Development and characterization of polyurethane-based tissue and blood mimicking materials for high intensity therapeutic ultrasound.

A polyurethane-based tissue mimicking material (TMM) and blood mimicking material (BMM) for the acoustic and thermal characterization of high intensity therapeutic ultrasound (HITU) devices has been developed. Urethane powder and other chemicals were dispersed into either a high temperature hydrogel matrix (gellan gum) or degassed water to form the TMM and BMM, respectively. The ultrasonic properties of both TMM and BMM, including attenuation coefficient, speed of sound, acoustical impedance, and backscatter coefficient, were characterized at room temperature. The thermal conductivity and diffusivity, BMM viscosity, and TMM Young's modulus were also measured. Importantly, the attenuation coefficient has a nearly linear frequency dependence, as is the case for most soft tissues and blood at 37 °C. Their mean values are 0.61f1.2 dB cm-1 (TMM) and 0.2f1.1 dB cm-1 (BMM) based on measurements from 1 to 8 MHz using a time delay spectrometry (TDS) system. Most of the other relevant physical parameters are also close to the reported values of soft tissues and blood. These polyurethane-based TMM and BMM are appropriate for developing standardized dosimetry techniques, validating numerical models, and determining the safety and efficacy of HITU devices.

Survey of Acoustic Output in Neonatal Brain Protocols.

BACKGROUND: Auditory and non-auditory safety concerns associated with the appreciable sound levels inherent to magnetic resonance imaging (MRI) procedures exist for neonates. However, current gaps in knowledge preclude making an adequate risk assessment. PURPOSE: To measure acoustic exposure (duration, intensity, and frequency) during neonatal brain MRI and compare these values to existing hearing safety limits and data. STUDY TYPE: Phantom. PHANTOM: Cylindrical doped water phantom. FIELD STRENGTH/SEQUENCE: Neonatal brain protocols acquired at 1-3 T. Scans in the model protocol included a diffusion tensor imaging scan, a gradient echo, a three-dimensional (3D) fast spin echo, 3D fast spin-echo single-shots, a spin echo, a turbo spin echo, a 3D arterial spin labeling scan, and a susceptibility-weighted fast spin-echo scan. ASSESSMENT: The sound pressure levels (SPLs), frequency profile, and durations of five neonatal brain protocols on five MR scanners (scanner A [3 T, whole-body], scanner B [1.5 T, whole-body], scanner C [1 T, dedicated neonatal], scanner D [1.5 T, whole-body], and scanner E [3 T, whole-body]) located at three different sites were recorded. The SPLs were then compared to the International Electrotechnical Commission (IEC) hearing safety limit and existing data of infant non-auditory responses to loud sounds to assess risk. STATISTICAL TESTS: Mann-Whitney U test to assess whether the dedicated neonatal scanner was quieter than the other machines. RESULTS: The average level A-weighted equivalent value (LAEQ) across all five MR scanners and scans was 92.88 dBA and the range of LAEQs across all five MR scanners and scans was 80.8-105.31 dBA. The duration of the recorded neonatal protocols maintained by neonatal scanning facilities (from scanners A, B, and C) ranged from 27:33 to 37:06 minutes. DATA CONCLUSION: Neonatal protocol sound levels straddled existing notions of risk, exceeding sound levels known to cause non-auditory responses in neonates but not exceeding the IEC MRI SPL safety limit. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5.

A closer look at ultrasonic attenuation and heating in a tissue-mimicking material.

A well-characterized ultrasound tissue-mimicking material (TMM) can be important in determining the acoustic output and temperature rise from high intensity therapeutic ultrasound (HITU) devices and also in validating computer simulation models. A HITU TMM previously developed and characterized in our laboratory has been used in our acoustic and temperature measurements as well as modeled in our HITU simulation program. A discrepancy between thermal measurement and simulation, though, led us to further investigate the TMM properties. We found that the 2-parameter analytic fit commonly used to represent the attenuation of the TMM in the computer modeling was not adequate over the entire frequency range of interest, 1 MHz to 8 MHz in this study, indicating that we and others may have not been characterizing TMMs, and possibly tissue, optimally. By comparing measurements and simulations, we found that a 3-parameter analytic fit for attenuation gave a more accurate value for attenuation at 1 MHz and 2 MHz, and using that fit the temperature rise measurements in the TMM that agreed more closely with the simulation results.

