Ultrasound imaging guided precision histotripsy: Effects of pulse settings on ablation properties in rat brain.

A high-frequency 6 MHz miniature handheld histotripsy device with an endoscopic form factor and co-registered high-resolution ultrasound imaging was developed. This device could allow precision histotripsy ablation during minimally invasive brain tumor surgeries with real-time image guidance. This study characterized the outcome of acute histotripsy in the normal in vivo rat brain using the device with a range of histotripsy pulse settings, including number of cycles, pulse repetition frequency, and pressure, as well as other experimental factors. The stability and shape of the bubble cloud were measured during ablations, as well as the post-histotripsy ablation shape in ultrasound B-mode and histology. The results were compared between histological images and the ultrasound imaging data to determine how well ultrasound data reflected observable damage in histology. The results indicated that while pulse settings can have some influence on ablation shape, sample-to-sample variation had a larger influence on ablation shape. This suggests that real-time ablation monitoring is essential for accurate knowledge of outcomes. Ultrasound imaging provided an accurate real-time indication of ablation shape both during ablation and post-ablation.

An 8 mm endoscopic histotripsy array with integrated high-resolution ultrasound imaging.

An 8 mm diameter, image-guided, annular array histotripsy transducer was fabricated and characterized. The array was laser etched on a 5 MHz, 1-3 dice and fill, PZT-5H/epoxy composite with a 45 % volume fraction. Flexible PCBs were used to electrically connect to the array elements using wirebonds. The array was backed with a low acoustic impedance epoxy mixture. A 3.6 by 3.8 mm, 64-element, 30 MHz phased array imaging probe was positioned in the center hole, to co-align the imaging plane with the bubble cloud produced by the therapy array. A custom 16-channel high voltage pulse generator was used to test the annular array for focal lengths ranging from 3- to 8-mm. An aluminum lens-focussed transducer with a 7 mm focal length was fabricated using the same piezocomposite and backing material and tested along with the histotripsy array. Simulated results from COMSOL FEM models were compared to measured results for low voltage characterization of the array and lens-focussed transducer. The measured transmit sensitivity of the array ranged from 0.113 to 0.167 MPa/V, while the lens-focussed transducer was 0.192 MPa/V. Simulated values were 0.160 to 0.174 MPa/V and 0.169 MPa/V, respectively. The measured acoustic fields showed a significantly increased depth-of-field compared the lens-focussed transducer, while the beamwidths of the array focus were comparable to the lens. The measured cavitation voltage in water was between 254 V and 498 V depending on the focal length, and 336 V for the lens-focussed transducer. The array had a lower cavitation voltage than the lens-focussed transducer for a comparable operating depth. The histotripsy array was tested in a tissue phantom and an in vivo rat brain. It was used to produce an elongated lesion in the brain by electronically steering the focal length from 3- to 8-mm axially. Real time ultrasound imaging with a Doppler overlay was used to target the tissue and monitor ablation progress, and histology confirmed the targeted tissue was fully homogenized.

Fabrication and characterization of a flat aperture Fresnel lens based histotripsy transducer.

Two single element, 8 mm focal depth, 6 MHz PZT-5A 40% volume fraction 1-3 composite Fresnel aluminum lens based therapeutic ultrasound transducers for use in small animal histotripsy applications were built with 15 mm outer diameters - one with a central hole of 5.7 mm diameter for future co-registration and one full-aperture. The device was built with the front face filled with acoustically transparent epoxy to create a flat aperture allowing gel-coupling to tissue, where the Fresnel lens design allowed flattening of the aperture with minimal epoxy fill. Epoxy fill resulted in a 6% loss of focal pressure. The full-aperture device achieved 37 MPa/100 V peak-to-peak focal pressures with the removed center element device achieving 25 MPa/100V - a 32% reduction, which matches COMSOL simulated results. Pulsing between 190 V and 270 V at 17 cycles and 1 kHz PRF, the full-aperture device generated bubble clouds in water ranging from 0.31 mm to 0.51 mm radially, and 0.53 mm to 0.81 mm axially. Cavitation for the removed center element device was observed to begin at 370 V, and was consistent at 400 V.

