Focused Ultrasound Transducer Research Articles

A Novel Concept of Transperineal Focused Ultrasound Transducer for Prostate Cancer Local Deep Hyperthermia Treatments

Design, embodiment, and experimental study of a novel concept of extracorporeal phased array ultrasound transducer for prostate cancer regional deep hyperthermia treatments using a transperineal acoustic window is presented. An optimized design of hyperthermia applicator was derived from a modelling software where acoustic and thermal fields were computed based on anatomical data. Performance tests have been experimentally conducted on gel phantoms and tissues, under 3T MRI guidance using PRFS thermometry. Feedback controlled hyperthermia (ΔT = 5 °C during 20min) was performed on two ex vivo lamb carcasses with prostate mimicking pelvic tissue, to demonstrate capability of spatio-temporal temperature control and to assess potential risks and side effects. Our optimization approach yielded a therapeutic ultrasound transducer consisting of 192 elements of variable shape and surface, pseudo randomly distributed on 6 columns, using a frequency of 700 kHz. Radius of curvature was 140 mm and active water circulation was included for cooling. The measured focusing capabilities covered a volume of 24 × 50 × 60 mm3. Acoustic coupling of excellent quality was achieved. No interference was detected between sonication and MR acquisitions. On ex vivo experiments the target temperature elevation of 5 °C was reached after 5 min and maintained during another 15 min with the predictive temperature controller showing 0.2 °C accuracy. No significant temperature rise was observed on skin and bonny structures. Reported results represent a promising step toward the implementation of transperineal ultrasound hyperthermia in a pilot study of reirradiation in prostate cancer patients.

Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation.

Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull. Although the acoustic properties of human skull have been studied for tFUS applications, such as tumor ablation using a multielement phased array, there is no consensus about how to choose a single-element focused ultrasound (FUS) transducer with a suitable frequency for neuromodulation. There are interests in exploring the magnitude and dimension of tFUS beam through human parietal bone for modulating specific brain lobes. Herein, we aim to investigate the wave propagation of tFUS on human skulls to understand and address the concerns above. Both experimental measurements and numerical modeling were conducted to investigate the transmission efficiency and beam pattern of tFUS on five human skulls (C3 and C4 regions) using single-element FUS transducers with six different frequencies (150-1500kHz). The degassed skull was placed in a water tank, and a calibrated hydrophone was utilized to measure acoustic pressure past it. The cranial computed tomography scan data of each skull were obtained to derive a high-resolution acoustic model (grid point spacing: 0.25mm) in simulations. Meanwhile, we modified the power-law exponent of acoustic attenuation coefficient to validate numerical modeling and enabled it to be served as a prediction tool, based on the experimental measurements. The transmission efficiency and -6dB beamwidth were evaluated and compared for various frequencies. An exponential decrease in transmission efficiency and a logarithmic decrease of -6dB beamwidth with an increase in ultrasound frequency were observed. It is found that a >750kHz ultrasound leads to a relatively lower tFUS transmission efficiency (<5%), whereas a <350kHz ultrasound contributes to a relatively broader beamwidth (>5mm). Based on these observations, we further analyzed the dependence of tFUS wave propagation on FUS transducer aperture size. We successfully studied tFUS wave propagation through human skulls at different frequencies experimentally and numerically. The findings have important implications to predict tFUS wave propagation for ultrasound neuromodulation in clinical applications, and guide researchers to develop advanced ultrasound transducers as neural interfaces.

Numerical and experimental evaluation of ultrasound-assisted convection enhanced delivery to transfer drugs into brain tumors

Central Nervous System (CNS) malignant tumors are a leading cause of death worldwide with a high mortality rate. While numerous strategies have been proposed to treat CNS tumors, the treatment efficacy is still low mainly due to the existence of the Blood–Brain Barrier (BBB). BBB is a natural cellular layer between the circulatory system and brain extracellular fluid, limiting the transfer of drug particles and confining the routine treatment strategies in which drugs are released in the blood. Consequently, direct drug delivery methods have been devised to bypass the BBB. However, the efficiency of these methods is not enough to treat deep and large brain tumors. In the study at hand, the effect of focused ultrasound (FUS) waves on enhancing drug delivery to brain tumors, through ultrasound-assisted convection-enhanced delivery (UCED), has been investigated. First, brain mimicking gels were synthesized to mimic the CNS microenvironment, and the drug solution was injected into them. Second, FUS waves with the resonance frequency of 1.1 MHz were applied to the drug injected zone. Next, a finite element (FE) model was developed to evaluate the pre-existing equation in the literature for describing the drug delivery via acoustic streaming in brain tissue. Experimental results showed that the FUS transducer was able to enhance the drug volume distribution up to 500% relative to convection-enhanced delivery alone (CED). Numerical analysis showed that the FE model could replicate the experimental penetration depths with a mean difference value of less than 21%, and acoustic streaming plays a significant role in UCED. Therefore, the results of this study could open a new way to develop FE models of the brain to better evaluate the UCED and reduce the costs of conducting clinical and animal studies.

