Focal Volume, Acoustic Radiation Force, and Strain in Two-Transducer Regimes.

Transcranial ultrasound stimulation (TUS) holds promise for noninvasive neural modulation in treating neurological disorders. Most clinically relevant targets are deep within the brain (near or at its geometric center), surrounded by other sensitive regions that need to be spared clinical intervention. However, in TUS, increasing frequency with the goal of improving spatial resolution reduces the effective penetration depth. We show that by using a pair of 1-MHz orthogonally arranged transducers, we improve the spatial resolution afforded by each of the transducers individually, by nearly 40 folds, achieving a subcubic millimeter target volume of [Formula: see text]. We show that orthogonally placed transducers generate highly localized standing waves with acoustic radiation force (ARF) arranged into periodic regions of compression and tension near the target. We further present an extended capability of the orthogonal setup, which is to impart selective pressures-either positive or negative, but not both-on the target. Finally, we share our preliminary findings that strain can arise from both particle motion (PM) and ARF with the former reaching its maximum value at the focus and the latter remaining null at the focus and reaching its maximum around the focus. As the field is investigating the mechanism of interaction in TUS by way of elucidating the mapping between ultrasound parameters and neural response, orthogonal transducers expand our toolbox by making it possible to conduct these investigations at much finer spatial resolutions, with localized and directed (compression versus tension) ARF and the capability of applying selective pressures at the target.

Therapeutic ultrasound transducer technology and monitoring techniques: a review with clinical examples.

The exponential growth of therapeutic ultrasound applications demonstrates the power of the technology to leverage the combinations of transducer technology and treatment monitoring techniques to effectively control the preferred bioeffect to elicit the desired clinical effect.Objective: This review provides an overview of the most commonly used bioeffects in therapeutic ultrasound and describes existing transducer technologies and monitoring techniques to ensure treatment safety and efficacy.Methods and materials: Literature reviews were conducted to identify key choices that essential in terms of transducer design, treatment parameters and procedure monitoring for therapeutic ultrasound applications. Effective combinations of these options are illustrated through descriptions of several clinical indications, including uterine fibroids, prostate disease, liver cancer, and brain cancer, that have been successful in leveraging therapeutic ultrasound to provide effective patient treatments.Results: Despite technological constraints, there are multiple ways to achieve a desired bioeffect with therapeutic ultrasound in a target tissue. Visualizations of the interplay of monitoring modality, bioeffect, and applied acoustic parameters are presented that demonstrate the interconnectedness of the field of therapeutic ultrasound. While the clinical indications explored in this review are at different points in the clinical evaluation path, based on the ever expanding research being conducted in preclinical realms, it is clear that additional clinical applications of therapeutic ultrasound that utilize a myriad of bioeffects will continue to grow and improve in the coming years.Conclusions: Therapeutic ultrasound will continue to improve in the next decades as the combination of transducer technology and treatment monitoring techniques will continue to evolve and be translated in clinical settings, leading to more personalized and efficient therapeutic ultrasound mediated therapies.

Generating and monitoring mild hyperthermia using a ring array ultrasound transducer.

OBJECTIVE: To demonstrate the feasibility of using a ring array ultrasound (US) transducer, guided by ultrasound tomography (UST), for generating and monitoring mild hyperthermia (MHTh). METHODS: In silico and in vitro experiments were designed to evaluate the efficacy of a ring array US transducer for generating MHTh and monitoring changes in temperature. In a series of in silico studies, we compared the acoustic focal profiles produced by a ring array US transducer transmitting at different frequencies and further investigated the effectiveness of UST-guidance in implementing aberration correction to enhance the focal profile. In vitro experiments evaluated the capability of using a ring array US transducer to generate and maintain MHTh and the accuracy of using UST to monitor temperature changes. RESULTS: The simulations demonstrated that a ring array US transducer achieves symmetrical and localized acoustic focusing. In a heterogenous tissue model, a ring array US transducer achieved a superior acoustic focus by implementing aberration correction with guidance from UST. In vitro experiments demonstrated the capability of a ring array US transducer to generate MHTh in a tissue-mimicking phantom in an average of 117 ± 18 s and subsequently maintain MHTh. Lastly, a ring array US transducer utilized UST to track temperature changes in a preheated water-filled inclusion while it passively cooled from 45 °C to 25 °C, with a maximum error of 0.58 °C. CONCLUSION: A ring array US transducer can noninvasively generate and monitor MHTh, overcoming many limitations of current clinical systems. The closed geometry of the transducer is optimal for acoustic focusing and UST-guidance allows for improved aberration correction in a heterogenous medium. Utilizing UST thermometry with the same ring array US transducer will allow for implementing an image-guided, temperature-controlled, all-acoustic MHTh system.

