The endorectal ultrasound (US)-guided thermal ablation of prostate cancer (PCa) using high-intensity focused ultrasound (HIFU) is a widely used focal intervention. While generally safe and effective, it is not without challenges associated with heat diffusion and prefocal heating, which has spurred interest toward nonthermal and mechanical HIFU ablation regimes. Another challenge is the necessity to mechanically translate the HIFU transducer-commonly single-element or annular array-for volumetric treatments, which results in target shifts and transducer position readjustment. The 2-D arrays would address this problem, but their design is challenging in a small form factor. The element pattern must be tightly packed and aperiodic to maximize the active surface area and to suppress grating lobes, respectively. Here, we report on the design, fabrication, and performance evaluation of a 1.5-MHz 128-element transrectal HIFU array driven by Verasonics system capable of mechanical tissue ablation via boiling histotripsy (BH) under real-time coaxial US imaging guidance. A recently developed method for designing randomized, fully populated mosaic arrays was used to create the element pattern. The measured focus steering ranges of the fabricated array were 26 mm axially and 12 mm laterally in the BH regime, with driving voltage compensation by less than 43% and no grating lobe formation. Stress tests with a five-element prototype confirmed safe operating voltage of 850-V peak-to-peak, corresponding to the acoustic intensity of 542 W/cm2 at the array surface. The array integrated with a 128-element US imaging probe driven by the same Verasonics system was successfully used to produce volumetric BH lesions in polyacrylamide (PAA) tissue-mimicking phantoms.

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.

Pulsed high-intensity focused ultrasound (pHIFU) uses nonlinearly distorted millisecond-long ultrasound pulses of moderate intensity to induce inertial cavitation in tissue without administration of contrast agents. The resulting mechanical disruption permeabilizes the tissue and enhances the diffusion of systemically administered drugs. This is especially beneficial for tissues with poor perfusion such as pancreatic tumors. Here, we characterize the performance of a dual-mode ultrasound array designed for image-guided pHIFU therapies in producing inertial cavitation and ultrasound imaging. The 64-element linear array (1.071 MHz, an aperture of $14.8\times51.2$ mm, and a pitch of 0.8 mm) with an elevational focal length of 50 mm was driven by the Verasonics V-1 ultrasound system with extended burst option. The attainable focal pressures and electronic steering range in linear and nonlinear operating regimes (relevant to pHIFU treatments) were characterized through hydrophone measurements, acoustic holography, and numerical simulations. The steering range at ±10% from the nominal focal pressure was found to be ±6 mm axially and ±11 mm azimuthally. Focal waveforms with shock fronts of up to 45 MPa and peak negative pressures up to 9 MPa were achieved at focusing distances of 38–75 mm from the array. Cavitation behaviors induced by isolated 1-ms pHIFU pulses in optically transparent agarose gel phantoms were observed by high-speed photography across a range of excitation amplitudes and focal distances. For all focusing configurations, the appearance of sparse, stationary cavitation bubbles occurred at the same ${P}_{-}$ threshold of 2 MPa. As the output level increased, a qualitative change in cavitation behavior occurred, to pairs and sets of proliferating bubbles. The pressure ${P}_{-}$ at which this transition was observed corresponded to substantial nonlinear distortion and shock formation in the focal region and was thus dependent on the focal distance of the beam ranging within 3–4 MPa for azimuthal ${F}$ -numbers of 0.74–1.5. The array was capable of B-mode imaging at 1.5 MHz of centimeter-sized targets in phantoms and in vivo pig tissues at depths of 3–7 cm, relevant to pHIFU applications in abdominal targets.

