Focused Ultrasound Transducer Research Articles

Prediction of high-intensity focused ultrasound (HIFU)-induced lesion size using the echo amplitude from the focus in tissue.

In the realm of high-intensity focused ultrasound (HIFU) therapy, the precise prediction of lesion size during treatment planning remains a challenge, primarily due to the difficulty in quantitatively assessing energy deposition at the target site and the acoustic properties of the tissue through which the ultrasound wave propagates. This study investigates the hypothesis that the echo amplitude originating from the focus is indicative of acoustic attenuation and is directly related to the resultant lesion size. Echoes from multi-layered tissues, specifically porcine tenderloin and bovine livers, with varying fat thickness from 0mm to 35mm were collected using a focused ultrasound (FUS) transducer operated at a low power output and short duration. Subsequent to HIFU treatment under clinical conditions, the resulting lesion areas in the ex vivo tissues were meticulously quantified. A novel treatment strategy that prioritizes treatment spots based on descending echo amplitudes was proposed and compared with the conventional raster scan approach. Our findings reveal a consistent trend of decreasing echo amplitudes and HIFU-induced lesion areas with the increasing fat thickness. For porcine tenderloin, the values decreased from 2541.7 ± 641.9 mV and 94.4 ± 17.9 mm2 to 385(342.5) mV and 24.9 ± 18.7 mm2, and for bovine liver, from 1406(1202.5) mV and 94.4 ± 17.9 mm2 to 502.1 ± 225.7 mV and 9.4 ± 6.3 mm2, respectively, as the fat thickness increases from 0mm to 35mm. Significant correlations were identified between preoperative echo amplitudes and the HIFU-induced lesion areas (R = 0.833 and 0.784 for the porcine tenderloin and bovine liver, respectively). These correlations underscore the potential for an accurate and dependable prediction of treatment outcomes. Employing the proposed treatment strategy, the ex vivo experiment yielded larger lesion areas in bovine liver at a penetration depth of 8cm compared to the conventional approach (58.84 ± 17.16 mm2 vs. 44.28 ± 15.37 mm2, p < 0.05). The preoperative echo amplitude from the FUS transducer is shown to be a reflective measure of acoustic attenuation within the wave propagation window and is closely correlated with the induced lesion areas. The proposed treatment strategy demonstrated enhanced efficiency in ex vivo settings, affirming the feasibility and accuracy of predicting HIFU-induced lesion size based on echo amplitude.

Radiosensitization of Allogenic Subcutaneous C6 Glioma Model with Focused Ultrasound-Induced Mild Hyperthermia.

The radiosensitization potential of focused ultrasound (FUS)-induced mild hyperthermia was assessed in an allogenic subcutaneous C6 glioma tumor model in rats. Mild hyperthermia at 42 °C was induced in tumors using a single-element 350 kHz FUS transducer. Radiation was delivered with a small animal radiation research platform using a single-beam irradiation technique. The combined treatment involved 20 min of FUS hyperthermia immediately before radiation. Tumor growth changes were observed one week post-treatment. A radiation dose of 2 Gy alone showed limited tumor control (30% reduction). However, when combined with FUS hyperthermia, there was a significant reduction in tumor growth compared to other treatments (tumor volumes: control-1174 ± 554 mm3, FUS-HT-1483 ± 702 mm3, 2 Gy-609 ± 300 mm3, FUS-HT + 2 Gy-259 ± 186 mm3; ANOVA p < 0.00001). Immunohistological analysis suggested increased DNA damage as a short-term mechanism for tumor control in the combined treatment. In conclusion, FUS-induced mild hyperthermia can enhance the effectiveness of radiation in a glioma tumor model, potentially improving the outcome of standard radiation treatments for better tumor control.