Optimized Schlieren imaging for real-time visualization of high-intensity focused ultrasound waves.

OBJECTIVES: This article presents an low-cost experimental setup for visualizing refraction anomalies caused by high-intensity focused ultrasound (HIFU). The technique is based on Schlieren imaging, commonly used to visualize temperature and pressure differences in a medium. With this setup, double images of the Schlieren or their shadows to be investigated occur, so that the experimental setup is modified to avoid these double image artifacts. METHODS: The optical setup mainly consists of a point light source, a parabolic mirror, and a camera. Birefringence artifacts are avoided by placing the point light source at a certain vertical distance to the camera, so that the light beam passes through the medium only once. The soundfield is generated by a HIFU transducer in a water tank placed in the beam path of the optical setup. RESULTS: The experimental setup is capable of capturing Schlieren or shadow images. These images show the soundfield without disturbing double images and enable further analysis and qualitative assessment of the soundfield. CONCLUSIONS: The presented setup provides a reliable and efficient method for visualizing refraction anomalies caused by the sonic field of a HIFU transducer and allows for accurate depiction of the refraction anomalies. The double images that usually occur are avoided.

CMUT as a Transmitter for Microbubble-Assisted Blood-Brain Barrier Opening.

Focused ultrasound (FUS) combined with microbubbles (MBs) has emerged as a promising strategy for transiently opening the blood-brain barrier (BBB) to enhance drug permeability in the brain. Current FUS systems for BBB opening use piezoelectric transducers as transmitters and receivers. While capacitive micromachined ultrasonic transducers (CMUTs) have been suggested as an FUS receiver alternative due to their broad bandwidth, their capabilities as transmitters have not been investigated. This is mainly due to the intrinsic nonlinear behavior of CMUTs, which complicates the detection of MB generated harmonic signals and their low-pressure output at FUS frequencies. Various methods have been proposed to mitigate CMUT nonlinearity; however, these approaches have primarily targeted contrast enhanced ultrasound imaging. In this study, we propose the use of polyphase modulation (PM) technique to isolate MB emissions when CMUTs are employed as transmitters for BBB opening. Our calculations for a human scale FUS system with multiple CMUT transmitters show that 10-kPa peak negative pressure (PNP) at 150-mm focal distance will be sufficient for MB excitation for BBB opening. Experimental findings indicate that this pressure level can be easily generated at 400-800 kHz using a readily available CMUT. Furthermore, more than 50-dB suppression of the fundamental harmonic signal is obtained in free field and transcranial hydrophone measurements by processing receive signals in response to phase-modulated transmit waveforms. In vitro validation of PM is also conducted using Definity MB flowing through a tube phantom. MB-filled tube phantoms show adequate nonlinear signal isolation and SNR for MB harmonic detection. Together our findings indicate that PM can effectively mitigate CMUT harmonic generation, thereby creating new opportunities for wideband transmission and receive operation for BBB opening in clinical and preclinical applications.

An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation.

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

Ultrasound-Guided Mechanical High-Intensity Focused Ultrasound (Histotripsy) Through an Acoustically Permeable Polyolefin-Based Cranioplasty Device.

Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect. OBJECTIVE: Recently, a biocompatible, polyolefin-based cranioplasty device was developed to allow ultrasound (US) transmission into the intracranial space with minimal distortion. In this study, we investigated the in vitro feasibility of applying US-guided histotripsy procedures across the prosthesis. METHODS: Pressure waveforms and beam profiles were collected for single- and multi-element histotripsy transducers. Then, high-speed optical images of the bubble cloud with and without the prosthesis were collected in water and tissue-mimicking agarose gel phantoms. Finally, red blood cell (RBC) tissue phantom and excised brain tissue experiments were completed to test the ablative efficacy across the prosthesis. RESULTS: Single element tests revealed increased pressure loss with increasing transducer frequency and increasing transducer-to-prosthesis angle. Array transducer measurements at 1 MHz showed average pressure losses of >50% across the prosthesis. Aberration correction recovered up to 18% of the pressure lost, and high-speed optical imaging in water, agarose gels, and RBC phantoms demonstrated that histotripsy bubble clouds could be generated across the prosthesis at pulse repetition frequencies of 50-500 Hz. Histologic analysis revealed a complete breakdown of brain tissue treated across the prosthesis. Conclusion & Significance: Overall, the results of this study demonstrate that the cranial prosthesis may be used as an acoustic window through which intracranial histotripsy can be applied under US guidance without the need for large transcranial array transducers.