An Affordable and Easy-to-Use Focused Ultrasound Device for Noninvasive and High Precision Drug Delivery to the Mouse Brain.

Focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) is not only a promising technique for clinical applications but also a powerful tool for preclinical research. However, existing FUS devices for preclinical research are expensive, bulky, and lack the precision needed for small animal research, which limits the broad adoption of this promising technique by the research community. Our objective was to design and fabricate an affordable, easy-to-use, high-precision FUS device for small animal research. We designed and fabricated in-house mini-FUS transducers (∼$80 each in material cost) with three frequencies (1.5, 3.0, and 6.0 MHz) and integrated them with a stereotactic frame for precise mouse brain targeting using established stereotactic procedures. The BBB opening volume by FUS at different acoustic pressures (0.20-0.57 MPa) was quantified using T1-weighted contrast-enhanced magnetic resonance imaging of gadolinium leakage and fluorescence imaging of Evans blue extravasation. The targeting accuracy of the device as measured by the offset between the desired target location and the centroid of BBBO was 0.63 ± 0.19 mm. The spatial precision of the device in targeting individual brain structures was improved by the use of higher frequency FUS transducers. The BBB opening volume had high linear correlations with the cavitation index (defined by the ratio between acoustic pressure and frequency) and mechanical index (defined by the ratio between acoustic pressure and the square root of frequency). The correlation coefficient of the cavitation index was slightly higher than that of the mechanical index. This study demonstrated that spatially accurate and precise BBB opening was achievable using an affordable and easy-to-use FUS device. The BBB opening volume was tunable by modulating the cavitation index. This device is expected to decrease the barriers to the adoption of the FUS-BBBO technique by the broad research community.

MODL-24. Focused ultrasound-mediated blood-brain barrier opening and panobinostat in a thalamic syngeneic murine DMG model is feasible and safe.

Abstract Diffuse Midline Glioma with H3K27M mutation (DMG) is an aggressive unresectable central nervous system tumor of the brainstem, midline thalamus, or spine. Prognosis is poor and systemic agents have been ineffective partially due to limited permeability of the blood brain barrier (BBB). Non-invasive low intensity focused ultrasound (FUS) can be used for BBB opening (BBBO). Our preclinical studies showed safety and feasibility of targeting and BBBO in the brainstem; however, to our knowledge, FUS-guided BBBO for thalamic DMG has yet to be reported. RNA-seq was performed on mouse syngeneic DMG cells 4423 (PDGFB+, H3.3K27M, p53−/−) and results recapitulated molecular programs seen in human tumors. 4423 cells were injected into the thalamus of male B6 (Cg)-Tyrc-2J/J mice at 1.6mm lateral and 1.8mm posterior to the bregma at a depth of 3.2mm. MRI at 14-21 days post injection confirmed thalamic tumor growth. Histological analysis with Hematoxylin and Eosin stain was consistent with thalamic DMG. Tumor implantation rate was 85% and median survival was 38 days post injection. To test safety and feasibility of BBBO for thalamic tumors, a 1.5 MHz FUS transducer was used with concurrent microbubble injection. BBBO assessed by contrast-enhanced MRI. FUS achieved BBBO targeting the thalamic tumor without increased morbidity or mortality and BBB closure was observed on day 3 post-sonication. Next we tested the tolerance of drug delivery with panobinostat post-FUS at a dose of 20mg/kg weekly. The results are preliminary at this time; however, animals tolerated the combination therapy without morbidity or mortality. Preclinical models are crucial to improve the development of new therapeutic strategies. Establishing this syngeneic thalamic DMG murine model provides the opportunity to test FUS as a non-invasive drug delivery technology for thalamic DMG compared to brainstem DMG, and to re-visit therapeutic agents previously considered ineffective due to limited penetration of the BBB.