Therapeutic ultrasound is proving to be viable in the clinic and is producing a high level of commercial activity in Therapeutic Ultrasound Systems globally across a wide variety of clinical indications. Recently there has been an increased level of commercial interest in systems delivering lower intensity ultrasound. Some examples of clinical indications include modulating nerves, sonodynamic therapy, or combining ultrasound with drugs to lower the threshold of required intensities. Regardless of the acoustic intensity required, new product inception will adopt an effective bio-acoustic result to match a clinical indication, creating a gap in product development. Sonic Concepts provides transmit ultrasound development services to fill this gap through a phased development program, accelerating first-in-man and time to market. Sonic Concepts has co-developed 30 + clinical systems, servicing customers with more than 100 years of accumulated experience, creative design techniques, and a spectrum of products and intellectual property to leverage. Examples of co-developed clinical systems will be presented, detailing the process from initial concept to first-in-man while using pre-clinical systems, HIFUPlex™ and NeuroFUS® to fast-track development.

Pulsed high-intensity focused ultrasound (pHIFU) is capable of inducing cavitation without the need for contrast agents, which can enhance drug transport in tissues with poor perfusion. We report on the experimental characterization of cavitation induced by a new dual-mode ultrasound arraydesigned for image-guided pHIFU therapies. The 64-element array (1.071 MHz, aperture of 14.8 × 51.2 mm2 and pitch of 0.8 mm) is driven by the Verasonics V1 ultrasound system, configured for pHIFU excitation. Acoustic properties of the beam in the focal region were characterized through hydrophone measurements in the linear and nonlinear operating regimes while steering the beam azimuthally and axially. A high-speed camera was used to observe the cavitation behaviors induced in tissue-mimicking gel phantoms near the focus of the beam for different pHIFU exposure parameters. As the focal pressure increases, a change in cavitation behavior occurs, from the appearance of single, stationary bubbles, to groups of proliferating bubbles. The pressure at which the transition from stationary to proliferating cavitation was observed corresponds to the onset of shocks in the focal region. Beams with larger F-numbers were shown to induce cavitation at lower pressures than beams with lower F-numbers. [Work supported by NIH R01EB023910 and RSF 20-12-00145.]

Pulsed focused ultrasound (pFUS) uses short acoustic pulses delivered at low duty cycle and moderate intensity to noninvasively apply mechanical stress or introduce disruption to tissue. Ultrasound-guided pFUS has primarily been used for inducing cavitation at the focus, with or without contrast agents, to promote drug delivery to tumors. When applied in tandem with contrast agents, pFUS is often administered using an ultrasound imaging probe, which has a small footprint and does not require a large acoustic window. The use of nonlinear pFUS without contrast agents was recently shown to be beneficial for localized tissue disruption, but required higher ultrasound pressure levels than a conventional ultrasound imaging probe could produce. In this work, we present the design of a compact dual-use 1-MHz transducer for ultrasound-guided pFUS without contrast agents. Nonlinear pressure fields that could be generated by the probe, under realistic power input, were simulated using the Westervelt equation. In water, fully developed shocks of 42-MPa amplitude and peak negative pressure of 8 MPa were predicted to form at the focus at 458-W acoustic power or 35% of the maximum reachable power of the transducer. In absorptive soft tissue, fully developed shocks formed at higher power (760 W or 58% of the maximum reachable power) with the shock amplitude of 33 MPa and peak negative pressure of 7.5 MPa. The electronic focus-steering capabilities of the array were evaluated and found to be sufficient to cover a target with dimensions of 19 mm in axial direction and 44 mm in transversal direction.

Ultrasound (US)-mediated gene delivery (UMGD) of nonviral vectors was demonstrated in this study to be an effective method to transfer genes into the livers of large animals via a minimally invasive approach. We developed a transhepatic venous nonviral gene delivery protocol in combination with transcutaneous, therapeutic US (tUS) to facilitate significant gene transfer in pig livers. A balloon catheter was inserted into the pig hepatic veins of the target liver lobes via jugular vein access under fluoroscopic guidance. tUS exposure was continuously applied to the lobe with simultaneous infusion of pGL4 plasmid (encoding a luciferase reporter gene) and microbubbles. tUS was delivered via an unfocused, two-element disc transducer (H105) or a novel focused, single-element transducer (H114). We found applying transcutaneous US using H114 and H105 with longer pulses and reduced acoustic pressures resulted in an over 100-fold increase in luciferase activity relative to untreated lobes. We also showed effective UMGD by achieving focal regions of >105 relative light units (RLUs)/mg protein with minimal tissue damage, demonstrating the feasibility for clinical translation of this technique to treat patients with genetic diseases.