The deep abdominal ultrasound transducer (DAX) increases the success rate and diagnostic accuracy of shear wave elastography for liver fibrosis assessment in patients with obesity-A prospective biopsy-controlled study.

BACKGROUND: Obesity impacts the diagnostic accuracy of shear wave elastography (SWE). A deep abdominal ultrasound transducer (DAX) capable of point (pSWE) and two-dimensional (2D)-SWE has recently been introduced to address this issue. METHODS: We performed a prospective study in a cohort of mostly patients with obesity undergoing liver biopsy with a high prevalence of metabolic dysfunction-associate steatotic liver disease (MASLD). Liver stiffness measurement (LSM) was measured using vibration-controlled transient elastography (VCTE), as well as pSWE and 2D SWE on the standard (5C1) and the DAX transducers. RESULTS: We included 129 patients with paired LSM and liver biopsy: median age 44.0 years, 82 (63.6%) women, median BMI: 43.2 kg/m2. Histologic fibrosis stages: F0: N = 55 (42.6%), F1: N = 14 (10.9%), F2: N = 50 (38.8%), F3: N = 2 (1.6%), F4: N = 8 (6.2%). VCTE-LSM failed (N = 13) or were unreliable (IQR/median ≤30% in ≥7.1 kPa, N = 14) in 20.9% of patients. The Pearson correlation of reliable VCTE-LSM with both pSWE and 2D SWE was strong (all >0.78). The diagnostic accuracy for all LSM techniques was poor for significant fibrosis (≥F2, AUC: 0.54-0.63); however, it was good to excellent for advanced fibrosis (≥F3, AUC: 0.87-0.99) and cirrhosis (F4, AUC: 0.86-1.00). In intention-to-diagnose analysis, pSWE on DAX was significantly superior to VCTE-LSM. CONCLUSIONS: pSWE- and 2D-SWE enable the non-invasive identification of advanced fibrosis and cirrhosis in patients with obese MASLD. The use of the DAX transducer for acoustic radiation force imaging (ARFI)-LSM avoids technical failures in an obese population and subsequently offers advantages over VCTE-LSM for the evaluation of fibrosis in an obese MASLD population at risk for fibrosis.

Lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation.

Ultrasound-driven bioelectronics could offer a wireless scheme with sustainable power supply; however, current ultrasound implantable systems present critical challenges in biocompatibility and harvesting performance related to lead/lead-free piezoelectric materials and devices. Here, we report a lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation, which integrates two developed lead-free sandwich porous 1-3-type piezoelectric composite elements with enhanced harvesting performance in a flexible printed circuit board. The implant is ultrasonically powered through a portable external dual-frequency transducer and generates programmable biphasic stimulus pulses in clinically relevant frequencies. Furthermore, we demonstrate ultrasound-driven implants for long-term biosafety therapy in deep brain stimulation through an epileptic rodent model. With biocompatibility and improved electrical performance, the lead-free materials and devices presented here could provide a promising platform for developing implantable ultrasonic electronics in the future.

Compound Acoustic Radiation Force Impulse Imaging of Bovine Eye by Using Phase-Inverted Ultrasound Transducer.

