Institute of Fundamental Technological Research

In research and industrial processes, it is increasingly common practice to combine multiple measurement modalities. Nevertheless, experimental tools that allow the co-linear combination of optical and ultrasonic transmission have rarely been reported. The aim of this study was to develop and characterise a water-matched ultrasound transducer architecture using standard components, with a central optical window larger than 10 mm in diameter allowing for optical transmission. The window can be used to place illumination or imaging apparatus such as light guides, miniature cameras, or microscope objectives, simplifying experimental setups.

Four design variations of a basic architecture were fabricated and characterised with the objective to assess whether the variations influence the acoustic output. The basic architecture consisted of a piezoelectric ring and a glass disc, with an aluminium casing. The designs differed in piezoelectric element dimensions: inner diameter, ID = 10 mm, outer diameter, OD = 25 mm, thickness, TH = 4 mm or ID = 20 mm, OD = 40 mm, TH = 5 mm; glass disc dimensions OD = 20–50 mm, TH = 2–4 mm; and details of assembly.

The transducers’ frequency responses were characterised using electrical impedance spectroscopy and pulse-echo measurements, the acoustic propagation pattern using acoustic pressure field scans, the acoustic power output using radiation force balance measurements, and the acoustic pressure using a needle hydrophone. Depending on the design and piezoelectric element dimensions, the resonance frequency was in the range 350–630 kHz, the −6 dB bandwidth was in the range 87–97%, acoustic output power exceeded 1 W, and acoustic pressure exceeded 1 MPa peak-to-peak.

3D stress simulations were performed to predict the isostatic pressure required to induce material failure and 4D acoustic simulations. The pressure simulations indicated that specific design variations could sustain isostatic pressures up to 4.8 MPa.The acoustic simulations were able to predict the behaviour of the fabricated devices. A total of 480 simulations, varying material dimensions (piezoelectric ring ID, glass disc diameter, glass thickness) and drive frequency indicated that the emitted acoustic profile varies nonlinearly with these parameters.

Ultrasound transducer, De-fouling, Optical window, Acoustic field simulation

Studying the effects of ultrasound on biological cells requires extensive knowledge of both the physical ultrasound and cellular biology. Translating knowledge between these fields can be complicated and time consuming. With the vast range of ultrasonic equipment available, nearly every research group uses different or unique devices. Hence, recreating the experimental conditions and results may be expensive or difficult. For this reason, we have developed devices to combat the common problems seen in state-of-the-art biomedical ultrasound research. In this paper, we present the design, fabrication, and characterisation of an open-source device that is easy to manufacture, allows for parallel sample sonication, and is highly reproducible, with complete acoustic calibration. This device is designed to act as a template for sample sonication experiments. We demonstrate the fabrication technique for devices designed to sonicate 24-well plates and OptiCell™ using three-dimensional (3D) printing and low-cost consumables. We increased the pressure output by electrical impedance matching of the transducers using transmission line transformers, resulting in an increase by a factor of 3.15. The devices cost approximately €220 in consumables, with a major portion attributed to the 3D printing, and can be fabricated in approximately 8 working hours. Our results show that, if our protocol is followed, the mean acoustic output between devices has a variance of <1%. We openly provide the 3D files and operation software allowing any laboratory to fabricate and use these devices at minimal cost and without substantial prior know-how.

Sonoporation, experimentation devices, rapid prototyping, ultrasound transducers

Single clouds of cavitation bubbles, driven by 254 kHz focused ultrasound at pressure amplitudes in the range of 0.48–1.22 MPa, have been observed via high-speed shadowgraphic imaging at 1 × 106 frames per second. Clouds underwent repetitive growth, oscillation and collapse (GOC) cycles, with shock-waves emitted periodically at the instant of collapse during each cycle. The frequency of cloud collapse, and coincident shock-emission, was primarily dependent on the intensity of the focused ultrasound driving the activity. The lowest peak-to-peak pressure amplitude of 0.48 MPa generated shock-waves with an average period of 7.9 ± 0.5 μs, corresponding to a frequency of f0/2, half-harmonic to the fundamental driving. Increasing the intensity gave rise to GOC cycles and shock-emission periods of 11.8 ± 0.3, 15.8 ± 0.3, 19.8 ± 0.2 μs, at pressure amplitudes of 0.64, 0.92 and 1.22 MPa, corresponding to the higher-order subharmonics of f0/3, f0/4 and f0/5, respectively. Parallel passive acoustic detection, filtered for the fundamental driving, revealed features that correlated temporally to the shock-emissions observed via high-speed imaging, p(two-tailed) < 0.01 (r = 0.996, taken over all data). Subtracting the isolated acoustic shock profiles from the raw signal collected from the detector, demonstrated the removal of subharmonic spectral peaks, in the frequency domain. The larger cavitation clouds (>200 μm diameter, at maximum inflation), that developed under insonations of peak-to-peak pressure amplitudes >1.0 MPa, emitted shock-waves with two or more fronts suggesting non-uniform collapse of the cloud. The observations indicate that periodic shock-emissions from acoustically driven cavitation clouds provide a source for the cavitation subharmonic signal, and that shock structure may be used to study intra-cloud dynamics at sub-microsecond timescales.

Acoustic cavitation, Subharmonic, Cloud dynamics, Collapse, Shock-wave

Introduction
High-intensity focused ultrasound is finding increasing therapeutic use. However, the frequencies at which it operates are typically limited to below 5 MHz, preventing research into therapy with ultrahigh spatial precision. A reason for this is that the design and fabrication of high-frequency biomedical ultrasound transducers to produce high intensities is an engineering challenge, especially for operating frequencies above 30 MHz, primarily because of the acoustic impedance mismatch and the high attenuation of water of 6dB/cm at 50 MHz leading to a low penetration depth. Commonly used materials such as PZT do not have the ability to produce a high enough intensity, due to de-poling or cracking. A potential application of high-intensity high-frequency ultrasound is non-invasive microsurgery.