In vivo evaluation of focused ultrasound ablation surgery (FUAS)-induced coagulation using echo amplitudes of the therapeutic focused ultrasound transducer

Objective Monitoring sensitivity of sonography in focused ultrasound ablation surgery (FUAS) is limited (no hyperechoes in ∼50% of successful coagulation in uterine fibroids). A more accurate and sensitive approach is required. Method The echo amplitudes of the focused ultrasound (FUS) transducer in a testing mode (short pulse duration and low power) were found to correlate with the ex vivo coagulation. To further evaluate its coagulation prediction capabilities, in vivo experiments were carried out. The liver, kidney, and leg muscles of three adult goats were treated using clinical FUAS settings, and the echo amplitude of the FUS transducer and grayscale in sonography before and after FUAS were collected. On day 7, animals were sacrificed humanely, and the treated tissues were dissected to expose the lesion. Echo amplitude changes and lesion areas were analyzed statistically, as were the coagulation prediction metrics. Results The echo amplitude changes of the FUS transducer correlate well with the lesion areas in the liver (R = 0.682). Its prediction in accuracy (94.4% vs. 50%), sensitivity (92.9% vs. 35.7%), and negative prediction (80% vs. 30.8%) is better than sonography, but similar in specificity (80% vs. 100%) and positive prediction (100% vs. 100%). In addition, the correlation between tissue depth and the lesion area is not good (|R| < 0.2). Prediction performances in kidney and leg muscles are similar. Conclusion The FUS echo amplitudes are sensitive to the tissue properties and their changes after FUAS. They are sensitive and reliable in evaluating and predicting FUAS outcomes.

Magnetic Resonance Imaging Monitoring of Thermal Lesions Produced by Focused Ultrasound

Abstract Background: The main goal of the study was to find the magnetic resonance imaging (MRI) parameters that optimize contrast between tissue and thermal lesions produced by focused ultrasound (FUS) using T1-weighted (T1-W) and T2-weighted (T2-W) fast spin echo (FSE) sequences. Methods: FUS sonications were performed in ex vivo porcine tissue using a single-element FUS transducer of 2.6 MHz in 1.5 and 3 T MRI scanners. The difference in relaxation times as well as the impact of critical MRI parameters on the resultant contrast-to-noise ratio (CNR) between coagulated and normal tissues were assessed. Discrete and overlapping lesions were inflicted in tissue with simultaneous acquisition of T2-W FSE images. Results: FUS lesions are characterized by lower relaxation times than intact porcine tissue. CNR values above 80 were sufficient for proper lesion visualization. For T1-W imaging, repetition time values close to 1500 ms were considered optimum for obtaining sufficiently high CNR at the minimum time cost. Echo time values close to 50 ms offered the maximum lesion contrast in T2-W FSE imaging. Monitoring of acute FUS lesions during grid sonications was performed successfully. Lesions appeared as hypointense spots with excellent contrast from surrounding tissue. Conclusion: MRI monitoring of signal intensity changes during FUS sonication in grid patterns using optimized sequence parameters can provide useful information about lesion progression and the success of ablation. This preliminary study demonstrated the feasibility of the proposed monitoring method in ex vivo porcine tissue and should be supported by in vivo studies to assess its clinical potential.

Improving Sonication Efficiency in Transcranial MR-Guided Focused Ultrasound Treatment: A Patient-Data Simulation Study.

The potential improvement in sonication efficiency achieved by tilting the focused ultrasound (FUS) transducer of the transcranial MR-guided FUS system is presented. A total of 56 cases of patient treatment data were used. The relative position of the clinical FUS transducer to the patient's head was reconstructed, and region-specific skull density and porosity were calculated based on the patient's CT volume image. The total transmission coefficient of acoustic waves emitted from each channel was calculated. Then, the total energy penetrating the human skull-which represents the sonication efficiency-was estimated. As a result, improved sonication efficiency was by titling the FUS transducer to a more appropriate angle achieved in all 56 treatment cases. This simulation result suggests the potential improvement in transcranial-focused ultrasound treatment by simply adjusting the transducer angle.

Acoustic Trapping and Manipulation of Hollow Microparticles under Fluid Flow Using a Single-Lens Focused Ultrasound Transducer.

Microparticle manipulation and trapping play pivotal roles in biotechnology. To achieve effective manipulation within fluidic flow conditions and confined spaces, it is necessary to consider the physical properties of microparticles and the types of trapping forces applied. While acoustic waves have shown potential for manipulating microparticles, the existing setups involve complex actuation mechanisms and unstable microbubbles. Consequently, the need persists for an easily deployable acoustic actuation setup with stable microparticles. Here, we propose the use of hollow borosilicate microparticles possessing a rigid thin shell, which can be efficiently trapped and manipulated using a single-lens focused ultrasound (FUS) transducer under physiologically relevant flow conditions. These hollow microparticles offer stability and advantageous acoustic properties. They can be scaled up and mass-produced, making them suitable for systemic delivery. Our research demonstrates the successful trapping dynamics of FUS within circular tubings of varying diameters, validating the effectiveness of the method under realistic flow rates and ultrasound amplitudes. We also showcase the ability to remove hollow microparticles by steering the FUS transducer against the flow. Furthermore, we present potential biomedical applications, such as active cell tagging and navigation in bifurcated channels as well as ultrasound imaging in mouse cadaver liver tissue.