Ultrasonic Thermal Monitoring of the Brain Using Golay-Coded Excitations-Feasibility Study.

Thermal monitoring during focused ultrasound (FUS) transcranial procedures is mandatory and commonly performed by MRI. Transcranial ultrasonic thermal monitoring is an attractive alternative. Furthermore, using the therapeutic FUS transducer itself for this task is highly desirable. Nonetheless, such application is challenged by massive skull-induced signal attenuation and aberrations. This study examined the feasibility of implementing the Golay-coded excitations (CoE) for temperature monitoring in bovine brain samples in the range of 35 °C-43 °C (hyperthermia). Feasibility was assessed using computer simulations, water-based phantoms, and ex vivo bovine brain white-matter samples. The samples were gradually heated to about 45 °C and sonicated during cool down with a 1-MHz therapeutic FUS implementing Golay CoE. Initially, a calibration curve correlating the normalized time-of-flight (TOF) changes and the temperature was generated. Next, a bovine bone was positioned between the FUS and the brain samples, and the scanning process was repeated for different fresh samples. The calibration curve was then used as a mean for estimating the temperature, which was compared to thermocouple measurements. The simulations demonstrated a substantial improvement in signal-to-noise ratio (SNR) and suggested that the implementation of 4-bit sequences is advantageous. The experimental measurements with bone demonstrated good temperature estimation with an average absolute error for the water phantoms and brains of 1.46 °C ± 1.22 °C and 1.23 °C ± 0.99 °C, respectively. In conclusion, a novel noninvasive method utilizing the Golay CoE for ultrasonic thermal monitoring using a therapeutic FUS transducer is introduced. This method can lead to the development of an acoustic tool for brain thermal monitoring.

Focused Ultrasound Thermometry: A Two-Dimensional Resistance Temperature Detector Array in a Tissue-Mimicking Material

A two-dimensional resistance temperature detector (RTD) array sensor for the measurement of temperature distribution inside a tissue-mimicking material was proposed to validate focused ultrasound (FUS) devices. The fully two-dimensional $10\times10$ RTD array sensor with 1 mm inter-RTD distance was fabricated on the $2.5~ \boldsymbol {\mu } \text{m}$ thick film and placed inside the tissue-mimicking material. The measurement uncertainty for the RTD array was 0.18 K. The temperature distribution inside the phantom caused by a FUS transducer was measured and compared depending on the input power and focal plane. A tissue-mimicking phantom with an implanted RTD array can be applied to validate the performance and safety of both high- and low-intensity focused ultrasound (HIFU and LIFU) devices.

RADT-17. FOCUSED ULTRASOUND MEDIATED BLOOD–BRAIN BARRIER OPENING IS SAFE AND FEASIBLE CONCURRENT WITH AND ADJUVANT TO A CLINICAL RADIATION SCHEME FOR BRAINSTEM DMG

Abstract Diffuse midline gliomas (DMG) are pediatric tumors with dismal prognosis. When these tumors emerge in the brainstem, there exists no feasible method of surgical resection or systemic intervention, making ionizing radiation the sole therapeutic avenue to date. However, radiotherapy (RT) provides only marginal survival benefit as the topographically diffuse and highly infiltrative tumors spread in areas in which the blood-brain barrier (BBB) is relatively intact. Focused ultrasound (FUS) with intravenous microbubbles provides a compelling solution, transiently and non-invasively opening the BBB to allow drug delivery across the cerebrovasculature. Nonetheless, it remains unclear whether FUS can be safely administered at the brainstem in patients receiving RT. Therefore, the goal of this study was to assess the safety and feasibility of FUS administered concurrent with and adjuvant to a clinical hypofractionated radiation scheme for brainstem DMG. Non-tumor bearing B6 albino mice were randomly assorted into control, RT, FUS, and RT+FUS groups. Mice designated RT+FUS received 39Gy/13fx (hypofractionated RT scheme) to the brainstem with two sessions of FUS approximately 1 week apart. A single-element, spherical-segment FUS transducer driven by a function generator through a power amplifier was used with concomitant microbubble injection to sonicate the brainstem. Magnetic resonance imaging (MRI) was used to confirm BBB opening and cardiopulmonary measures were recorded throughout sonication. Vitals were assessed daily, and all treatment animals underwent Kondziela inverted screen testing and sequential weight lifting to assess brainstem-related strength and motor coordination deficits. In both FUS and RT+FUS mice, MRI confirmed brainstem BBB opening and subsequent closure within 96 hours. Mouse weights were stable, with slight drops (mean=5.5%) following FUS that resolved within three days. No attenuation in cardiorespiratory, strength, and motor coordination measurements was observed from FUS. FUS is a safe and feasible technique for brainstem BBB opening concurrent with and adjuvant to clinical hypofractionated RT.

