of MRgFUS robotic systems.

Focused ultrasound robotic system for very small bore magnetic resonance imaging.

BACKGROUND: A magnetic resonance imaging (MRI) compatible robotic system for focused ultrasound was developed for small animal like mice or rats that fits into a 9.4 T MRI scanner (Bruker Biospec 9420, Bruker Biospin, Ettlingen, Germany). The robotic system includes two computer-controlled linear stages. MATERIALS AND METHODS: The robotic system was evaluated in a mouse-shaped, real-size agar-based mimicking material, which has similar acoustical properties as soft tissues. The agar content was 6% weight per volume (w/v), 4% w/v silica while the rest was degassed water. The transducer used has a diameter of 4 cm, operates with 2.6 MHz and focuses energy at 5 cm. RESULTS: The MRI compatibility of the robotic system was evaluated in a 9.4 T small animal scanner. The efficacy of the ultrasonic transducer was evaluated in the mimicking material using temperature measurements. CONCLUSIONS: The proposed robotic system can be utilized in a 9.4 T small animal MRI scanner. The proposed system is functional, compact and simple thus providing a useful tool for preclinical research in mice and rats.

MRI-guided frameless biopsy robotic system with the inclusion of unfocused ultrasound transducer for brain cancer ablation.

BACKGROUND: A magnetic resonance image (MRI) guided robotic system dedicated for brain biopsy was developed. The robotic system carries a biopsy needle and a small rectangular unfocused, single element, planar ultrasonic transducer which can be potentially utilized to ablate small and localized brain cancer. MATERIALS AND METHODS: The robotic device includes six computer-controlled axes. An agar-based phantom was developed which included an olive that mimics brain target. A rectangular ultrasonic transducer operated at 4 MHz was used. RESULTS: The functionality of the robotic system was assessed by means of ultrasound imaging, MRI imaging, and MR thermometry, demonstrating effective targeting. The heating capabilities of the ultrasonic transducer were also evaluated. CONCLUSIONS: A functional MRI-guided robotic system was produced which can perform frameless brain biopsy. In the future, if a tumour is proven malignant, the needle can be pulled-out and a small ultrasonic transducer can be inserted to ablate the tumour.