FUS-mediated blood–brain barrier disruption for delivering anti-Aβ antibodies in 5XFAD Alzheimer’s disease mice

PurposeAmyloid-β (Aβ) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aβ antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood–brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device.MethodsThe initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD. Pulsed FUS was applied using a single-element FUS transducer of 1 MHz (80 mm radius of curvature and 50 mm diameter). The success and extent of BBBD were assessed by Evans Blue extravasation and brain damage by hematoxylin and eosin staining. 5XFAD mice were divided into different subgroups; control (n = 1), FUS + MBs alone (n = 5), antibody alone (n = 5), and FUS + antibody combined (n = 10). The changes in antibody deposition among groups were determined by immunohistochemistry.ResultsIt was confirmed that the antibody could not normally enter the brain parenchyma. A single treatment with MBs-enhanced pulsed FUS using the optimized protocol (1 MHz, 0.5 MPa in-situ pressure, 10 ms bursts, 1% duty factor, 100 s duration) transiently disrupted the BBB allowing for non-invasive antibody delivery to amyloid plaques within the sonicated brain regions. This was consistently reproduced in ten mice.ConclusionThese preliminary findings should be confirmed by longer-term studies examining the antibody effects on plaque clearance and cognitive benefit to hold promise for developing disease-modifying anti-Aβ therapeutics for clinical use.

Intravascular Sono-Ablation for In-Stent Restenosis Relief: Transducer Development and the In-Vitro Demonstration.

This study aimed to propose a new clinical modality for the relief of in-stent restenosis (ISR) using focused ultrasound (FUS) ablation. In the first research stage, a miniaturized FUS device was developed for the sonification of the remaining plaque after stenting, known as one of the causes of ISR. This study presents a miniaturized (<2.8 mm) intravascular FUS transducer for ISR treatment. The performance of the transducer was predicted through a structural-acoustic simulation, followed by fabrication of the prototype device. Using the prototype FUS transducer, we demonstrated tissue ablation with bio-tissues over metallic stents, mimicking in-stent tissue ablation. Next, we conducted a safety test by detecting the existence of thermal damage to the arterial tissue upon sonication with a controlled dose. The prototype device successfully delivered sufficient acoustic intensity (> 30 W/cm2) to a bio tissue (chicken breast) through a metallic stent. The ablation volume was approximately 3.9×7.8×2.6 mm3. Furthermore, 1.5 min sonication was sufficient to obtain an ablating depth of approximately 1.0 mm, not thermally damaging the underlying artery vessel. Conclusion: We demonstrated in-stent tissue sonoablation, suggesting it could be as a future ISR treatment modality. Significance: Comprehensive test results provide a key understanding of FUS applications using metallic stents. Furthermore, the developed device can be used for sonoablation of the remaining plaque, providing a novel approach to the treatment of ISR.

Improving the quality of ultrasound images acquired using a therapeutic transducer

To enhance the effectiveness and safety of focused ultrasound (FUS) therapy, ultrasound image-based guidance and treatment monitoring are crucial. However, the use of FUS transducers for both therapy and imaging is impractical due to their low spatial resolution, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). To address this issue, we propose a new method that significantly improve the quality of images obtained by a FUS transducer. The proposed method employs coded excitation to enhance SNR and Wiener deconvolution to solve the problem of low axial resolution resulting from the narrow spectral bandwidth of FUS transducers. Specifically, the method eliminates the impulse response of a FUS transducer from received ultrasound signals using Wiener deconvolution, and pulse compression is performed using a mismatched filter. Simulation and commercial phantom experiments confirmed that the proposed method significantly improves the quality of images acquired by the FUS transducer. The −6 dB axial resolution was improved 1.27 mm to 0.37 mm that was similar to the resolution achieved by the imaging transducer, i.e., 0.33 mm. SNR and CNR also increased from 16.5 dB and 0.69 to 29.1 dB and 3.03, respectively, that were also similar to those by the imaging transducer (27.8 dB and 3.16). Based on the results, we believe that the proposed method has great potential to enhance the clinical utility of FUS transducers in ultrasound image-guided therapy.

