Hydrophobic drug concentration affects the acoustic susceptibility of liposomes.

The purpose of this study was to investigate the effect of encapsulated hydrophobic drug concentration on ultrasound-mediated leakage from liposomes. Studies have shown that membrane modifications affect the acoustic susceptibility of liposomes, likely because of changes in membrane packing. An advantage of liposome as drug carrier is its ability to encapsulate drugs of different chemistries. However, incorporation of hydrophobic molecules into the bilayer may cause changes in membrane packing, thereby affecting the release kinetics. Liposomes containing calcein and varying concentrations of papaverine, a hydrophobic drug, were exposed to 20 kHz, 2.2 Wcm(-2) ultrasound. Papaverine concentration was observed to affect calcein leakage although the effects varied widely based on liposome phase. For example, incorporation of 0.5mg/mL papaverine into Ld liposomes increased the leakage of hydrophilic encapsulants by 3× within the first minute (p=0.004) whereas the same amount of papaverine increased leakage by only 1.5× (p<0.0001). Papaverine was also encapsulated into echogenic liposomes and its concentration did not significantly affect calcein release rates, suggesting that burst release from echogenic liposomes is predictable regardless of encapsulants chemistry and concentration.

Ultrasound transducer selection in clinical imaging practice.

Many types of medical ultrasound transducers are used in clinical practice. They operate at different center frequencies, have different physical dimensions, footprints, and shapes, and provide different image formats. However, little information is available about which transducers are most appropriate for a given application, and the purpose of this article is to address this deficiency. Specifically, the relationship between the transducer, imaging format, and clinical applications is discussed, and systematic selection criteria that allow matching of transducers to specific clinical needs are presented. These criteria include access to and coverage of the region of interest, maximum scan depth, and coverage of essential diagnostic modes required to optimize a patient's diagnosis. Three comprehensive figures organize and summarize the imaging planes, scanning modes, and types of diagnostic transducers to facilitate their selection in clinical diagnosis.

Low-frequency (<100 kHz), low-intensity (<100 mW/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments.

The purpose of this study was to examine whether low frequency (<100 kHz), low intensity (<100 mW/cm(2), spatial peak temporal peak) ultrasound can be an effective treatment of venous stasis ulcers, which affect 500 000 patients annually costing over $1 billion per year. Twenty subjects were treated with either 20 or 100 kHz ultrasound for between 15 and 45 min per session for a maximum of four treatments. Healing was monitored by changes in wound area. Additionally, two in vitro studies were conducted using fibroblasts exposed to 20 kHz ultrasound to confirm the ultrasound's effects on proliferation and cellular metabolism. Subjects receiving 20 kHz ultrasound for 15 min showed statistically faster (p < 0.03) rate of wound closure. All five of these subjects fully healed by the fourth treatment session. The in vitro results indicated that 20 kHz ultrasound at 100 mW/cm(2) caused an average of 32% increased metabolism (p < 0.05) and 40% increased cell proliferation (p < 0.01) after 24 h when compared to the control, non-treated cells. Although statistically limited, this work supports the notion that low-intensity, low-frequency ultrasound is beneficial for treating venous ulcers.

Design of Point-of-Care Ultrasound Device to be Used in at-Home Setting - A Holistic Approach.

The primary purpose of this work was to design and implement a compact, battery-powered, fully wearable applicator for delivering therapeutic low-frequency (20-40kHz), low-intensity (100mW/cm2 ISPTP) (LFLI) ultrasound to enable treatment of chronic wounds in home setting. Such a device does not currently exist, and in addition to engineering aspects associated with electromechanical design, its implementation requires a novel approach involving consideration of feedback received not only from healthcare professionals, but also caregivers. One strong motivation for the novel design approach is to enable individuals with chronic wounds to enhance self-care management of wounds in the home setting instead of a hospital or outpatient clinic setting. In the home setting, the device may be exposed to physical maltreatment, requiring precautions with respect to its sturdiness. Although the holistic approach presented have been applied to the design of an applicator for chronic wounds, the design considerations and execution are transferable to any device targeted for home use. The implementation exemplified here examines transformation of an early, relatively fragile design into a robust, time-programmable, safe tool. The modification, which includes comprehensive reconfiguration and redesign of the electronics driving a piezoelectric transducer is presented along with methodology devised with the field feedback obtained from focus groups. This feedback evinced that in addition to electrical engineering, an extensive background in mechanical engineering, material science, biology, and clinical practice is needed to fabricate an end-user friendly, quality-of-life improving, ergonomic device.

A Miniature Ultrasound Source for Neural Modulation.

This work describes a unique ultrasound (US) exposure system designed to create very localized ( [Formula: see text]) sound fields at operating frequencies that are currently being used for preclinical US neuromodulation. This system can expose small clusters of neuronal tissue, such as cell cultures or intact brain structures in target animal models, opening up opportunities to examine possible mechanisms of action. We modified a dental descaler and drove it at a resonance frequency of 96 kHz, well above its nominal operating point of 28 kHz. A ceramic microtip from an ultrasonic wire bonder was attached to the end of the applicator, creating a 100- [Formula: see text] point source. The device was calibrated with a polyvinylidene difluoride (PVDF) membrane hydrophone, in a novel, air-backed, configuration. The experimental results were confirmed by simulation using a monopole model. The results show a consistent decaying sound field from the tip, well-suited to neural stimulation. The system was tested on an existing neurological model, Drosophila melanogaster, which has not previously been used for US neuromodulation experiments. The results show brain-directed US stimulation induces or suppresses motor actions, demonstrated through synchronized tracking of fly limb movements. These results provide the basis for ongoing and future studies of US interaction with neuronal tissue, both at the level of single neurons and intact organisms.