We have achieved significant enhancement of gene delivery into livers of large animals using ultrasound (US)-targeted microbubble (MB) destruction methods. An infusion of pGL4 (encoding a luciferase reporter gene) plasmid DNA (pDNA) and MBs into a portal-vein segmental branch of a porcine liver was exposed to US for 4 min. Therapeutic US induced cavitation of MBs to temporarily permeabilize the vascular endothelium and cell membranes, allowing entry of pDNA. We obtained a 64-fold enhancement in luciferase expression in pig livers compared to control without US using an unfocused, dual-element transducer (H105, center frequency [f(c)] = 1.10 MHz) at 2.7 MPa peak negative pressure (PNP). However, input electrical energy was limited, and modified transducers were designed to have spherical (H185A, f(c) = 1.10 MHz) or cylindrical foci (H185B, f(c) = 1.10 MHz; H185D, f(c) = 1.05 MHz) to enhance PNP output. The revised transducers required less electrical input to achieve 2.7 MPa PNP compared to H105, thereby allowing PNP outputs of up to 6.2 MPa without surpassing the piezo-material limitations. Subsequently, luciferase expression significantly improved up to 9,000-fold compared to controls with minor liver damage. These advancements will allow us to modify our current protocols toward minimally invasive US gene therapy.

BACKGROUND:High-intensity focused US (HIFU) is becoming more widely used for noninvasive and minimally invasive ablation of benign and malignant tumors. Recent studies suggest that HIFU can also enhance targeted drug delivery and stimulate an antitumor immune response in many tumors. However, targeting pancreatic and liver tumors by using an extracorporeal source is challenging due to the lack of an adequate acoustic window. The development of an EUS-guided HIFU transducer has many potential benefits including improved targeting, decreased energy requirements, and decreased potential for injury to intervening structures.OBJECTIVE:To design, develop, and test an EUS-guided HIFU transducer for endoscopic applications.DESIGN:A preclinical, pilot characterization and feasibility study.SETTING:Academic research center.PATIENTS:Studies were performed in an in vivo porcine model.INTERVENTION:Thermal ablation of in vivo porcine pancreas and liver was performed with EUS-guided focused US through the gastric tract.RESULTS:The transducer successfully created lesions in gel phantoms and ex vivo bovine livers. In vivo studies demonstrated that targeting and creating lesions in the porcine pancreas and liver are feasible.LIMITATIONS:This was a preclinical, single-center feasibility study with a limited number of subjects.CONCLUSION:An EUS-guided HIFU transducer was successfully designed and developed with dimensions that are appropriate for endoscopic use. The feasibility of performing EUS-guided HIFU ablation in vivo was demonstrated in an in vivo porcine model. Further development of this technology will allow endoscopists to perform precise therapeutic ablation of periluminal lesions without breaching the wall of the gastric tract.