Characterization of the Targeting Accuracy of a Neuronavigation-Guided Transcranial FUS System In Vitro, In Vivo, and In Silico.

Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized in vitro, in vivo, and in silico. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized in vitro in a water tank using a hydrophone. The performance of the device in BBB disruption was verified in vivo using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated in silico using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 ± 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 ± 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 ± 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in GBM patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic.

Focused ultrasound for the remote modulation of nitric oxide release from injectable PEG-fibrinogen hydrogels for tendon repair

Introduction: Tendon disorders such as tendinosis, the degradation of collagen in tendon, or tendonitis, inflammation of tendon tissue, contribute to 30% of musculoskeletal complaints. To address the limitations of currently available treatments for tendon repair, an injectable polyethylene glycol (PEG)-fibrinogen hydrogel encompassing nitric oxide (NO) releasing µ-particles was generated. The release of nitric oxide, a therapeutic molecule that modulates many wound healing processes, from the hydrogel can be modified with thermal and mechanical stimulus. To achieve remote control over NO release from hydrogels after deployment, focused ultrasound (FUS) was explored as it provides highly controlled thermal and mechanical stimulus non-invasively.Methods: In this work, the ability of FUS to remotely elicit on-demand NO generation from acoustically active composite hydrogels via thermal and/or mechanical stimulus was explored. Specifically, the temperature and time-dependent release of NO was simulated and characterized when applying FUS to composite hydrogels.Results: Results from acoustic simulations as well as thermocouple heating studies indicated that high spatial and temporal control over hydrogel warming could be achieved non-invasively with a 3.5 MHz FUS transducer. FUS was also able to remotely control NO release from hydrogels with various thermal magnitudes and durations. Additionally, no apparent changes in the mechanical properties of hydrogels were observed with FUS treatment.Discussion: Utilizing FUS thermal and mechanical stimulus provides a potential method of remotely controlling NO release from hydrogels at a wound site to aid in tendon repair.

An Efficient and Multi-Focal Focused Ultrasound Technique for Harmonic Motion Imaging.

Harmonic motion imaging (HMI) is an ultrasound-based elasticity imaging technique that utilizes oscillatory acoustic radiation force to estimate the mechanical properties of tissues, as well as monitor high-intensity focused ultrasound (HIFU) treatment. Conventionally, in HMI, a focused ultrasound (FUS) transducer generates oscillatory tissue displacements, and an imaging transducer acquires channel data for displacement estimation, with each transducer being driven with a separate system. The fixed position of the FUS focal spot requires mechanical translation of the transducers, which can be a time-consuming and challenging procedure. In this study, we developed and characterized a new HMI system with a multi-element FUS transducer with the capability of electronic focal steering of ±5 mm and ±2 mm from the geometric focus in the axial and lateral directions, respectively. A pulse sequence was developed to drive both the FUS and imaging transducers using a single ultrasound data acquisition (DAQ) system. The setup was validated on a tissue-mimicking phantom with embedded inclusions. Integrating beam steering with the mechanical translation of the transducers resulted in a consistent high contrast-to-noise ratio (CNR) for the inclusions with Young's moduli of 22 and 44 kPa within a 5-kPa background while the data acquisition speed is increased by 4.5-5.2-fold compared to the case when only mechanical movements were applied. The feasibility of simultaneous generation of multiple foci and tracking the induced displacements is demonstrated in phantoms for applications where imaging or treatment of a larger region is needed. Moreover, preliminary feasibility is shown in a human subject with a breast tumor, where the mean HMI displacement within the tumor was about 4 times lower than that within perilesional tissues. The proposed HMI system facilitates data acquisition in terms of flexibility and speed and can be potentially used in the clinic for breast cancer imaging and treatment.