Broadband characterization of plastic and high intensity therapeutic ultrasound phantoms using time delay spectrometry-With validation using Kramers-Kronig relations.

Time delay spectrometry (TDS) is extended for broadband characterization of plastics (low-density polyethylene, LDPE) and tissue-mimicking material (TMM). The results suggest that TDS and the conventional broadband pulse method give comparable measurements for frequency-dependent attenuation coefficient and phase velocity near the center frequency, where signal-to-noise ratio is high. However, TDS measurements show enhanced bandwidth for attenuation coefficient of 30%-40% (LDPE) and 89%-100% (TMM) and for phase velocity of 43% (LDPE) and 36% (TMM) for a single transmitter/receiver pair. In addition, TDS provides measurements of dispersion that are consistent with predictions based on the Kramers-Kronig relations to within 5 m/s over the band from 2 to 12 MHz in LDPE and to within 1 m/s in TMM over the band from 0.5 to 29 MHz.

Thermochromic tissue-mimicking phantom for optimisation of thermal tumour ablation.

Purpose The purpose of this study was to (1) develop a novel tissue-mimicking thermochromic (TMTC) phantom that permanently changes colour from white to magenta upon heating above ablative temperatures, and (2) assess its utility for specific applications in evaluating thermal therapy devices. Materials and methods Polyacrylamide gel mixed with thermochromic ink was custom made to produce a TMTC phantom that changes its colour upon heating above biological ablative temperatures (> 60 °C). The thermal properties of the phantom were characterised, and compared to those of human tissue. In addition, utility of this phantom as a tool for the assessment of laser and microwave thermal ablation was examined. Results The mass density, thermal conductivity, and thermal diffusivity of the TMTC phantom were measured as 1033 ± 1.0 kg/m(3), 0.590 ± 0.015 W/m.K, and 0.145 ± 0.002 mm(2)/s, respectively, and found to be in agreement with reported values for human soft tissues. Heating the phantom with laser and microwave ablation devices produced clearly demarcated regions of permanent colour change geographically corresponding to regions with temperature elevations above 60 °C. Conclusion The TMTC phantom provides direct visualisation of ablation dynamics, including ablation volume and geometry as well as peak absolute temperatures within the treated region post-ablation. This phantom can be specifically tailored for different thermal therapy modalities, such as radiofrequency, laser, microwave, or therapeutic ultrasound ablation. Such modality-specific phantoms may enable better quality assurance, device characterisation, and ablation parameter optimisation, or optimise the study of dynamic heating parameters integral to drug device combination therapies relying upon heat.

Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields.

For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively).

Correction for frequency-dependent hydrophone response to nonlinear pressure waves using complex deconvolution and rarefactional filtering: application with fiber optic hydrophones.

Nonlinear acoustic signals contain significant energy at many harmonic frequencies. For many applications, the sensitivity (frequency response) of a hydrophone will not be uniform over such a broad spectrum. In a continuation of a previous investigation involving deconvolution methodology, deconvolution (implemented in the frequency domain as an inverse filter computed from frequency-dependent hydrophone sensitivity) was investigated for improvement of accuracy and precision of nonlinear acoustic output measurements. Timedelay spectrometry was used to measure complex sensitivities for 6 fiber-optic hydrophones. The hydrophones were then used to measure a pressure wave with rich harmonic content. Spectral asymmetry between compressional and rarefactional segments was exploited to design filters used in conjunction with deconvolution. Complex deconvolution reduced mean bias (for 6 fiber-optic hydrophones) from 163% to 24% for peak compressional pressure (p+), from 113% to 15% for peak rarefactional pressure (p-), and from 126% to 29% for pulse intensity integral (PII). Complex deconvolution reduced mean coefficient of variation (COV) (for 6 fiber optic hydrophones) from 18% to 11% (p+), 53% to 11% (p-), and 20% to 16% (PII). Deconvolution based on sensitivity magnitude or the minimum phase model also resulted in significant reductions in mean bias and COV of acoustic output parameters but was less effective than direct complex deconvolution for p+ and p-. Therefore, deconvolution with appropriate filtering facilitates reliable nonlinear acoustic output measurements using hydrophones with frequency-dependent sensitivity.