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull.

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.

Focused Ultrasound-Mediated Blood-Brain Barrier Opening Enhances Panobinostat Efficacy in a Murine Diffuse Intrinsic Pontine Glioma Model

Purpose/Objective(s)Diffuse intrinsic pontine glioma (DIPG) is the most lethal brain tumor in children with no effective treatment options to date. The prognosis remains poor with a median overall survival of less than 1 year. Recent in vitro drug screening studies found the histone deacetylase (HDAC) inhibitor, panobinostat, to be highly effective against DIPG. However, as panobinostat has poor blood-brain barrier (BBB) penetration, phase 1 clinical trials using systemic administration of panobinostat have been unsuccessful. Therefore, improved efficacy will require enhancement of delivery into the brain. Focused ultrasound (FUS), a non-ionizing acoustic form of radiation, has been shown to safely and non-invasively open the BBB, which can increase drug delivery. In this study, we hypothesize that FUS-mediated BBB opening (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG.Materials/MethodsA syngeneic DIPG model was established by injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) intracranially. A single-element, spherical-segment FUS transducer (center frequency: 0.5 MHz) driven by a function generator through a power amplifier was used with concurrent microbubble injection to perform BBBO. We then utilized magnetic resonance imaging to evaluate BBBO and tumor progression.ResultsWe first demonstrated that FUS-mediated BBBO is safe and feasible in mice with DIPG tumors by MRI and passive cavitation detection. Our DIPG cell line was shown to be very sensitive to panobinostat in cell viability assay (IC50 = 0.012 μM). The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival.ConclusionThe current results demonstrate that FUS could increase the treatment efficacy of panobinostat in a DIPG animal model due to the improved targeted dose of systemic panobinostat in the DIPG tumors. We believe these data establish a strong preclinical rationale to assess the combination of FUS-mediated BBB opening with panobinostat in pediatric patients with DIPG. Diffuse intrinsic pontine glioma (DIPG) is the most lethal brain tumor in children with no effective treatment options to date. The prognosis remains poor with a median overall survival of less than 1 year. Recent in vitro drug screening studies found the histone deacetylase (HDAC) inhibitor, panobinostat, to be highly effective against DIPG. However, as panobinostat has poor blood-brain barrier (BBB) penetration, phase 1 clinical trials using systemic administration of panobinostat have been unsuccessful. Therefore, improved efficacy will require enhancement of delivery into the brain. Focused ultrasound (FUS), a non-ionizing acoustic form of radiation, has been shown to safely and non-invasively open the BBB, which can increase drug delivery. In this study, we hypothesize that FUS-mediated BBB opening (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. A syngeneic DIPG model was established by injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) intracranially. A single-element, spherical-segment FUS transducer (center frequency: 0.5 MHz) driven by a function generator through a power amplifier was used with concurrent microbubble injection to perform BBBO. We then utilized magnetic resonance imaging to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBBO is safe and feasible in mice with DIPG tumors by MRI and passive cavitation detection. Our DIPG cell line was shown to be very sensitive to panobinostat in cell viability assay (IC50 = 0.012 μM). The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrate that FUS could increase the treatment efficacy of panobinostat in a DIPG animal model due to the improved targeted dose of systemic panobinostat in the DIPG tumors. We believe these data establish a strong preclinical rationale to assess the combination of FUS-mediated BBB opening with panobinostat in pediatric patients with DIPG.