In general, it is difficult to visualize internal ocular structure and detect a lesion such as a cataract or glaucoma using the current ultrasound brightness-mode (B-mode) imaging. This is because the internal structure of the eye is rich in moisture, resulting in a lack of contrast between tissues in the B-mode image, and the penetration depth is low due to the attenuation of the ultrasound wave. In this study, the entire internal ocular structure of a bovine eye was visualized in an ex vivo environment using the compound acoustic radiation force impulse (CARFI) imaging scheme based on the phase-inverted ultrasound transducer (PIUT). In the proposed method, the aperture of the PIUT is divided into four sections, and the PIUT is driven by the out-of-phase input signal capable of generating split-focusing at the same time. Subsequently, the compound imaging technique was employed to increase signal-to-noise ratio (SNR) and to reduce displacement error. The experimental results demonstrated that the proposed technique could provide an acoustic radiation force impulse (ARFI) image of the bovine eye with a broader depth-of-field (DOF) and about 80% increased SNR compared to the conventional ARFI image obtained using the in-phase input signal. Therefore, the proposed technique can be one of the useful techniques capable of providing the image of the entire ocular structure to diagnose various eye diseases.

Compressed Sensing for Biomedical Photoacoustic Imaging: A Review.

Photoacoustic imaging (PAI) is a rapidly developing emerging non-invasive biomedical imaging technique that combines the strong contrast from optical absorption imaging and the high resolution from acoustic imaging. Abnormal biological tissues (such as tumors and inflammation) generate different levels of thermal expansion after absorbing optical energy, producing distinct acoustic signals from normal tissues. This technique can detect small tissue lesions in biological tissues and has demonstrated significant potential for applications in tumor research, melanoma detection, and cardiovascular disease diagnosis. During the process of collecting photoacoustic signals in a PAI system, various factors can influence the signals, such as absorption, scattering, and attenuation in biological tissues. A single ultrasound transducer cannot provide sufficient information to reconstruct high-precision photoacoustic images. To obtain more accurate and clear image reconstruction results, PAI systems typically use a large number of ultrasound transducers to collect multi-channel signals from different angles and positions, thereby acquiring more information about the photoacoustic signals. Therefore, to reconstruct high-quality photoacoustic images, PAI systems require a significant number of measurement signals, which can result in substantial hardware and time costs. Compressed sensing is an algorithm that breaks through the Nyquist sampling theorem and can reconstruct the original signal with a small number of measurement signals. PAI based on compressed sensing has made breakthroughs over the past decade, enabling the reconstruction of low artifacts and high-quality images with a small number of photoacoustic measurement signals, improving time efficiency, and reducing hardware costs. This article provides a detailed introduction to PAI based on compressed sensing, such as the physical transmission model-based compressed sensing method, two-stage reconstruction-based compressed sensing method, and single-pixel camera-based compressed sensing method. Challenges and future perspectives of compressed sensing-based PAI are also discussed.

Enhancing Electric Field Distribution in the Pancreas for Improved TTFields Therapy: A Computational Modeling Investigation.

BACKGROUND: Tumor treating fields (TTFields) therapy has shown effectiveness in glioblastoma treatment and holds potential for other cancers. However, its application in pancreatic cancer and the distribution of electric fields in pancreas remain unexplored. This study aims to investigate the electric field distributions in pancreatic regions using different array configurations for TTFields therapy. METHODS: Computational modelling was employed to simulate electric field distributions, and quantitative analysis was conducted. Human body impedance measurements were used to optimize the electric properties of the model. Various array configurations were examined to assess their impact on the electric field distributions. RESULTS: The study revealed that well-positioned arrays, specifically the combination of 20-piece transducer arrays in anterior-posterior orientation and 13-piece transducer arrays in left-right orientation, consistently achieved electric fields exceeding the 1V/cm threshold in over 99.4% of the pancreas. Even with a reduced number of transducers (13 pieces for both orientations), sufficient electric field coverage was achieved, exceeding the threshold in over 92.9% of the pancreas. Additionally, different array placements within the same orientation were explored to address clinical challenges such as skin rash and patient anatomical variations. CONCLUSIONS: This research lays the groundwork for understanding TTFields distribution within the abdomen, offering insights into optimizing array configurations for improved electric field delivery. These results offer promises of advancing TTFields therapy for pancreatic cancer towards clinical applications, and potentially enhancing treatment efficacy and patient outcomes.

Demonstration Study of Reflector-Based Volumetric Speed-of-Sound Imaging With Linear Ultrasound Arrays.