Methods
To overcome these problems, we used Y-36o Lithium Niobate (LiNbO3). This crystal has a high Curie temperature and is much more difficult to de-pole at high-power inputs. In addition, Y-36o LiNbO3 has a resonant frequency of 3.3 MHz mm-1, thus allowing for much thicker elements at higher frequencies compared to PZT. A bowl transducer was manufactured using a total of 7 0.5-mm thick elements (4 hexagonal and 5 pentagonal) with a maximum width of 25 mm. The bowl had a curvature radius of 50 mm. The transducer was microballoon-backed in order to simplify the manufacturing process. The pentagonal elements were linked and driven by a 50-dB amplifier, whereas the hexagonal elements were linked and driven by a 55-dB amplifier. To test the available working frequency; single element transducers were manufactured with element thickness ranging from 500 μm to 200 μm, having working frequencies between 6.6 MHz and 20 MHz.

Results
The multi-element focused transducer generated a modulated sound field with an enveloped wavelength of 550 kHz at a frequency of 6.6 MHz with a maximum peak-to-peak pressure of 24.3 MPa; equivalent to mechanical index of 4.7. The modulation could be varied by changing the phase of either the pentagonal or hexagonal linked elements. The microballoon-backed transducers had a 5% reduced acoustic output compared to the air-backed transducer. Single- element transducers produced a maximum peak-to-peak pressure of 14 MPa at 6.3 MHz in the acoustic focus at 12 mm. These transducers were capable of producing over 6 MPa and 4 MPa at the 3rd and 5th harmonics, respectively, corresponding to frequencies of 21 MHz and 35 MHz.

Conclusion
We have established that manufacturing a high frequency, high intensity, multi-element, focused ultrasound transducer using LiNbO3 is feasible. We have also shown it is possible to use the resonant frequency and up to the 5th harmonic to achieve higher working frequencies.

High-frequency ultrasound, Ultrasound transducer, MR-guided Focussed Ultrasound Surgery

Focused ultrasound surgery (FUS) is usually based on frequencies below 5 MHz—typically around 1 MHz. Although this allows good penetration into tissue, it limits the minimum lesion dimensions that can be achieved. In this study, we investigate devices to allow FUS at much higher frequencies, in principle, reducing the minimum lesion dimensions. Furthermore, FUS can produce deep-sub-millimeter demarcation between viable and necrosed tissue; high-frequency devices may allow this to be exploited in super cial applications which may include dermatology, ophthalmology, treatment of the vascular system, and treatment of early dysplasia in epithelial tissue. In this paper, we explain the methodology we have used to build high-frequency high-intensity transducers using Y-36°-cut lithium niobate. This material was chosen because its low losses give it the potential to allow very-high- frequency operation at harmonics of the fundamental operating frequency. A range of single-element transducers with center frequencies between 6.6 and 20.0 MHz were built and the transducers’ e ciency and acoustic power output were measured. A focused 6.6-MHz transducer was built with multiple elements operating together and tested using an ultrasound phantom and MRI scans. It was shown to increase phantom temperature by 32°C in a localized area of 2.5 × 3.4 mm in the plane of the MRI scan. Ex vivo tests on poultry tissue were also performed and shown to create lesions of similar dimensions. This study, therefore, demonstrates that it is feasible to produce high-frequency transducers capable of high-resolution FUS using lithium niobate.

Lithium Niobite, Ultrasound Transducer, MRI-Guided ultrasound, Microsurgery

Glass windowed ultrasound transducers have several potential uses ranging from multi-modal research (ultrasound and optics) to industrial application in oil and gas or chemistry. In our work here we compare four different designs for transparent glass windowed ultrasound transducers. Each design was characterised using field scanning, radiation force measurements, frequency sensitivity measurement and FEM simulations. Field scans showed that small variations in design can greatly affect the size and location of the acoustic focus. The results coincided with those seen in the simulations. Radiation force measurements showed that the devices were able to easily exceed acoustic powers of 10W, with efficiencies of up to 40%. Isostatic simulations shows that the design also affects the physical strength of the devices. Current designs were able to withstand between 300 and 700 psi on the front surface. The devices were cost effective due to the minimal amount of materials necessary and the simple fabrication process. More work needs to be done to improve the power output and stress handling capabilities.

Ultrasound transducer

Focused ultrasound surgery (FUS) is usually based on frequencies below 5 MHz, typically around 1 MHz. Whilst this allows good penetration into tissue, it limits the minimum lesion dimensions that can be achieved. In the study reported here, we investigated devices to allow FUS at much higher frequencies, therefore in principle reducing the minimum lesion dimensions. We explain the methodology we have used to build high-frequency high-intensity transducers using Y-36o cut lithium niobate. This material was chosen as its low losses give it the potential to allow very high-frequency operation at harmonics of the fundamental operating frequency. A range of single element transducers with a centre frequency between 6.6 MHz and 20.0 MHz was built and the transducers’ efficiency and acoustic power output were measured. A focussed 6.6-MHz transducer was built with multiple elements operated together and tested using an ultrasound phantom and MRI scans. It was shown to increase phantom temperature by 32OC in a localised area of 2.5 mm × 3.4 mm in the plane of the MRI scan. This study therefore demonstrates that it is feasible to produce high-frequency transducers capable of high-resolution focused ultrasound surgery using lithium niobate.

FUS, high frequency, lithium niobate, high resolution, transducer manufacture, MRI compatibility