A High-Performance 3-D Imaging Technique Using Simultaneous Azimuth and Elevation Compounding.

A new technique for 3-D imaging with a row-column array (RCA) configuration has been developed. The technique requires an electrostrictive piezoelectric for the active substrate. While the top set of electrodes is connected to RF transmit and receive channels for conventional diverging wave imaging (DWI), the orthogonal bottom set of electrodes is connected to independently controlled variable dc bias channels. By implementing modulated bias patterns compounded across multiple pulses, fine delay control across the bottom elements can be achieved simultaneously with imaging with the top set of electrodes. This resulted in a high-quality two-way focus in both azimuth and elevation. A 20-MHz electrostrictive composite substrate was fabricated, and 64 top ×64 bottom electrodes were patterned and connected to custom beamforming and biasing electronics. The point spread functions were generated in all dimensions, and the -6 dB resolution was measured to be 93 [Formula: see text] axially, [Formula: see text] in the azimuth, and 328 [Formula: see text] in the elevation dimension. This was in good agreement with the simulated resolutions of 80, 273, and 280 [Formula: see text], respectively.

A Real-Time Dual-Mode High-Frequency Beamformer for Ultrafast and Focused Imaging.

A firmware-based high-frequency beam- former implementing both conventional transmit focused B-mode imaging and diverging wave ultrafast (UF) imaging for Doppler overlay was developed. The beamformer can generate one transmit focused frame with four transmit focal zones (FZs), and 68 UF frames with 16 diverging waves each at a 10-Hz frame rate. The beamformer firmware stores the beamforming delays as a single bit, enabling efficient compression within the internal memory. The beamformer was characterized using a 30-MHz 64-element phased array endoscope. The hybrid system generates a 128 line by 768-pixel focused B-mode image spanning 1.2-12.6 mm axially over a ±32° range of steering angles. In addition, the system generates an UF image that is 64 lines by 384-pixels spanning 3.5-10.8 mm axially over a ±16° angle.

Fabrication and Characterization of a 5 mm × 5 mm Aluminum Lens-Based Histotripsy Transducer.

Two 5 mm by 5 mm square aluminum lenses with a 6 mm depth of focus were machined and tested for histotripsy with a 40% volume fraction 1-3 PZT-5A composite and a Meggitt Pz-39 porous ceramics lapped to 315 [Formula: see text] as the piezoelectric elements. The devices were air-backed, and an 89 [Formula: see text] layer of Parylene-C was deposited on the lens, matching aluminum to water. Both devices were driven single-ended at 5.8 MHz, their optimal frequency after bonding to the lens, with ten cycles at a PRF of 1 kHz. The composite-based device showed no sign of free-field cavitation in water up to a drive level of 600 V, whereas the Pz39-based device was able to cavitate in water at a drive level of 220 V. In vivo ablation of a rat brain tissue was demonstrated through an opening in the skull and required the drive voltage be increased to 280 V. The ablation was monitored using B-mode imaging with an endoscopic 30 MHz ultrasound phased array and power Doppler overlay. Ablation was maintained for 12 s and, in the power Doppler image, the ablation zone grew steadily over this time to 1.9 mm by 3.4 mm. Immediately after treatment, the ablated area appeared anechoic, slowly filling with specular material.

Endoscopic Coregistered Ultrasound Imaging and Precision Histotripsy: Initial In Vivo Evaluation.