Improved measurement of acoustic output using complex deconvolution of hydrophone sensitivity.

The traditional method for calculating acoustic pressure amplitude is to divide a hydrophone output voltage measurement by the hydrophone sensitivity at the acoustic working frequency, but this approach neglects frequency dependence of hydrophone sensitivity. Another method is to perform a complex deconvolution between the hydrophone output waveform and the hydrophone impulse response (the inverse Fourier transform of the sensitivity). In this paper, the effects of deconvolution on measurements of peak compressional pressure (p+), peak rarefactional pressure (p_), and pulse intensity integral (PII) are studied. Time-delay spectrometry (TDS) was used to measure complex sensitivities from 1 to 40 MHz for 8 hydrophones used in medical ultrasound exposimetry. These included polyvinylidene fluoride (PVDF) spot-poled membrane, needle, capsule, and fiber-optic designs. Subsequently, the 8 hydrophones were used to measure a 4-cycle, 3 MHz pressure waveform mimicking a pulsed Doppler waveform. Acoustic parameters were measured for the 8 hydrophones using the traditional approach and deconvolution. Average measurements (across all 8 hydrophones) of acoustic parameters from deconvolved waveforms were 4.8 MPa (p+), 2.4 MPa (p_), and 0.21 mJ/cm(2) (PII). Compared with the traditional method, deconvolution reduced the coefficient of variation (ratio of standard deviation to mean across all 8 hydrophones) from 29% to 8% (p+), 39% to 13% (p_), and 58% to 10% (PII).

Effects of ultrasound and ultrasound contrast agent on vascular tissue.

BACKGROUND: Ultrasound (US) imaging can be enhanced using gas-filled microbubble contrast agents. Strong echo signals are induced at the tissue-gas interface following microbubble collapse. Applications include assessment of ventricular function and virtual histology. AIM: While ultrasound and US contrast agents are widely used, their impact on the physiological response of vascular tissue to vasoactive agents has not been investigated in detail. METHODS AND RESULTS: In the present study, rat dorsal aortas were treated with US via a clinical imaging transducer in the presence or absence of the US contrast agent, Optison. Aortas treated with both US and Optison were unable to contract in response to phenylephrine or to relax in the presence of acetylcholine. Histology of the arteries was unremarkable. When the treated aortas were stained for endothelial markers, a distinct loss of endothelium was observed. Importantly, terminal deoxynucleotidyl transferase mediated dUTP nick-end-labeling (TUNEL) staining of treated aortas demonstrated incipient apoptosis in the endothelium. CONCLUSIONS: Taken together, these ex vivo results suggest that the combination of US and Optison may alter arterial integrity and promote vascular injury; however, the in vivo interaction of Optison and ultrasound remains an open question.

Pulsed high-intensity-focused US and tissue plasminogen activator (TPA) versus TPA alone for thrombolysis of occluded bypass graft in swine.