C-mode passive cavitation images for predicting large volume FUS-mediated drug delivery outcome

Passive cavitation detection has been commonly used to monitor focused ultrasound (FUS)-mediated blood-brain barrier disruption (FUS-BBBD). Previous research by our team has shown the feasibility to correlate passive cavitation imaging (PCI) with drug delivery outcome via FUS-BBBD at a single target. This study proposed to perform c-mode PCI for predicting the spatial distribution of aPD-L1 delivered by FUSBBBD. A single-element FUS transducer was used to perform sonication iteratively in a 3×3 grid at the whole brainstem of wild-type mice. PCI were acquired using an ultrasound imaging probe co-aligned with the FUS transducer. Reconstruction was performed to obtain c-mode PCI for the whole sonicated area in the plane normal to the PCI imaging plane (axial plane of FUS transducer). Fluorescence-labeled aPD-L1 was intravenously injected after FUS sonication and the delivery outcome was quantified using ex vivo fluorescence imaging. A high correlation (R2 = 0.79) was obtained between the fluorescence intensity and the cavitation dosage calculated from the c-mode PCI. No significant difference was found between 3dB area of the fluroescence images (6.93 ± 2.24mm2) and the 3 dB area of the c-mode PCI images (7.20 ± 0.74mm2). This study demonstrated that the c-mode PCI had the potential to predict drug delivery outcome by large volume FUS-BBBD.

Reliable and safe blood–brain barrier opening by closed-loop feedback control of focused ultrasound

Real-time cavitation monitoring and feedback controller is critical to safe and effective brain drug delivery by focused ultrasound (FUS)-mediated blood-brain barrier disruption (FUS-BBBD). However, existing controllers were either open-loop or using a generalized target cavitation level (TCL). This study aimed to develop a closed-loop feedback controller with TCL defined based on the baseline stable cavitation level (SCL) of each subject. A single-element FUS transducer with a coaxially aligned passive cavitation detector (PCD) was used. PCD signals were first acquired with “dummy” sonication to determine TCL defined to be 0.5, 1, 2, 3, or 4 dB above baseline SCL. A custom closed-loop feedback controller was developed to control SCL to be at each TCL. After sonication, wild-type mice were intravenously injected with Evans Blue (EB) to quantify FUS-BBBD using ex vivo fluorescence imaging. The fluorescence intensity of delivered EB increased in an average of 1.4-fold, 2.6-fold, and 3.9-fold at 1, 2, and 3dB respectively compared to the 0.5-dB group. No apparent hemorrhage was found in lower TCLs, and hemorrhage was consistently found in the 4-dB group. This study demonstrated that the individualized feedback controller achieved reliable and safe FUS-BBBD at selected TCL.

Simultaneous measurements of acoustic emission and sonochemical luminescence for monitoring ultrasonic cavitation.

In the present study, a novel hybrid method was considered to identify and measure inertial cavitation activity using acoustic and optical emissions from violent bubble collapses. A photomultiplier (PMT) tube and a calibrated cylindrical needle hydrophone were used to simultaneously detect sonochemical luminescence (SCL) signals and acoustic emissions, respectively, during sonication. A cylindrical focusing ultrasound transducer operating at 398.4 kHz was employed to produce a dense cavitation bubble cloud at the focus. The results clearly showed that a similar trend between the PMT output (i.e., the SCL results) and the broad band acoustic emissions started to appear at the frequencies considered above the fourth harmonic of the sonication frequency. The experimental observation suggests that the occurrence of inertial cavitation can be monitored using the high pass spectral acoustic power and the cut-off frequency can be effectively chosen with the aid of sonochemical luminescence measurement. The hybrid method is expected to be useful for cavitation dosimetry in various medical and industrial applications.

An Ellipsoidal Focused Ultrasound Transducer for Extend-Focus Photoacoustic Microscopy

Limited by spherical focused ultrasound transducer (SUT) with a high acoustic numerical aperture, photoacoustic microscopy (PAM) suffers a rapidly degrading sensitivity and lateral resolution as increased depth. In this study, an ellipsoidal focused ultrasound transducer (EUT) was developed to address the above restriction via providing high sensitivity and lateral resolution over a large depth of field (DOF). To fabricate the EUT, the piezoelectric element was laminated onto a curved steel surface for self-focusing (the ellipsoidal continuous-focus geometry was employed instead of the spherical single-focus one). Additionally, phantoms and in vivo animal experiments were performed by an extend-focus PAM equipped with EUT to characterize its performance. The EUT involved over 30 MHz center frequency and -6 dB bandwidth of 124% with a resolution-invariant focal depth of 1.39 mm, more than 3 times the DOF of the SUT. The in vivo imaging results demonstrated that the EUT was capable of extending the focal depth to get rid of the restriction of the visual field, while the DOF of the SUT was limited by the nature of spherical geometry. The EUT markedly enhances the image quality at different imaging depths, which has great potential for promoting the biomedical development of in vivo rapid-noninvasive PAM.