Transcranial cavitation mapping of blood–brain barrier opening regions in Alzheimer’s disease patients using a neuronavigation-guided focused ultrasound system

We present real-time cavitation monitoring and mapping in a clinical trial for blood-brain barrier (BBB) opening in Alzheimer’s disease (AD) patients using a neuronavigation-guided focused ultrasound (FUS) system. Six AD patients (N = 6, age = 68.5 ± 9.5) were sonicated at the right prefrontal lobe with a single-element FUS transducer (PNP = 0.2 MPa, fc = 0.25 MHz, pulse length = 10 ms, PRF = 2 Hz, duration = 2 min) with the microbubble administration (Definity). We performed passive cavitation detection (PCD) using a single-element hydrophone (N = 4), and passive acoustic mapping (PAM) with a 64-element phased array transducer (N = 2). Five patients showed successful BBB opening (volume = 654 ± 394 mm3) on day0, and closure on day3, confirmed by contrast-enhanced T1-weighted MRI, while one patient served as a negative BBB opening case due to the insufficient microbubble administration. Ultra-harmonic cavitation dose (CD) correlated with the opening volume (R2 = 0.66, N = 4), but harmonic and broadband CDs showed a relatively poor correlation (R2 = 0.06 and 0.33). Cavitation maps (N = 2) showed a spatial distribution of acoustic energy that roughly coincided with the respective BBB opening location. We thus demonstrated the successful BBB opening and cavitation monitoring with the neuronavigation-guided system that allowed for a cost-effective procedure compared to the MR-guided approaches. The PCD and PAM showed promising results for potentially predicting the BBB opening volume and location found in MRI.

Ultrasound Histotripsy on a Viable Perfused Whole Porcine Liver: Histological Aspects, Including 3D Reconstruction of the Histotripsy Site.

Non-invasive therapeutic-focused ultrasound (US) can be used for the mechanical dissociation of tissue and is described as histotripsy. We have performed US histotripsy in viable perfused ex vivo porcine livers as a step in the development of a novel approach to hepatocyte cell transplantation. The histotripsy nidus was created with a 2 MHz single-element focused US transducer, producing 50 pulses of 10 ms duration, with peak positive and negative pressure values of P+ = 77.7 MPa and P- = -13.7 MPaat focus, respectively, and a duty cycle of 1%. Here, we present the histological analysis, including 3D reconstruction of histotripsy sites. Five whole porcine livers were retrieved fresh from the abattoir using human transplant retrieval and cold static preservation techniques and were then perfused using an organ preservation circuit. Whilst under perfusion, histotripsy was performed to randomly selected sites on the live. Fifteen lesional sites were formalin-fixed and paraffin-embedded. Sections were stained with Haematoxylin and Eosin and picro-Sirius red, and they were also stained for reticulin. Additionally, two lesion sites were used for 3D reconstruction. The core of the typical lesion consisted of eosinophilic material associated with reticulin loss, collagen damage including loss of birefringence to fibrous septa, and perilesional portal tracts, including large portal vein branches, but intact peri-lesional hepatic plates. The 3D reconstruction of two histotripsy sites was successful and confirmed the feasibility of this approach to investigate the effects of histotripsy on tissue in detail.

Numerical Study of a Miniaturized, 1–3 Piezoelectric Composite Focused Ultrasound Transducer

This study aimed to develop an optimal methodology for the design of a miniaturized, 1–3 piezoelectric composite focused ultrasound transducer. Miniaturized focused ultrasound (FUS) devices, generally guided through catheters, have received considerable attention in the biomedical and ultrasound fields as they can overcome the technical restrictions of typical FUS transducers. However, miniaturized transducers cannot readily generate a high acoustic intensity because of their small aperture sizes and the vibration mode coupling. As such, 1–3 composite transducers, having a high electromechanical coupling and efficient vibration directivity, break through the current technical restrictions. However, the systematic methodology for designing miniaturized FUS transducers has not been thoroughly discussed so far. Therefore, in this study, we designed 1–3 piezoelectric composite transducers using analytical and numerical methods. Specifically, extensive parametric studies were performed through finite element analysis under the coupled field with piezoelectricity, structural vibration, and acoustic pressure. The simulation results confirmed that the optimal design of the 1–3 composite type transducer produces much higher (&gt;160%) acoustic pressure output at the focal point than the single-phase device. Furthermore, the array type of the interstitial transducer was predicted to produce an unprecedented acoustic intensity of approximately 188 W/cm2 under a short duty cycle (1%). This study will provide valuable technical methodology for the development of interstitial, 1–3 composite FUS transducers and the selection of optimal design parameters.

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.