Objective. Initial performance evaluation of a system for simultaneous high-resolution ultrasound imaging and focused mechanical submillimeter histotripsy ablation in rat brains. Impact Statement. This study used a novel combination of high-resolution imaging and histotripsy in an endoscopic form. This would provide neurosurgeons with unprecedented accuracy in targeting and executing nonthermal ablations in minimally invasive surgeries. Introduction. Histotripsy is a safe and effective nonthermal focused ablation technique. However, neurosurgical applications, such as brain tumor ablation, are difficult due to the presence of the skull. Current devices are too large to use in the minimally invasive approaches surgeons prefer. We have developed a combined imaging and histotripsy endoscope to provide neurosurgeons with a new tool for this application. Methods. The histotripsy component had a 10 mm diameter, operating at 6.3 MHz. Affixed within a cutout hole in its center was a 30 MHz ultrasound imaging array. This coregistered pair was used to ablate brain tissue of anesthetized rats while imaging. Histological sections were examined, and qualitative descriptions of ablations and basic shape descriptive statistics were generated. Results. Complete ablations with submillimeter area were produced in seconds, including with a moving device. Ablation progress could be monitored in real time using power Doppler imaging, and B-mode was effective for monitoring post-ablation bleeding. Collateral damage was minimal, with a 100 µm maximum distance of cellular damage from the ablation margin. Conclusion. The results demonstrate a promising hardware suite to enable precision ablations in endoscopic procedures or fundamental preclinical research in histotripsy, neuroscience, and cancer.

A Dual-Frequency Lens-Focused Endoscopic Histotripsy Transducer.

A forward-looking miniature histotripsy transducer has been developed that incorporates an acoustic lens and dual-frequency stacked transducers. An acoustic lens is used to increase the peak negative pressure through focal gain and the dual-frequency transducers are designed to increase peak negative pressure by summing the pressure generated by each transducer individually. Four lens designs, each with an f -number of approximately 1, were evaluated in a PZT5A composite transducer. The finite-element model (FEM) predicted axial beamwidths of 1.61, 2.40, 2.84, and 2.36 mm for the resin conventional, resin Fresnel, silicone conventional, and silicone Fresnel lenses, respectively; the measured axial beamwidths were 1.30, 2.28, 2.71, and 2.11 mm, respectively. Radial beamwidths from the model were between 0.32 and 0.35 mm, while measurements agreed to within 0.2 mm. The measured peak negative was 0.150, 0.124, 0.160, and 0.160 MPa/V for the resin conventional, resin Fresnel, silicone conventional, and silicone Fresnel lenses, respectively. For the dual-frequency device, the 5-MHz (therapy) transducer had a measured peak negative pressure of 0.136 MPa/V for the PZT5A composite and 0.163 MPa/V for the PMN-PT composite. The 1.2-MHz (pump) transducer had a measured peak negative pressure of 0.028 MPa/V. The pump transducer significantly lowered the cavitation threshold of the therapy transducer. The dual-frequency device was tested on an ex vivo rat brain, ablating tissue at up to 4-mm depth, with lesion sizes as small as [Formula: see text].

Ultrafast Phased-Array Imaging Using Sparse Orthogonal Diverging Waves.

We present a new transmit pulse encoding scheme for ultrafast phased-array imaging called sparse orthogonal diverging wave imaging (SODWI). In SODWI, Hadamard encoding is used to selectively invert transmit pulse phases beamformed with a diverging wave delay profile. This approach has the advantage of delivering energy to a much wider field of view than conventional Hadamard-encoded multielement synthetic transmit aperture (HMSTA), making it more suitable for phased-array applications. With SODWI, we use a synthetic transmit element delay insertion (STEDI) approach which produces significant improvements in resolution, grating lobe level, and signal-to-noise ratio (SNR) over HMSTA. We also show how in SODWI a subset of the Hadamard codes can be sparsely selected to increase the imaging frame rate at the expense of image quality. SODWI is then compared with a variety of beamforming schemes for phased-array applications, including HMSTA, STEDI-HMSTA, diverging wave imaging (DWI), synthetic aperture (SA), and focused imaging. We present the results by implementing this technique on a 64-channel custom beamforming platform with a 40-MHz phased array. When a full set of codes is used, SODWI outperforms focused imaging contrast and SNR by 2.7 and 1.8 dB in addition to an 8× increase in frame rate, respectively.

A Low-Cost Miniature Histotripsy Transducer for Precision Tissue Ablation.