Conventional B-mode ultrasound imaging has difficulty in delineating homogeneous soft tissues with similar acoustic impedances, as the reflectivity depends on the acoustic impedance at the interface. As a quantitative imaging biomarker sensitive to alteration of biomechanical properties, speed-of-sound (SoS) holds promising potential for tissue and disease differentiation such as delineation of different breast tissue types with similar acoustic impedance. Compared to two-dimensional (2D) SoS images, three-dimensional (3D) volumetric SoS images achieved through a full-angle ultrasound scan can reveal more intricate morphological structures of tissues; however, they generally require a ring transducer. In this study, we introduce a 3D SoS reconstruction system that utilizes hand-held linear arrays instead. This system employs a passive reflector positioned opposite the linear arrays, serving as an echogenic reference for time-of-flight (ToF) measurements, and a high-definition camera to track the location corresponding to each group of transmit-receive data. To merge these two streams of ToF measurements and location tracking, a voxel-based reconstruction algorithm is implemented. Experimental results with gelatin phantom and ex vivo tissue have demonstrated the stability of our proposed method. Moreover, the results underscore the potential of this system as a complementary diagnostic modality, particularly in the context of diseases such as breast cancer.

A Radiological Clip Design Using Ultrasound Identification to Improve Localization.

OBJECTIVE: We demonstrate the use of ultrasound to receive an acoustic signal transmitted from a radiological clip designed from a custom circuit. This signal encodes an identification number and is localized and identified wirelessly by the ultrasound imaging system. METHODS: We designed and constructed the test platform with a Teensy 4.0 microcontroller core to detect ultrasonic imaging pulses received by a transducer embedded in a phantom, which acted as the radiological clip. Ultrasound identification (USID) signals were generated and transmitted as a result. The phantom and clip were imaged using an ultrasonic array (Philips L7-4) connected to a Verasonics™ Vantage 128 system operating in pulse inversion (PI) mode. Cross-correlations were performed to localize and identify the code sequences in the PI images. RESULTS: USID signals were detected and visualized on B-mode images of the phantoms with up to sub-millimeter localization accuracy. The average detection rate across 30,400 frames of ultrasound data was 98.1%. CONCLUSION: The USID clip produced identifiable, distinguishable, and localizable signals when imaged. SIGNIFICANCE: Radiological clips are used to mark breast cancer being treated by neoadjuvant chemotherapy (NAC) via implant in or near treated lesions. As NAC progresses, available marking clips can lose visibility in ultrasound, the imaging modality of choice for monitoring NAC-treated lesions. By transmitting an active signal, more accurate and reliable ultrasound localization of these clips could be achieved and multiple clips with different ID values could be imaged in the same field of view.

Asymmetric-Backed Multi-Frequency Ultrasonic Transducer for Conformal Tumor Ablation.

OBJECTIVE: Minimally invasive ultrasound ablation transducers have been widely studied. However, conventional designs are limited by the single working frequency, restricting their conformal ablation ability (i.e., ablation size and shape controllability). METHODS: New multi-frequency ultrasonic transducer design method is proposed based on the asymmetric backing layer, which divides the transducer into non-backing-layer region (i.e., front-piezoelectric region) and backing-layer region (i.e., front-piezoelectric-backing region) with multiple local thickness mode resonant frequencies. Ablation zone can be controlled by exciting the local resonance within or between the regions, and its control flexibility is further enhanced by driven under a frequency modulation signal. Experiments and calculations are combined for verifying the proposal. RESULTS: The fabricated transducer with a Y-direction asymmetric backing layer shows five resonances, with two in each region and one resonance excited in both regions. Spatial ultrasound emission is demonstrated by acoustic measurements. Tissue ablation experiments verified spatial ablation zone control, and frequency modulation driving method enables the spatial transition of ablation zone from one region to the other, generating different ablation sizes and shapes. Finally, patient-specific simulations verified the effectiveness of conformal ablation. CONCLUSION: The proposed transducer enables flexible control of ablation zone. SIGNIFICANCE: This study demonstrates a new method for conformal tumor ablation.

Development of an MR-Guided Focused Ultrasound (MRgFUS) Lesioning Approach for the Fornix in the Rat Brain.

OBJECTIVE: High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive therapy to lesion brain tissue, used clinically in patients and pre-clinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. METHODS: The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n = 7 lesions) was compared to a craniectomy approach (n = 22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using histologic methods from a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. RESULTS: Comparing a motorized adjustment system (∼1 mm precision, n = 17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n = 14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. CONCLUSIONS: The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

Evaluation of Dual-Frequency Switching HIFU for Optimizing Superficial Ablation.