Previously we demonstrated that ultrasound (US)-mediated gene delivery (UMGD) can significantly enhance reporter gene transfer into the mouse and rat livers. This nonviral gene transfer strategy can bypass many obstacles encountered by viral gene therapy. Most significantly, we have achieved therapeutic levels of FVIII following UMGD into hemophilia A mice. Recently we have successfully developed prototype US systems including several unfocused and semi-focused transducers to treat large tissue volumes in canine and swine. In order to facilitate the translation of this technology to treat hemophilia, we have recently treated 2 normal dogs with UMGD of FVIII plasmids using an open surgery procedure. Four mg of a high-expressing, liver-specific pBS-HCRHPI-FVIIIA plasmid and 3 ml of Definity® MBs in 8 ml total PBS solution were injected via the segmental portal vein branch with simultaneous exposure of the target liver lobe to therapeutic US (1.1 MHz frequency, 20 cycle pulses, 50 Hz pulse repetition frequency) for 4 minutes using the large diameter transducers. A sham-treated dog received an equivalent pGL4/MB dose, but was not exposed to tUS. We used an apodized dual element unfocused transducer H105 at 2.5Mpa peak negative pressure (PNP) in the first dog experiment and observed low levels of hFVIII gene expression in the treated liver lobes. The second dog experiment was performed using a cylindrically 6.2 MPa at the focal area. One day following treatment, the treated liver lobes were sectioned, and representative sections were fixed and stained for FVIII expression by histochemical staining using a polyclonal anti-FVIII antibody. Untreated normal dog liver and human liver were used as negative and positive controls. Significant hFVIII gene expression was obtained in both treated liver lobes with the expression levels slightly lower than control human liver lobe. Furthermore, fairly homogeneous distribution of FVIII gene expression was observed in hepatocytes. Next, we performed Western blot analysis to confirm if the staining is specific to human FVIII protein. A heavy chain band specific to hFVIII was observed in treated dog plasma and positive hFVIII control, but not in control normal dog plasma and pre-bleed plasma sample from the dog before treatment. Significant enhancement of FVIII-specific clotting activity was also obtained in the second treated dog compared to pre-treatment and the first treated dog. In addition, transaminase levels and histology analysis indicated minimal tissue damage in treated dog livers. Enhancement of FVIII gene expression by UMGD is currently evaluated in hemophilia dogs. Our results sugges that UMGD has great potential for therapeutic treatment of hemophilia A.

This project implements previously developed techniques for guiding and monitoring thermal HIFU therapy using imaging arrays with a spherically shaped therapeutic array for dual-mode operation. Three-dimensional motion tracking, thermal strain measurement, and radiation force rebound measurement within the HIFU steering volume are performed using only the therapy array. The techniques have typically been studied for conventional ultrasound imaging using linear, curvilinear, or phased arrays which are usually placed coaxially in the center of the HIFU array. While the dual-mode approach does not provide the image quality and wide field of view of an imaging array, the perfect co-registration of the therapy array, and its 3D view of the region of interest present a valuable opportunity for ultrasound-guided focused ultrasound (USgFUS) therapy systems. A family of Sonic Concepts broadband spherically-focused HIFU array transducers, driven with the Verasonics HIFU-configured ultrasound system, is used to assess real-time performance of the dual-mode approach, in simulation and experiment. Simulations using the Verasonics acquisition software with a set of point scatterers produce the RF backscatter data used by the monitoring algorithms. The particles are displaced in time using motions that mimic the true or apparent displacements of tissue-like media either in translation, heated by a HIFU focus, or deformed by a radiation force beam. Preliminary experiments using a 128-element HIFU array and a scattering hydrogel phantom indicate that the simulations are effective for studying a range of tradeoffs in transducer design and therapy monitoring approaches.

High-intensity focused ultrasound (HIFU) is a promising technology for non-invasive and minimally invasive ablation of benign and malignant tumors. In HIFU therapy, ultrasound energy is focused within the body to induce thermal denaturation of tissue at the focus without affecting surrounding organs. Recent studies also found that the mechanical effect of HIFU may help to enhance drug delivery and stimulate an anti-tumor immune response in certain tumors, including pancreatic tumors. However, targeting of pancreatic tumors using an extracorporeal source is often not possible due to lack of an adequate acoustic window through overlying bowel gas. The major challenges that complicate HIFU ablation of pancreatic tumors are the presence bowel gas, respiratory motion, and the absence of monitoring. Bowel gas can obstruct the acoustic window for HIFU energy delivery, leading not only to incomplete ablation of the target, but also to thermal bowel injury due to rapid heat deposition at the gas-tissue interface. Respiratory motion during HIFU therapy leads to redistribution of acoustic energy over the target area larger than intended, with possible resultant damage to adjacent tissues. The development of an endoscopic ultrasound (EUS)-guided HIFU transducer enables avoidance of both bowel gas blockage and respiration motion redistribution and provides a reliable monitoring method. EUS-guided HIFU also has many potential benefits including improved targeting, decreased energy requirements and decreased potential for injury to intervening structures.

