Focused Ultrasound Transducer Research Articles

Monitoring focused ultrasound ablation surgery (FUAS) using echo amplitudes of the therapeutic focused transducer

ObjectiveB-mode sonography is commonly used to monitor focused ultrasound ablation surgery (FUAS), but has limitations in sensitivity. More accurate and reliable prediction of coagulation is required. MethodsThe focused ultrasound (FUS) transducer was adapted for echo reception. Numerical simulations compared the normalized echo amplitudes from the FUS transducer and imaging probe at varying tissue depths and frequencies with a 3 mm necrosis at focus. An ex vivo experiment then evaluated echo changes from the FUS transducer and ultrasound imaging probe under different settings. Finally, coagulation prediction using FUS echo data was compared to sonography in a clinical ex vivo context. ResultsThe echo amplitudes from the FUS transducer exhibit a less pronounced decline with increasing tissue penetration depth compared to the ultrasound imaging probe. In ex vivo bovine liver experiments at depths of 2 cm and 4 cm, the FUS transducer detected normalized echo amplitudes that were significantly larger (i.e., 2∼3 folds) than those received by the ultrasound imaging probe. Moreover, multi-layered ex vivo tissue experiments that replicate clinical conditions revealed that coagulation prediction utilizing the FUS transducer's echo amplitudes achieved superior accuracy (91.2% vs. 60.3 %), sensitivity (92.1% vs. 54.5 %), and negative prediction (78.9% vs. 30.6 %), but similar specificity (88.2% vs. 84.6 %) and positive prediction (95.9% vs. 93.8 %) in comparison to sonography. ConclusionThe echo amplitude of the FUS transducer serves as a sensitive and dependable metric for monitoring the FUAS outcomes. Its utilization may augment the procedure's safety and efficacy.

Feasibility of Hologram-Assisted Bilateral Blood-Brain Barrier Opening in Non-Human Primates.

Focused ultrasound (FUS) and microbubbles facilitate blood-brain barrier opening (BBBO) noninvasively, transiently, and safely for targeted drug delivery. Unlike state-of-the-art approaches, in this study, we demonstrate for the first time the simultaneous, bilateral BBBO in non-human primates (NHPs) using acoustic holograms at caudate and putamen structures. The simple and low-cost system with a single-element FUS transducer and 3-D printed acoustic hologram was guided by neuronavigation and a robotic arm. The advantages of holograms are transcranial aberration correction, simultaneous multifocus and high localization, and target-independent transducer positioning, defining a promising alternative for time- and cost-efficient FUS procedures. Holograms were designed with the k-space method by time-reversal techniques. T1-weighted MRI was used for treatment planning, while the computed tomography (CT) scan provided the head tissues acoustic properties. For the BBBO procedure, a robotic arm allowed transducer positioning errors below 0.1 mm and 0.1°. Following positioning, 0.5-0.6-MPa, 513-kHz microbubble-enhanced FUS was applied for 4 min. For BBBO assessment, Post-FUS T1-weighted MRI was acquired, and contrast enhancement indicated bilateral gadolinium extravasation at both caudate or putamen structures. The two BBBO locations were separated by 13.13 mm with a volume of 91.81 mm3 in the caudate, compared with 9.40 mm with a volume of 124.52 mm3 in simulation, while they were separated by 21.74 mm with a volume of 145.38 mm3 in the putamen and compared with 22.32 mm with a volume of 156.42 mm3 in simulation. No neurological damage was observed through T2-weighted and susceptibility-weighted imaging. This study demonstrates the feasibility and safety of hologram-assisted neuronavigation-guided-FUS for BBBO in NHP, providing thus an avenue for clinical translation.

Pulsed focused ultrasound ablation assisted by a surface modified catheter for thrombolysis: a feasibility study

Interventional procedures for the recanalization of blood vessels to treat deep vein thrombosis carry a high risk of vessel wall injuries or hemorrhaging. Focused ultrasound (FUS) has been used to non-invasively break down blood clots that occlude the vessels in both in vitro and in vivo studies. Previous studies have either used thrombolytic drugs or ultrasound contrast agents (e.g., microbubbles) in combination with FUS. Several studies have applied very high peak-negative-pressures (PNP) during FUS treatment to achieve successful thrombolysis without the use of contrast agents. In the current study, we demonstrated that cavitation activity could be significantly enhanced by placing a nitinol wire, whose surface was roughed by laser etching, in the focal region of a FUS field. We demonstrated in vitro in a mock thrombosis that the thrombolysis efficacy of a 500 kHz FUS transducer was significantly enhanced using a surface-etched nitinol wire as compared to an unetched nitinol wire, whereas FUS-alone at the same pressure level did not result in any thrombolysis. These results suggest that a surface modified nitinol catheter exposed to FUS can result in intense cavitation activities leading to enhanced thrombolysis without the use of additional pharmacological or contrast agents.

