Development of a Small-Footprint 50 MHz Linear Array: Fabrication and Micro-Ultrasound Imaging Demonstration.

Compact high-frequency arrays are of interest for clinical and preclinical applications in which a small-footprint or endoscopic device is needed to reach the target anatomy. However, the fabrication of compact arrays entails the connection of several dozens of small elements to the imaging system through a combination of flexible printed circuit boards at the array end and micro-coaxial cabling to the imaging system. The methods currently used, such as wire bonding, conductive adhesives, or a dry connection to a flexible circuit, considerably increase the array footprint. Here, we propose an interconnection method that uses vacuum-deposited metals, laser patterning, and electroplating to achieve a right-angle, compact, reliable connection between array elements and flexible-circuit traces. The array elements are thickened at the edges using patterned copper traces, which increases their cross-sectional area and facilitates the connection. We fabricated a 2.3 mm by 1.7 mm, 64-element linear array with elements at a 36 µm pitch connected to a 4 cm long flexible circuit, where the interconnect adds only 100 µm to each side of the array. Pulse-echo measurements yielded an average center frequency of 55 MHz and a -6 dB bandwidth of 41%. We measured an imaging resolution of 35 µm in the axial direction and 114 µm in the lateral direction and demonstrated the ex vivo imaging of porcine esophageal tissue and the in vivo imaging of avian embryonic vasculature.

Fine Pitch Flexible Printed Circuit Board Patterning for Miniaturized Endoscopic MicroUltrasound Arrays.

Microultrasound (micro-US) has become an invaluable tool for preclinical research and in emerging applications in clinical diagnosis and treatment guidance. Several such applications can benefit from arrays with a small footprint and endoscopic form factor. However, critical challenges arise in making electrical connections to array elements in such spatial constraints. In this work, we describe a method to pattern a high-density flexible circuit cabling on a copper-on polyimide film, using laser ablation of a polymer resist and wet etching, and then demonstrate a connection to a micro-US array. We investigate laser ablation process parameters and evaluate the ability to consistently pattern continuous copper traces. A minimum 30- [Formula: see text] pitch was achieved with 5- [Formula: see text]-wide electrode lines, and continuity of a 5-m-long trace is demonstrated. A flexible circuit with 30-mm-long traces with 30- [Formula: see text] line and 30- [Formula: see text] space before fan-out was fabricated to connect in an interleaved manner to a 32-element array with 30- [Formula: see text] element pitch. Metal deposition and laser ablation were used to connect and pattern the element electrodes to the copper traces of the flexible circuit. Electrical and acoustic measurements show good yield and consistent impedance across channels. Element pulse-echo tests demonstrated device functionality; the two-way pulse had 43-MHz center frequency and 40% fractional bandwidth (-6 dB). The proposed manufacturing methods facilitate the prototyping and fabrication of flexible endoscopic or small-footprint micro-US devices.

A novel, hands-free ultrasound patch for continuous monitoring of quantitative Doppler in the carotid artery.

Quantitative Doppler ultrasound of the carotid artery has been proposed as an instantaneous surrogate for monitoring rapid changes in left ventricular output. Tracking immediate changes in the arterial Doppler spectrogram has value in acute care settings such as the emergency department, operating room and critical care units. We report a novel, hands-free, continuous-wave Doppler ultrasound patch that adheres to the neck and tracks Doppler blood flow metrics in the common carotid artery using an automated algorithm. String and blood-mimicking test objects demonstrated that changes in velocity were accurately measured using both manually and automatically traced Doppler velocity waveforms. In a small usability study with 22 volunteer users (17 clinical, 5 lay), all users were able to locate the carotid Doppler signal on a volunteer subject, and, in a subsequent survey, agreed that the device was easy to use. To illustrate potential clinical applications of the device, the Doppler ultrasound patch was used on a healthy volunteer undergoing a passive leg raise (PLR) as well as on a congestive heart failure patient at resting baseline. The wearable carotid Doppler patch holds promise because of its ease-of-use, velocity measurement accuracy, and ability to continuously record Doppler spectrograms over many cardiac and respiratory cycles.

Interference-free Detection of Lipid-laden Atherosclerotic Plaques by 3D Co-registration of Frequency-Domain Differential Photoacoustic and Ultrasound Radar Imaging.

As lipid composition of atherosclerotic plaques is considered to be one of the primary indicators for plaque vulnerability, a diagnostic modality that can sensitively evaluate their necrotic core is highly desirable in atherosclerosis imaging. In this regard, intravascular photoacoustic (IVPA) imaging is an emerging plaque detection modality that provides lipid-specific chemical information of arterial walls. Within the near-infrared window, a 1210-nm optical source is usually chosen for IVPA applications because lipid exhibits a strong absorption peak at that wavelength. However, other arterial tissues also show some degree of absorption near 1210 nm and generate undesirable interfering PA signals. In this study, a novel wavelength-modulated Intravascular Differential Photoacoustic Radar (IV-DPAR) modality was introduced as an interference-free detection technique for a more accurate and reliable diagnosis of plaque progression. By using two low-power continuous-wave laser diodes in a differential manner, IV-DPAR could efficiently suppress undesirable absorptions and system noise, while dramatically improving system sensitivity and specificity to cholesterol, the primary ingredient of plaque necrotic core. When co-registered with intravascular ultrasound imaging, IV-DPAR could sensitively locate and characterize the lipid contents of plaques in human atherosclerotic arteries, regardless of their size and depth.