A miniature, 10 mm aperture histotripsy transducer with an f-number of 0.7 was fabricated using an elliptically shaped aluminum lens, which was epoxy-bonded to an air-backed 5.0 MHz, PTZ-5A, 1-3 dice-and-fill piezoelectric composite, and the lens coupled to water using a quarter-wavelength matching layer of Parylene-C. A Krimholtz-Leedom-Matthaei model of the device and curved lens was developed. The epoxy layer resulted in an increased power output at 6.8 MHz compared to the 5 MHz composite design. Cavitation was observed in water by driving the composite with a 173 V single-cycle, unipolar 6.8 MHz pulse at a pulse repetition frequency of 50 Hz, and a bubble cloud 264 long by 124 wide was measured. A coregistered imaging and ablation device was also fabricated and characterized. The coregistered device was modified to include a mm square hole through the center, allowing access for a high-frequency imaging array, and both imaging and ablation are demonstrated in cerebral tissue with this device. Radial -3 dB beam widths were measured as 0.145 and 0.116 mm, and axial -3 dB depths of field were 0.698 and 0.752 mm for the noncoregistered and coregistered transducers, respectively. Total material cost for the transducer and pulser board is below $200 USD.

3D photoacoustic imaging using Hadamard-bias encoding with a crossed electrode relaxor array.

A novel 3D photoacoustic imaging technique is experimentally demonstrated using a 64×64 element bias-sensitive crossed-electrode relaxor array. This technique allows for large 2D arrays to receive across all elements while using minimal channel counts. Hadamard-bias patterns are applied to column electrodes while signals are measured from row electrodes. Photoacoustic signals are measured from a crossed-wire phantom in an intralipid scattering medium. The Hadamard-bias-encoded imaging scheme showed a signal-to-noise (SNR) of 25.3 dB, while the single-column biasing strategy (or identity-matrix-bias pattern) showed a SNR of 8.8 dB.

Simultaneous Azimuth and Fresnel Elevation Compounding: A Fast 3-D Imaging Technique for Crossed-Electrode Arrays.

We have developed a new, fast, and simple 3-D imaging approach referred to as Simultaneous Azimuth and Fresnel Elevation (SAFE) compounding using a bias-sensitive crossed-electrode array. The principle behind this technique is to perform conventional plane-wave compounding with a back set of electrodes, while implementing a reconfigurable Fresnel elevation lens with an orthogonal set of front electrodes. While a Fresnel lens would usually result in unacceptable secondary lobe levels, these lobes can be suppressed by compounding different Fresnel patterns. The azimuthal and elevational planes can be simultaneously compounded to increase the beam quality with no loss in frame rate. A 10-MHz, $64 \times 64$ element crossed-electrode relaxor array was fabricated on an electrostrictive one-to-three composite substrate to demonstrate the SAFE compounding approach. The electrostrictive composite array has a measured electromechanical coupling coefficient ( $k_{t}$ ) of 0.62 with a bias voltage of 90 V and a measured two-way pulse bandwidth of 60%. The electrical impedance magnitude of array elements on resonance was measured to be $90~\Omega$ with a phase angle of -35°. Radiation patterns were simulated showing a -6-dB beamwidth of $330~\mu \text{m}$ with secondary lobe levels suppressed more than -60 dB in the azimuth dimension, and a -6-dB beamwidth of $450~\mu \text{m}$ with secondary lobe levels suppressed to -50 dB in the elevation dimension after 64 compounds. Experimental radiation patterns were collected and found to be in good agreement with simulations. Experimental 3-D images of wire phantoms were collected using a Verasonics experimental ultrasound system.

No effect of prolonged pulsed high frequency ultrasound imaging of the basilar membrane on cochlear function or hair cell survival found in an initial study.

Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure.

Real-time intracochlear imaging of automated cochlear implant insertions in whole decalcified cadaver cochleas using ultrasound.