A Robotic Platform to Navigate MRI-guided Focused Ultrasound System

Focused ultrasound (FUS) technology attracts increasing interests accrediting to its non-invasive and painless treatment of tumors. Magnetic resonance imaging (MRI) guidance has been introduced to monitor this procedure, thus allowing the ultrasound foci to be precisely controlled. However, manual positioning of the FUS transducers is challenging, especially for the intra-operative (intra-op) adjustment in the MRI room. Currently, there are very few devices capable to provide robotic transducer positioning for the treatment of abdominopelvic organ diseases under MRI. The high intensity focused ultrasound (HIFU) spot would have to be “steered” to ablate large (>Ø 3.5 cm) or multiple tumors (e.g., in liver). To this end, we proposed a hydraulic-driven tele-operated robot platform that enables 5-DoF manipulation of the FUS transducer. Even operated close to the MRI iso-center, the robot can guarantee zero electromagnetic (EM) artifact to the MR image. Our proof-of-concept robot prototype can offer a large workspace (100 mm × 100 mm × 35 mm) for FUS foci steering. Accurate manipulation (0.2 mm in translation, 0.4° in rotation) of the FUS transducer holder is achieved using rolling diaphragm-sealed hydraulic actuators. The robot control responsiveness (from 0.1 to 4 Hz) is also evaluated to show the potential to compensate for the spot tracking error induced by respiratory motion. We also demonstrate the use of wireless radiofrequency (RF) markers to continuously register the robot task space in the MRI coordinates.

DDEL-13. FOCUSED ULTRASOUND MEDIATED BLOOD BRAIN BARRIER DISRUPTION IN A MURINE MODEL OF PONTINE GLIOMA: A SAFETY AND FEASIBILITY STUDY

BACKGROUNDDrug delivery remains a major obstacle in DIPG, as the blood brain barrier (BBB) limits the penetration of systemic therapies to the brainstem. Focused ultrasound (FUS) is an exciting new technology that, when combined with microbubbles, can open the BBB permitting the entry of drugs across the cerebrovasculature. Given that the utility of FUS in brainstem tumors remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model.METHODSA syngeneic orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells (10,000/1ul) into the pons of B6 albino mice. A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier (acoustic pressure=0.7MPa) was used with concurrent intravenous microbubble injection (FUS+MB) to sonicate the tumor on post-injection day 14. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS) testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored for survival.RESULTSIn mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5) was similar. Lastly, there was no difference in survival between the groups (control, n=6, median=26 days; FUS, n=6, median=25 days, p>0.05).CONCLUSIONFUS+MB is a safe and feasible technique to open the BBB in a preclinical pontine glioma model.

Considerations for ultrasound exposure during transcranial MR acoustic radiation force imaging

The aim of this study was to improve the sensitivity of magnetic resonance-acoustic radiation force imaging (MR-ARFI) to minimize pressures required to localize focused ultrasound (FUS) beams, and to establish safe FUS localization parameters for ongoing ultrasound neuromodulation experiments in living non-human primates. We developed an optical tracking method to ensure that the MR-ARFI motion-encoding gradients (MEGs) were aligned with a single-element FUS transducer and that the imaged slice was prescribed at the optically tracked location of the acoustic focus. This method was validated in phantoms, which showed that MR-ARFI-derived displacement sensitivity is maximized when the MR-ARFI MEGs were maximally aligned with the FUS propagation direction. The method was then applied in vivo to acquire displacement images in two healthy macaque monkeys (M fascicularis) which showed the FUS beam within the brain. Temperature images were acquired using MR thermometry to provide an estimate of in vivo brain temperature changes during MR-ARFI, and pressure and thermal simulations of the acoustic pulses were performed using the k-Wave package which showed no significant heating at the focus of the FUS beam. The methods presented here will benefit the multitude of transcranial FUS applications as well as future human applications.