Monitoring Blood-Brain Barrier Opening in Rats with a Preclinical Focused Ultrasound System.

The brain has a highly selective semipermeable blood barrier, termed the blood-brain barrier (BBB), which prevents the delivery of therapeutic macromolecular agents to the brain. The integration of MR-guided low-intensity pulsed focused ultrasound (FUS) with microbubble pre-injection is a promising technique for non-invasive and non-toxic BBB modulation. MRI can offer superior soft-tissue contrast and various quantitative assessments, such as vascular permeability, perfusion, and the spatial-temporal distribution of MRI contrast agents. Notably, contrast-enhanced MRI techniques with gadolinium-based MR contrast agents have been shown to be the gold standard for detecting BBB openings. This study outlines a comprehensive methodology involving MRI protocols and animal procedures for monitoring BBB opening in a rat model. The rat model provides the added benefit of jugular vein catheter utilization, which facilitates rapid medication administration. A stereotactic-guided preclinical FUS transducer facilitates the refinement and streamlining of animal procedures and MRI protocols. The resulting methods are characterized by reproducibility and simplicity, eliminating the need for specialized surgical expertise. This research endeavors to contribute to the optimization of preclinical procedures with rat models and encourage further investigation into the modulation of the BBB to enhance therapeutic interventions in neurological disorders.

Investigating the potential of catheter-assisted pulsed focused ultrasound ablation for atherosclerotic plaques.

Atherosclerosis is a condition in which an adhesive substance called plaque accumulates over time inside the arteries. Plaque buildup results in the constriction of arteries, causing a shortage of blood supply to tissues and organs. Removing atherosclerotic plaques controls the development of acute ischemic stroke and heart diseases. It remains imperative for positive patient outcomes. This study sought to develop a minimally invasive technique for removing arterial plaques by applying focused ultrasound (FUS) energy on the metal surface of a nitinol catheter wire to induce inertial cavitation. The induced cavitation can deplete plaque mechanically inside the arteries, leading towards improved recanalization of blood vessels. The enhanced cavitation effect induced by combining FUS with a metal catheter was first verified by exposing agar phantom gels with or without a 0.9-mm diameter nitinol wire to an acoustic field produced by a 0.5-MHz FUS transducer. The phenomenon was further confirmed in pork belly fat samples with or without a 3-mm diameter nitinol catheter wire. Cavitation was monitored by detecting the peaks of emitted ultrasound signals from the samples using a passive cavitation detector (PCD). Cavitation threshold values were determined by observing the jump in the peak amplitude of signals received by the PCD when the applied FUS peak negative pressure (PNP) increased. To simulate arterial plaque removal, FUS with or without a catheter was used to remove tissues from pork belly fat samples and the lipid cores of human atherosclerotic plaque samples using 2500-cycle FUS bursts at 10% duty cycle and a burst repetition rate of 20Hz. Treatment outcomes were quantified by subtracting the weight of samples before treatment from the weight of samples after treatment. All measurements were repeated 5 times (n=5) unless otherwise indicated, and paired t-tests were used to compare the means of two groups. A p-value of <0.05 will be considered significant. Our results showed that with a nitinol wire, the cavitation threshold in agar phantoms was reduced to 2.6MPa from 4.3MPa PNP when there was no nitinol wire in the focal region of FUS. For pork belly fat samples, cavitation threshold values were 1.0 and 2.0MPa PNP, with and without a catheter wire, respectively. Pork belly fat tissues and lipid cores of atherosclerotic plaques were depleted at the interface between a catheter and the samples at 2 and 4MPa FUS PNP, respectively. The results showed that with a catheter wire in the focal region of a 3-min FUS treatment session, 24.7 and 25.6mg of lipid tissues were removed from pork belly fat and human atherosclerotic samples, respectively. In contrast, the FUS-only group showed no reduction in sample weight. The differences between FUS-only and FUS-plus-catheter groups were statistically significant (p<0.001 for the treatment on pork belly samples, and p<0.01 for the treatment on human atherosclerotic samples). This study demonstrated the feasibility of catheter-assisted FUS therapy for removing atherosclerotic plaques.

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.