PURPOSE: Prosthetic arteriovenous or arterial-arterial bypass grafts can thrombose and be resistant to revascularization. A thrombosed bypass graft model was created to evaluate the potential therapeutic enhancement and safety profile of pulsed high-intensity-focused ultrasound (pHIFU) on pharmaceutical thrombolysis. MATERIALS AND METHODS: In swine, a right carotid-carotid expanded polytetrafluoroethylene bypass graft was surgically constructed, containing a 40% stenosis at its distal end to induce graft thrombosis. The revascularization procedure was performed 7 days after surgery. After model development and dose response experiments (n = 11), two cohorts were studied: pHIFU with tissue plasminogen activator (TPA; n = 4) and sham pHIFU with TPA (n = 3). The experiments were identical in both groups except no energy was delivered in the sham pHIFU group. Serial angiograms were obtained in all cases. The area of graft opacified by contrast medium on angiograms was quantified with digital image processing software. A blinded reviewer calculated the change in the graft area opacified by contrast medium and expressed it as a percentage, representing percentage of thrombolysis. RESULTS: Combining pHIFU with 0.5 mg of TPA resulted in a 52% ± 4% increase in thrombolysis on angiograms obtained at 30 minutes, compared with a 9% ± 14% increase with sham pHIFU and 0.5 mg TPA (P = .003). Histopathologic examination demonstrated no differences between the groups. CONCLUSIONS: Thrombolysis of occluded bypass grafts was significantly increased when combining pHIFU and TPA versus sham pHIFU and TPA. These results suggest that application of pHIFU may augment thrombolysis with a reduced time and dose.

Time-delay spectrometry measurement of magnitude and phase of hydrophone response.

A method based on time-delay spectrometry (TDS) was developed for measuring both magnitude and phase response of a hydrophone. The method was tested on several types of hydrophones used in medical ultrasound exposimetry over the range from 5 to 18 MHz. These included polyvinylidene fluoride (PVDF) spot-poled membrane, needle, and capsule designs. One needle hydrophone was designed for high-intensity focused ultrasound (HIFU) applications. The average reproducibility (after repositioning the hydrophone) of the phase measurement was 2.4°. The minimum-phase model, which implies that the phase response is equal to the inverse Hilbert transform of the natural logarithm of the magnitude response, was tested with TDS hydrophone data. Direct TDS-based measurements of hydrophone phase responses agreed well with calculations based on the minimum-phase model, with rms differences of 1.76° (PVDF spot-poled membrane hydrophone), 3.10° (PVDF capsule hydrophone), 3.43° (PVDF needle hydrophone), and 3.36° (ceramic needle hydrophone) over the range from 5 to 18 MHz. Therefore, phase responses for several types of hydrophones may be inferred from measurements of their magnitude responses. Calculation of phase response based on magnitude response using the minimumphase model is a relatively simple and practical alternative to direct measurement of phase.

Development and characterization of a tissue-mimicking material for high-intensity focused ultrasound.

A tissue-mimicking material (TMM) for the acoustic and thermal characterization of high-intensity focused ultrasound (HIFU) devices has been developed. The material is a high-temperature hydrogel matrix (gellan gum) combined with different sizes of aluminum oxide particles and other chemicals. The ultrasonic properties (attenuation coefficient, speed of sound, acoustical impedance, and the thermal conductivity and diffusivity) were characterized as a function of temperature from 20 to 70°C. The backscatter coefficient and nonlinearity parameter B/A were measured at room temperature. Importantly, the attenuation coefficient has essentially linear frequency dependence, as is the case for most mammalian tissues at 37°C. The mean value is 0.64f(0.95) dB·cm(-1) at 20°C, based on measurements from 2 to 8 MHz. Most of the other relevant physical parameters are also close to the reported values, although backscatter signals are low compared with typical human soft tissues. Repeatable and consistent temperature elevations of 40°C were produced under 20-s HIFU exposures in the TMM. This TMM is appropriate for developing standardized dosimetry techniques, validating numerical models, and determining the safety and efficacy of HIFU devices.

Egg white as a blood coagulation surrogate.