OBJECTIVES: This study aimed to determine the feasibility of combining high-frequency ultrasound imaging, automated insertion, and force sensing to yield more information about cochlear implant insertion dynamics. METHODS: An apparatus was developed combining these aspects along with software to control implant and imaging probe positions. Decalcified unfixed human cochleas were implanted at various speeds, insertion sites, and implant models while imaging near the implant tip throughout insertion and recording force data from the cochlea mounting stage. Ultrasound video data were also captured. RESULTS: The basilar membrane (BM) was frequently penetrated by the implant in either the mid-basal or lower middle turn. Measurements were also performed of apical BM motion in response to upstream implant movement at varying insertion speeds. Increasing insertion speed resulted in greater BM displacement. DISCUSSION: Multiple insertions per cochlea increase the volume of data per specimen while also reducing variability due to differences between cochleas. However, to image inside the cochlea with ultrasound, the bone had to be decalcified, which likely had a significant effect upon the response of tissue to contact by the implant. As calcified bone strongly reflects ultrasound, we also found ultrasound imaging to be an excellent method for easily assessing bone decalcification progress. CONCLUSION: This technique may be very useful for some studies, although the confounding effects of bone decalcification may make results of other studies too difficult to generalize. The approach could be adapted to other real-time imaging modalities, such as optical coherence tomography.

In vivo measurement of basilar membrane vibration in the unopened chinchilla cochlea using high frequency ultrasound.

The basilar membrane and organ of Corti in the cochlea are essential for sound detection and frequency discrimination in normal hearing. There are currently no methods used for real-time high resolution clinical imaging or vibrometry of these structures. The ability to perform such imaging could aid in the diagnosis of some pathologies and advance understanding of the causes. It is demonstrated that high frequency ultrasound can be used to measure basilar membrane vibrations through the round window of chinchilla cochleas in vivo. The basic vibration characteristics of the basilar membrane agree with previous studies that used other methods, although as expected, the sensitivity of ultrasound was not as high as optical methods. At the best frequency for the recording location, the average vibration velocity amplitude was about 4 mm/s/Pa with stimulus intensity of 50 dB sound pressure level. The displacement noise floor was about 0.4 nm with 256 trial averages (5.12 ms per trial). Although vibration signals were observed, which likely originated from the organ of Corti, the spatial resolution was not adequate to resolve any of the sub-structures. Improvements to the ultrasound probe design may improve resolution and allow the responses of these different structures to be better discriminated.

A Sub-Nyquist, Variable Sampling, High-Frequency Phased Array Beamformer.

A digital receive beamformer implementing a "one sample per pixel" variable sampling technique is described. The sampling method reduces the required sampling rates by a factor of 3, and reduces the data capture rate by a factor of 2, in comparison with the previous systems based on variable sampling. The sampling method is capable of estimating broadband pulse envelopes accurate for bandwidths up to 83.0%. This beamforming method has been implemented on a field-programmable gate array with maximum transmit and receive delay errors measured to be less than ±1.0 ns. The beamformer was tested and verified on a previously described 45-MHz 64-element phased array. The system generates images with 128 lines, 512 pixels per RF line, and 2 transmit focal zones. The system generates images with approximately 55 dB of dynamic range and was tested by imaging wire targets submersed in a water bath, wire targets embedded in a tissue phantom, and real-time in vivo imaging of a human wrist.

High Frequency Ex Vivo Ultrasound Imaging of the Middle Ear to Show Simulated Ossicular Pathology.

HYPOTHESIS: To illustrate the ability of high frequency ultrasound (HFUS) using a transducer array to demonstrate a variety of simulated clinical scenarios involving the ossicular chain. BACKGROUND: HFUS (>20 MHz) is a relatively new area of ultrasonic imaging that provides an order of magnitude better image resolution than the conventional low-frequency systems. HFUS may be a real-time imaging system that could be used in the clinic and would complement computed tomography (CT) and magnetic resonance imaging (MRI) to enhance the decision-making process for patients with middle ear pathology. METHODS: Using a commercially available HFUS scanner, we imaged a variety of simulated clinical scenarios to demonstrate the ability of HFUS to image middle ear pathology. RESULTS: We were able to clearly demonstrate real-time visualization of ossicular pathology in human temporal bones, whereas there are some limitations in the current technique to be addressed before it is used in vivo. CONCLUSION: HFUS allows excellent visualization of middle ear anatomy and pathology through an intact tympanic membrane (TM), and these experiments go some way towards giving the otologist access to high resolution, real-time imaging of the middle ear in the clinic.