This paper describes a series of high intensity focused ultrasound (HIFU) phased array transducers with a single Archimedean spiral close packed element arrangement on a spherical surface extending from the central axis outward. Simulation and measurement reveal using the spiral element arrangement on a spherical bowl reduces grating side lobes while maximizing power density at the focus.

Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics.

Ultrasound (US)-targeted microbubble (MB) destruction (UTMD) can significantly enhance gene delivery in mouse livers when pDNA/MBs were injected into the portal vein (PV) with simultaneous US exposure using a focused transducer. However, this transducer was ineffective in enhancing gene transfer into rats. A 13-mm diameter unfocused transducer was designed and the delivery route of pDNA/MBs was modified into a specific liver lobe, resulting in >100-fold increase in luciferase expression in rats. To facilitate the translation into human application, many technical issues were explored in large animal models. We applied 1.1 MHz US to a targeted canine liver lobe with simultaneous injection of pDNA/MBs into a PV segmental branch and occlusion of the inferior vena cava. For more effective treatment of large tissue volumes, a 52-mm planar unfocused transducer was specifically constructed. Its apodized dual element configuration greatly reduced the near field transaxial pressure variations, producing a uniform field of US exposure for the treated tissues. Together with a 15 kW-capacity US amplifier, a 692-fold increase of gene expression in canines was achieved at 2.7-MPa. Transaminase levels and histology analysis indicated minimal tissue damage. These results demonstrated that UTMD is highly promising for safe and efficient gene delivery into the liver.

This paper describes a novel therapeutic high intensity non-focused ultrasound (HIU) transducer designed with uniform pressure distribution to aid in accelerated gene transfer in large animal liver tissues in vivo. The underlying HIU transducer was used to initiate homogeneous cavitation throughout the tissue while delivering up to 2.7 MPa at 1.1 MHz across its radiating surface. The HIU transducer was built into a 6 cm diameter x 1.3 cm tall housing ergonomically designed to avoid collateral damage to the surrounding anatomy during dynamic motion. The ultrasound (US) radiation was applied in a 'paintbrush-like' manner to the surface of the liver. The layers and geometry of the transducer were carefully selected to maximize the active diameter (5.74 cm), maximize the electrical to acoustic conversion efficiency (85%) to achieve 2.7 MPa of peak negative pressure, maximize the frequency operating band at the fundamental resonance to within a power transfer delta of 1 dB, and reduce the pressure delta to within 2 dB across the radiating surface. For maximum peak voltage into the transducer, a high performance piezoceramic was chosen and a DC bias circuit was built integral to the system. An apodized two element annular pattern was made from a single piezoceramic element, resulting in significant pressure uniformity enhancement. In addition to using apodization for pressure uniformity, a proprietary multi-layered structure was used to improve efficiency while sustaining an operating band from 900 kHz to 1.3 MHz. The resultant operating band allowed for dithering techniques using frequency modulation. The underlying HIU transducer for use in large animals enhances gene expression up to 6300-fold.

In order to fully characterize transducers used in high-intensity focused ultrasound, it is useful to measure the source field at the transducer’s radiating surface while the transducer is radiating into water. A new, ruggedized hydrophone has been recently developed to enable direct-contact scanning at the radiating surface without damage to the source transducer. The hydrophone enables the acquisition of high-resolution images of the source fields for single-element and array transducers. This allows beam features such as unexpected side lobes or other anomalies to be traced back to local conditions at the radiating surface. The compact size of the hydrophone also allows source field measurements to be made in the presence of reflective structures located within the field of the transducer. This hydrophone is useful in the testing of transducer quality. In array transducers, it is also useful in verifying the geometric locations, radiating areas, and channel numbering of array elements, and in the measurement of channel-to-channel crosstalk.