Egg white, a protein-containing solution, is characterized as a blood coagulation surrogate for the acoustical and thermal evaluation of therapeutic ultrasound, especially high intensity focused ultrasound (HIFU) devices. Physical properties, including coagulation temperature, frequency dependent attenuation, sound speed, viscosity, and thermal properties, were measured as a function of temperature (20-95 degrees C). Thermal coagulation and attenuation (5-12 and 1 MHz) of cow blood, pig blood, and human blood also were assessed and compared with egg white. For a 30 s thermal exposure, both egg white and blood samples (3 mm thickness) started to denature at 65 degrees C and coagulate into an elastic gel at 85 degrees C. The attenuation of egg white was found to be similar to that of the blood samples, having values of 0.23f(1.09), 1.58f(0.61), and 2.7f(0.5) dB/cm at 20, 75, and 95 degrees C, respectively. This significant attenuation increase with temperature was determined to be caused mainly by bubble cavity formation. The other temperature-dependent parameters are also similar to the reported values for blood. These properties make egg white a potentially useful bench testing tool for the safety and efficacy evaluation of therapeutic ultrasound devices.

Development and characterization of a blood mimicking fluid for high intensity focused ultrasound.

A blood mimicking fluid (BMF) has been developed for the acoustic and thermal characterizations of high intensity focused ultrasound (HIFU) ablation devices. The BMF is based on a degassed and de-ionized water solution dispersed with low density polyethylene microspheres, nylon particles, gellan gum, and glycerol. A broad range of physical parameters, including attenuation coefficient, speed of sound, viscosity, thermal conductivity, and diffusivity, were characterized as a function of temperature (20-70 degrees C). The nonlinear parameter B/A and backscatter coefficient were also measured at room temperature. Importantly, the attenuation coefficient is linearly proportional to the frequency (2-8 MHz) with a slope of about 0.2 dB cm(-1) MHz(-1) in the 20-70 degrees C range as in the case of human blood. Furthermore, sound speed and bloodlike backscattering indicate the usefulness of the BMF for ultrasound flow imaging and ultrasound-guided HIFU applications. Most of the other temperature-dependent physical parameters are also close to the reported values in human blood. These properties make it a unique HIFU research tool for developing standardized exposimetry techniques, validating numerical models, and determining the safety and efficacy of HIFU ablation devices.

Characterization of high intensity focused ultrasound transducers using acoustic streaming.

A new approach for characterizing high intensity focused ultrasound (HIFU) transducers is presented. The technique is based upon the acoustic streaming field generated by absorption of the HIFU beam in a liquid medium. The streaming field is quantified using digital particle image velocimetry, and a numerical algorithm is employed to compute the acoustic intensity field giving rise to the observed streaming field. The method as presented here is applicable to moderate intensity regimes, above the intensities which may be damaging to conventional hydrophones, but below the levels where nonlinear propagation effects are appreciable. Intensity fields and acoustic powers predicted using the streaming method were found to agree within 10% with measurements obtained using hydrophones and radiation force balances. Besides acoustic intensity fields, the streaming technique may be used to determine other important HIFU parameters, such as beam tilt angle or absorption of the propagation medium.

An ultrasonic time-delay spectrometry system employing digital processing.

Time-delay spectrometry (TDS) is a swept-frequency technique that has proven useful in several ultrasonic applications. Commercial TDS systems are available, but only in the audio frequency range. Several ultrasonic research TDS systems have been constructed, and they have been used effectively for substitution calibration of hydrophones and for measurement of attenuation and sound velocity in materials. Unfortunately these systems depend on features of commercial equipment no longer manufactured, so a new system has been designed using modern equipment and straightforward signal processing. This system requires a frequency source with a reasonably linear sweep of frequency versus time, audio frequency filters, a standard double-balanced mixer, a power splitter, a waveform digitizer capable of handling audio frequency signals, and a personal computer. An optional implementation that shifts the signal to a lower frequency for more convenient digitization and easier velocity measurements additionally requires an audio frequency oscillator and an audio-range analog multiplier. The processing steps are performed with standard signal processing software. To demonstrate the operation of the system, substitution calibration measurements of hydrophones as well as attenuation measurements on a tissue mimicking material were obtained and compared to a custom TDS system previously described by the authors. The data from these two TDS systems agree to within +/- 0.5 dB in the 1-10 MHz frequency range used. Higher frequency source transducers could be used to extend this range.

Acoustic power calibration of high-intensity focused ultrasound transducers using a radiation force technique.