Evaluation of Focal Ablation of Magnetic Resonance Imaging Defined Prostate Cancer Using Magnetic Resonance Imaging Controlled Transurethral Ultrasound Therapy with Prostatectomy as the Reference Standard.

PURPOSE: We evaluated magnetic resonance imaging controlled transurethral ultrasound therapy as a treatment for magnetic resonance imaging defined focal prostate cancer using subsequent prostatectomy and histology as the reference standard. MATERIALS AND METHODS: Five men completed this pilot study, which was approved by the institutional review board. Prior to radical prostatectomy focal tumors identified by magnetic resonance imaging were treated by coagulating targeted subtotal 3-dimensional volumes of prostate tissue using magnetic resonance imaging controlled transurethral focused ultrasound. Treatment was performed with a 3 Tesla clinical magnetic resonance imaging unit combined with modified clinical planning software for high intensity focused ultrasound therapy. After prostatectomy whole mount histological sections parallel to the magnetic resonance imaging treatment planes were used to compare magnetic resonance imaging measurements with thermal damage at the cellular level and, thus, evaluate treatment and target accuracy. RESULTS: Three-dimensional target volumes of 4 to 20 cc and with radii up to 35 mm from the urethra were treated successfully. Mean ± SD temperature control accuracy at the target boundary was -1.6 ± 4.8C and the mean spatial targeting accuracy achieved was -1.5 ± 2.8 mm. Mean treatment accuracy with respect to histology was -0.4 ± 1.7 mm with all index tumors falling inside the histological outer limit of thermal injury. CONCLUSIONS: Magnetic resonance imaging guided transurethral ultrasound therapy is capable of generating thermal coagulation and tumor destruction in targeted 3-dimensional angular sectors out to the prostate capsule for prostate glands up to 70 cc in volume. Ultrasound parameters needed to achieve ablation at the prostate capsule were determined, providing a foundation for future studies.

MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: initial feasibility in humans.

PURPOSE: To evaluate the feasibility and safety of magnetic resonance (MR) imaging-controlled transurethral ultrasound therapy for prostate cancer in humans. MATERIALS AND METHODS: This pilot study was approved by the institutional review board and was performed in eight men (mean age, 60 years; range, 49-70 years) with localized prostate cancer (Gleason score≤7, prostate-specific antigen level #15 µg/L) immediately before radical prostatectomy. All patients provided written informed consent. This phase 0 feasibility and safety study is the first evaluation in humans. Transurethral ultrasound therapy was performed with the patient under spinal anesthesia by using a clinical 1.5-T MR unit. Patients then underwent radical prostatectomy, and the resected gland was sliced in the plane of treatment to compare the MR imaging measurements with the pattern of thermal damage. The overall procedure time and coagulation rate were measured. In addition, the spatial targeting accuracy was evaluated, as was the thermal history along the thermal damage boundaries in the gland. RESULTS: The average procedure time was 3 hours, with 2 or fewer hours spent in the MR unit. The treatment was well tolerated by all patients, and a temperature uncertainty of less than 2°C was observed in the treatments. The mean temperature and thermal dose measured along the boundary of thermal coagulation were 52.3°C±2.1 and 3457 (cumulative equivalent minutes at 43°C)±5580, respectively. The mean treatment rate was 0.5 mL/min, and a spatial targeting accuracy of -1.0 mm±2.6 was achieved. CONCLUSION: MR imaging-controlled transurethral ultrasound therapy is feasible, safe, and well tolerated. This technology could be an attractive approach for whole-gland or focal therapy.

MRI-guided transurethral ultrasound therapy of the prostate gland using real-time thermal mapping: initial studies.

OBJECTIVE: To confirm the correlation between planning and thermal injury of the prostate as determined by magnetic resonance imaging (MRI) and histology in canine and humans treated with transurethral ultrasound. MATERIAL AND METHODS: Canine studies: 2 sets of in vivo studies were performed under general anesthesia in 1.5 T clinical MRI. Nine dogs were treated using single transducer; 8 dogs were treated using urethral applicator with multiple transducers. Rectal cooling was maintained. After initial imaging, a target boundary was selected and high-intensity ultrasound energy delivered. The spatial temperature distribution was measured continuously every 5 seconds with MR thermometry using the proton-resonant frequency shift method. The goal was to achieve 55 °C at the target boundary. After treatment, the prostate was harvested and fixed with adjoining tissue, including rectum. Temperature maps, anatomical images, and histologic sections were registered to each other and compared. Human studies: To date, 5 patients with localized prostate cancer have been treated immediately before radical prostatectomy. Approximately 30% of the gland volume was targeted. RESULTS: A continuous pattern of thermal coagulation was successfully achieved within the target region, with an average spatial precision of 1-2 mm. Radical prostatectomy was routine, with an uncomplicated postoperative course in all patients. The correlation between anatomical, thermal, and histologic images was ≤3 mm. Treatment time was <30 minutes. No thermal damage to rectal tissue was observed. CONCLUSIONS: Thermal ablation within the prescribed target of the prostate has been successfully demonstrated in canine studies. The treatment is also feasible in humans.