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is currently being investigated in clinical trials. Here, we describe a portable clinical system with a therapeutic transducer suitable for humans, which eliminates the need for in-line magnetic resonance imaging (MRI) guidance. A neuronavigation-guided 0.25-MHz single-element FUS transducer was developed for non-invasive clinical BBB opening. Numerical simulations and experiments were performed to determine the characteristics of the FUS beam within a human skull. We also validated the feasibility of BBB opening obtained with this system in two non-human primates using U.S. Food and Drug Administration (FDA)-approved treatment parameters. Ultrasound propagation through a human skull fragment caused 44.4 ± 1% pressure attenuation at a normal incidence angle, while the focal size decreased by 3.3 ± 1.4% and 3.9 ± 1.8% along the lateral and axial dimension, respectively. Measured lateral and axial shifts were 0.5 ± 0.4 mm and 2.1 ± 1.1 mm, while simulated shifts were 0.1 ± 0.2 mm and 6.1 ± 2.4 mm, respectively. A 1.5-MHz passive cavitation detector transcranially detected cavitation signals of Definity microbubbles flowing through a vessel-mimicking phantom. T1-weighted MRI confirmed a 153 ± 5.5 mm3 BBB opening in two non-human primates at a mechanical index of 0.4, using Definity microbubbles at the FDA-approved dose for imaging applications, without edema or hemorrhage. In conclusion, we developed a portable system for non-invasive BBB opening in humans, which can be achieved at clinically relevant ultrasound exposures without the need for in-line MRI guidance. The proposed FUS system may accelerate the adoption of non-invasive FUS-mediated therapies due to its fast application, low cost and portability.

Correlation Between Brain Tissue Damage and Inertial Cavitation Dose Quantified Using Passive Cavitation Imaging

Focused ultrasound (FUS)-induced cavitation-mediated brain therapies have become emerging therapeutic modalities for neurologic diseases. Cavitation monitoring is essential to ensure the safety of all cavitation-mediated therapeutic techniques as inertial cavitation can be associated with tissue damage. The objective of this study was to reveal the correlation between the inertial cavitation dose, quantified by passive cavitation imaging (PCI), and brain tissue histologic-level damage induced by FUS in combination with microbubbles. An ultrasound image-guided FUS system consisting of a single-element FUS transducer (1.5 MHz) and a co-axially aligned 128-element linear ultrasound imaging array was used to perform FUS treatment of mice. Mice were sonicated by FUS with different peak negative pressures (0.5 MPa, 1.1 MPa, 4.0 MPa and 6.5 MPa) in the presence of systemically injected microbubbles. The acoustic emissions from the FUS-activated microbubbles were passively detected by the imaging array. The pre-beamformed channel data were acquired and processed offline using the frequency-domain delay, sum and integration algorithm to generate inertial cavitation maps. All the mice were sacrificed after the FUS treatment, and their brains were harvested and processed for hematoxylin and eosin staining. The obtained inertial cavitation maps revealed the dynamic changes of microbubble behaviors during FUS treatment at different pressure levels. It was found that the inertial cavitation dose quantified based on PCI had a linear correlation with the scale of histologic-level tissue damage. Findings from this study suggested that PCI can be used to predict histologic-level tissue damage associated with the FUS-induced cavitation.

Mapping Microbubble and Ultrasound Spatio-temporal Interaction by M-mode Imaging: The Study of Feasibility

Ultrasound (US) and microbubble (MB) interaction is an important factor in the research of bioacoustics, as well as targeted drug and gene delivery. In this study, we demonstrate the feasibility of pulse−echo M-mode imaging system to be used for the visualization and quantification of US–MB interaction in both spatial and temporal dimensions. The system incorporates an exposure chamber with the cell–MB suspension, a 2.7 MHz focused US transducer, a US pulser–receiver and the customized LabView software. The results of cell and MB interaction obtained after M-mode image analysis have showed the US–MB interaction to be non-uniform in space and non-stationary in time. In order to quantify the spatio-temporal US–MB interaction, we have introduced the time function of spatial homogeneity dynamics. We have observed that the effective duration of interaction can be characterized at the predefined threshold of spatial homogeneity. For example, at the US excitation of 360 kPa peak negative pressure (15 bursts transmitted at 80 Hz pulse repetition frequency), the US–MB interaction persists for more than 5 seconds in the range at 4 mm depth of the exposure chamber with more than 50% of homogeneity. The system proposed in this assay is feasible for the characterization of US–MB interaction and can be exploited to optimize the MB concentration and/or the US excitation parameters.