Compensating for Tissue Changes in an Ultrasonic Power Link for Implanted Medical Devices.

Ultrasonic power transfer using piezoelectric devices is a promising wireless power transfer technology for biomedical implants. However, for sub-dermal implants where the separation between the transmitter and receiver is on the order of several acoustic wavelengths, the ultrasonic power transfer efficiency (PTE) is highly sensitive to the distance between the transmitter and receiver. This sensitivity can cause large swings in efficiency and presents a serious limitation on battery life and overall performance. A practical ultrasonic transcutaneous energy transfer (UTET) system design must accommodate different implant depths and unpredictable acoustic changes caused by tissue growth, hydration, ambient temperature, and movement. This paper describes a method used to compensate for acoustic separation distance by varying the transmit (Tx) frequency in a UTET system. In a benchtop UTET system we experimentally show that without compensation, power transfer efficiency can range from 9% to 25% as a 5 mm porcine tissue sample is manipulated to simulate in situ implant conditions. Using an active frequency compensation method, we show that the power transfer efficiency can be kept uniformly high, ranging from 20% to 27%. The frequency compensation strategy we propose is low-power, non-invasive, and uses only transmit-side measurements, making it suitable for active implanted medical device applications.

Real-time imaging of in-vitro human middle ear using high frequency ultrasound.

Imaging techniques currently used in the clinic to inspect ears in patients are generally limited to views terminating at the tympanic membrane (TM) surface. For imaging past the TM, methods such as computed tomography are typically used, but in addition to disadvantages such as being costly, time consuming, and causing radiation exposure, these often do not provide sufficient resolution of the middle ear structures of interest. This study presents an investigation into the capability of high frequency ultrasound to image the middle ear with high resolution in real-time, as well as measure vibrations of TM and middle ear structures in response to sound stimuli. In unfixed cadaver ears, the TM, ossicles, and ossicular support tissues were all readily identifiable, with capabilities demonstrated for real-time imaging and video capture, and vibrometry of middle ear structures. Based on these results, we conclude that high frequency ultrasonography is a relatively simple and minimally invasive technology with great potential to provide clinicians with new tools for diagnosing and monitoring middle ear pathologies.

Fabrication and performance of a single-crystal lead magnesium niobate-lead titanate cylindrical hydrophone.

The development of a piezoelectric hydrophone based on lead magnesium niobate-lead titanate [PbMg1/3Nb2/3O3-PbTiO3 (PMN-PT)] single-crystal piezoelectric as the hydrophone substrate is reported. Although PMN-PT can possess much higher piezoelectric sensitivity than traditional lead zirconate titanate (PZT) piezoelectrics, it is highly anisotropic and therefore there is a large gain in sensitivity only when the crystal structure is oriented in a specific direction. Because of this, simply replacing the PZT substrate with a PMN-PT cylinder is not an optimal solution because the crystal orientation does not uniformly align with the circumferential axis of the hydrophone. Therefore, a composite hydrophone that maintains the optimal crystal axis around the hydrophone circumference has been developed. An 11.3 mm diameter composite hydrophone cylinder was fabricated from a single <110> cut PMN-PT rectangular plate. Solid end caps were applied to the cylinder and the sensitivity was directly compared with a solid PZT-5A cylindrical hydrophone of equal dimensions in a hydrophone test tank. The charge sensitivity showed a 9.1 dB improvement over the PZT hydrophone and the voltage sensitivity showed a 3.5 dB improvement. This was in good agreement with the expected theoretical improvements of 10.1 and 4.5 dB, respectively.