Analysis of the spatial and temporal accuracy of heating in the prostate gland using transurethral ultrasound therapy and active MR temperature feedback.

A new MRI-guided therapy is being developed as a minimally invasive treatment for localized prostate cancer utilizing high-intensity ultrasound energy to generate a precise region of thermal coagulation within the prostate gland. The purpose of this study was to evaluate in vivo the capability to produce a spatial heating pattern in the prostate that accurately matched the shape of a target region using transurethral ultrasound heating and active MR temperature feedback. Experiments were performed in a canine model (n = 9) in a 1.5 T MR imager using a prototype device comprising a single planar transducer operated under rotational control. The spatial temperature distribution, measured every 5 s with MR thermometry, was used to adjust the acoustic power and rotation rate in order to achieve a temperature of 55 degrees C along the outer boundary of the target region. The results demonstrated the capability to produce accurate spatial heating patterns within the prostate gland. An average temperature of 56.2 +/- 0.6 degrees C was measured along the outer boundary of the target region across all experiments in this study. The average spatial error between the target boundary and the 55 degrees C isotherm was 0.8 +/- 0.7 mm (-0.2 to 3.2 mm), and the overall treatment time was < or =20 min for all experiments. Excellent spatial agreement was observed between the temperature information acquired with MRI and the pattern of thermal damage measured on H&E-stained tissue sections. This study demonstrates the benefit of adaptive energy delivery using active MR temperature feedback, and an excellent capability to treat precise regions within the prostate gland with this technology.

MRI-compatible transurethral ultrasound system for the treatment of localized prostate cancer using rotational control.

Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy is a potential minimally invasive treatment for localized prostate cancer offering precise targeting of tissue within the gland, short treatment times, and the capability to quantify the spatial heating pattern delivered during therapy. A significant challenge in MRI-guided ultrasound therapy is the design and construction of MRI-compatible equipment capable of operation in a closed-bore MR imager. We describe a prototype system developed for MRI-guided transurethral ultrasound therapy and characterize the performance of the different components including the heating applicator design, rotational motor, and radio frequency electronics. The ultrasound heating applicator described in this study incorporates a planar transducer and is capable of producing high intensity ultrasound energy in a localized region of tissue. Results demonstrated that the heating applicator exhibits excellent MRI-compatibility, enabling precise MR temperature measurements to be acquired as close as 6 mm from the device. Simultaneous imaging and rotational motion was also possible during treatment using a motor based on piezoelectric actuators. Heating experiments performed in both phantoms and in a canine model with the prototype system verified the capability to perform simultaneous MR imaging and therapy delivery with this system. Real-time control over therapy using MR temperature measurements acquired during heating can be implemented to achieve precise patterns of thermal damage within the prostate gland. The technical feasibility of using the system developed in this study for MRI-guided transurethral ultrasound therapy in a closed-bore MR imager has been demonstrated.

Prostate tissue analysis immediately following magnetic resonance imaging guided transurethral ultrasound thermal therapy.

PURPOSE: Preclinical experiments were performed in an acute canine model to analyze the spatial pattern of thermal damage generated in the prostate gland following treatment with a prototype magnetic resonance imaging guided transurethral ultrasound heating system. In particular the boundary of tissue coagulation was analyzed to quantify the treatment margin resulting from this technology. MATERIALS AND METHODS: A heating device incorporating a planar 20 x 3.5 mm transducer operated at 9.1 MHz was used to deliver ultrasound energy to targeted regions in the prostate gland in 7 animals monitored with magnetic resonance imaging thermometry during heating. The animals were sacrificed approximately 45 minutes after treatment. The thermal damage pattern was evaluated using contrast enhanced magnetic resonance imaging, vital tissue staining, and whole mount hematoxylin and eosin stained histological sections. An image warping technique enabled quantitative comparison of these data. RESULTS: Regions of thermal fixation, coagulative necrosis and hemorrhage were observed in the treated prostate glands. The extent of the necrotic region was relatively insensitive to vessel cooling effects. Metabolic enzyme functionality coincided with tissue outside of the treatment area. At the edge of the thermal damage pattern the transition from coagulative necrosis to no visible damage occurred within 3 mm or less. CONCLUSIONS: The narrow extent of the thermal margin suggests that tissue sparing outside of the prostate could be an advantage of this treatment. Histological measurements showed a high level of spatial accuracy, useful for developing accurate control techniques for directional transurethral ultrasound thermal therapy in the treatment of prostate diseases.