To address the challenges associated with measuring the ultrasonic power from high-intensity focused ultrasound transducers via radiation force, a technique based on pulsed measurements was developed and analyzed. Two focused ultrasound transducers were characterized in terms of an effective duty factor, which was then used to calculate the power during the pulse at high applied power levels. Two absorbing target designs were used, and both gave comparable results and displayed no damage and minimal temperature rise if placed near the transducer and away from the focus. The method yielded reproducible results up to the maximum pulse power generated of approximately 230 W, thus allowing the radiated power to be calibrated in terms of the peak-to-peak voltage applied to the transducer.

Optical monitoring of ultrasound-induced bioeffects in glass catfish.

This study is an investigation of the therapeutic ultrasound (US) effects on the blood vessels of optically transparent fish in vivo. Although many investigators have characterized cavitation in vivo using remote-sensing methods (i.e., measuring the acoustic emissions caused by oscillating bubbles) very few have made direct observations of cavitation-induced damage. Anesthetized glass catfish, which are optically transparent, was injected with the contrast agent, Optison, and then insonified at pressures that ranged from 0.5-10 MPa (peak negative pressures). Two focused transducers were used in these experiments to cover a frequency range of 0.7-3.3 MHz. Sonications were pulsed with pulse durations of 100, 10, 1, 0.1 and 0.01 ms and a pulse repetition frequency (PRF) of 1 Hz. The entire length of one sonication at a specific pressure level was 20 s. An inverted microscope combined with a digital camera and video monitor were used optically to monitor and record US interaction with the blood vessels in the tail of the anesthetized fish at 200x magnification. The effects of the burst sonication were analyzed visually at each pressure level. For the 1.091-MHz sonications, the first type of damage that occurred due to the US interaction was structural damage to the cartilage rods that comprise the tail of the fish, and was characterized by a disintegration of the lining of the rod. Damage to the rods occurred, starting at 3.5 MPa, 3.1 MPa, 4.1 MPa and 5.5 MPa for the 100-ms, 10-ms, 1-ms and 100-micros sonications, respectively. The formation of large gas bubbles was observed in the blood vessels of the fish at threshold values of 3.8 MPa, 3.8 MPa and 5.3 MPa, for the 100-ms, 10-ms and 1-ms sonications, respectively. Neither gas bubble formation nor hemorrhaging was observed during 100-micros sonications. Bubble formation was always accompanied by an increase of damage to the rods at the area surrounding the bubble. At 1.091 MHz, petechial hemorrhage thresholds were observed at 4.1 MPa, 4.1 MPa and 6.1 MPa, respectively, for the three pulse durations. The thresholds for damage were the lowest for the 0.747-MHz sonications: they were 2.6 MPa for damage to the rods, 3.7 MPa for gas bubble formation and 2.4 MPa for hemorrhaging.

High-frequency backscatter and attenuation measurements of porcine erythrocyte suspensions between 30-90 MHz.

There are now diagnostic ultrasonic imaging devices that operate at very high frequencies (VHF) of 20 MHz and beyond for clinical applications in ophthalmology, dermatology and vascular surgery. To be able to better interpret these images and to further the development of these devices, knowledge of ultrasonic attenuation and scattering of biologic tissues, such as blood, in the high-frequency range is crucial. VHF attenuation and backscatter experiments were made on porcine red blood cell (RBC) suspensions, for which much data on attenuation and backscatter can be found in the literature in the lower frequency range. Attenuation and backscatter at hematocrits of 6%, 10%, 15%, 20%, 25% and 30% from 30 to 90 MHz were measured using a modified substitution method that allows the utilization of focused transducers. The results show that the attenuation coefficient from all suspensions increased linearly with frequency and the backscatter coefficient for low hematocrit suspensions was found to have a maximum between 10% and 15%. At higher hematocrits, a decrease in the frequency-dependence was observed, possibly indicating that Rayleigh scattering is no longer valid because the wavelength in the VHF range is comparable to the size of a porcine RBC.