OBJECTIVE: Dual-frequency high-intensity focused ultrasound (HIFU) thermal ablation is an exceptionally promising technique for treating tumors due to its precision and effectiveness. However, there are still a few studies on improving the accuracy and efficiency of HIFU in superficial ablation applications. This study proposes a method utilizing dual frequency switching ultrasound (DFSU) to enhance the efficiency and precision of superficial treatments. METHODS: A dual-frequency HIFU transducer operating at 4.5 MHz and 13.7 MHz was designed, and a dual-frequency impedance matching network was designed to optimize electro-acoustic conversion efficiency. Phantom and ex vivo tests were conducted to measure and compare thermal lesion areas and temperature rises caused by single-frequency ultrasound (SFU) and DFSU. RESULTS: In both phantom and ex vivo tests, the utilization of DFSU resulted in larger lesion areas compared to SFU. Moreover, DFSU provided improved control and versatility, enabling precise and efficient ablation. CONCLUSION: DFSU exhibits the ability to generate larger ablation areas in superficial tissue compared to SFU, and DFSU allows flexible control over the ablation area and temperature rise rate. The acoustic power deposition of HIFU can be optimized to achieve precise ablation.

Histoplasty Modification of the Tumor Microenvironment in a Murine Preclinical Model of Breast Cancer.

PURPOSE: To develop a noninvasive therapeutic approach able to alter the biophysical organization and physiology of the extracellular matrix (ECM) in breast cancer. MATERIALS AND METHODS: In a 4T1 murine model of breast cancer, histoplasty treatment with a proprietary 700-kHz multielement therapy transducer using a coaxially aligned ultrasound (US) imaging probe was used to target the center of an ex vivo tumor and deliver subablative acoustic energy. Tumor collagen morphology was qualitatively evaluated before and after histoplasty with second harmonic generation. Separately, mice bearing bilateral 4T1 tumors (n = 4; total tumors = 8) were intravenously injected with liposomal doxorubicin. The right flank tumor was histoplasty-treated, and tumors were fluorescently imaged to detect doxorubicin uptake after histoplasty treatment. Next, 4T1 tumor-bearing mice were randomized into 2 treatment groups (sham vs histoplasty, n = 3 per group). Forty-eight hours after sham/histoplasty treatment, tumors were harvested and analyzed using flow cytometry. RESULTS: Histoplasty significantly increased (P = .002) liposomal doxorubicin diffusion into 4T1 tumors compared with untreated tumors (2.12- vs 1.66-fold increase over control). Flow cytometry on histoplasty-treated tumors (n = 3) demonstrated a significant increase in tumor macrophage frequency (42% of CD45 vs 33%; P = .022) and a significant decrease in myeloid-derived suppressive cell frequency (7.1% of CD45 vs 10.3%; P = .044). Histoplasty-treated tumors demonstrated increased CD8+ (5.1% of CD45 vs 3.1%; P = .117) and CD4+ (14.1% of CD45 vs 11.8%; P = .075) T-cell frequency. CONCLUSIONS: Histoplasty is a nonablative focused US approach to noninvasively modify the tumor ECM, increase chemotherapeutic uptake, and alter the tumor immune microenvironment.

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.

Piezoelectric Multi-Channel Bilayer Transducer for Sensing and Filtering Ossicular Vibration.

This paper presents an acoustic transducer for fully implantable cochlear implants (FICIs), which can be implanted on the hearing chain to detect and filter the ambient sound in eight frequency bands between 250 and 6000 Hz. The transducer dimensions are conventional surgery compatible. The structure is formed with 3  × 3 × 0.36 mm active space for each layer and 5.2 mg total active mass excluding packaging. Characterization of the transducer is carried on an artificial membrane whose vibration characteristic is similar to the umbo vibration. On the artificial membrane, piezoelectric transducer generates up to 320.3 mVpp under 100 dB sound pressure level (SPL) excitation and covers the audible acoustic frequency. The measured signal-to-noise-ratio (SNR) of the channels is up to 84.2 dB. Sound quality of the transducer for fully implantable cochlear implant application is graded with an objective qualification method (PESQ) for the first time in the literature to the best of the knowledge, and scored 3.42/4.5.