Hydrophone Measurements for Biomedical Ultrasound Applications: A Review.

This article presents basic principles of hydrophone measurements, including mechanisms of action for various hydrophone designs, sensitivity and directivity calibration procedures, practical considerations for performing measurements, signal processing methods to correct for both frequency-dependent sensitivity and spatial averaging across the hydrophone sensitive element, uncertainty in hydrophone measurements, special considerations for high-intensity therapeutic ultrasound, and advice for choosing an appropriate hydrophone for a particular measurement task. Recommendations are made for information to be included in hydrophone measurement reporting.

Gene expression changes in therapeutic ultrasound-treated venous leg ulcers.

Introduction: Low-frequency, low-intensity ultrasound has been previously shown to promote healing of chronic wounds in humans, but mechanisms behind these effects are poorly understood. The purpose of this study was to evaluate gene expression differences in debrided human venous ulcer tissue from patients treated with low-frequency (20 kHz), low-intensity (100 mW/cm2) ultrasound compared to a sham treatment in an effort to better understand the potential biological mechanisms. Methods: Debrided venous ulcer tissue was collected from 32 subjects one week after sham treatment or low-frequency, low-intensity ultrasound treatment. Of these samples, 7 samples (3 ultrasound treated and 4 sham treated) yielded sufficient quality total RNA for analysis by ultra-high multiplexed PCR (Ampliseq) and expression of more than 24,000 genes was analyzed. 477 genes were found to be significantly differentially expressed between the ultrasound and sham groups using cut-off values of p < 0.05 and fold change of 2. Results and Discussion: The top differentially expressed genes included those involved in regulation of cell metabolism, proliferation, and immune cell signaling. Gene set enrichment analysis identified 20 significantly enriched gene sets from upregulated genes and 4 significantly enriched gene sets from downregulated genes. Most of the enriched gene sets from upregulated genes were related to cell-cell signaling pathways. The most significantly enriched gene set from downregulated genes was the inflammatory response gene set. These findings show that therapeutic ultrasound influences cellular behavior in chronic wounds as early as 1 week after application. Considering the well-known role of chronic inflammation in impairing wound healing in chronic wounds, these results suggest that a downregulation of inflammatory genes is a possible biological mechanism of ultrasound-mediated venous chronic wound healing. Such increased understanding may ultimately lead to the enhancement of ultrasound devices to accelerate chronic wound healing and increase patient quality of life.

Thin film metal coated fiber optic hydrophone probe.

Our purpose is to improve the performance sensitivity of a fiber sensor used as a fiber optic hydrophone probe (FOHP) by the addition of nanoscale thin film gold coating. The fiber is designed to provide a uniform and spatial averaging free response up to 100 MHz by etching down to an active diameter of approximately 9 mum. The performance sensitivity of straight cleaved (i.e., full size core and cladding) uncoated, tapered uncoated, and tapered thin film gold-coated fiber sensors was compared in the frequency range from 1.5 to 20 MHz in the presence of acoustic amplitude pressure levels as high as 6 MPa. An unprecedented voltage sensitivity of -245 dB relative to 1 V/muPa (560 mV/MPa) was measured for a thin film gold-coated FOHP by optimizing the gold coating thickness.

Improving broadband ultrasound attenuation assessment in cancellous bone by mitigating the influence of cortical bone: Phantom and in-vitro study.

The purpose of this work was to present a new approach that allows the influence of cortical bone on noninvasive measurement of broadband ultrasound attenuation (BUA) to be corrected. The method, implemented here at 1 MHz makes use of backscattered signal and once refined and clinically confirmed, it would offer an alternative to ionizing radiation based methods, such as DEXA (Dual-energy X-ray absorptiometry), quantitative computed tomography (QCT), radiographic absorptiometry (RA) or single X-ray absorptiometry (SXA), which are clinically approved for assessment of progress of osteoporosis. In addition, as the method employs reflected waves, it might substantially enhance the applicability of BUA - from being suitable to peripheral bones only it would extend this applicability to include such embedded bones as hip and femoral neck. The proposed approach allows the cortical layer parameters used for correction and the corrected value and parameter of the cancellous bone (BUA) to be determined simultaneously from the single (pulse-echo) bone backscattered wave; to the best of the authors' knowledge such approach was not previously reported. The validity of the method was tested using acoustic data obtained from a custom-designed bone-mimicking phantom and a calf femur. The relative error of the attenuation coefficient assessment was determined to be 3.9% and 4.7% for the bone phantom and calf bone specimens, respectively. When the cortical shell influence was not taken into account the corresponding errors were considerably higher 8.3% (artificial bone) and 9.2% (calf femur). As indicated above, once clinically proven, the use of this BUA measurement technique in reflection mode would augment diagnostic power of the attending physician by permitting to include bones, which are not accessible for transmission mode evaluation, e.g. hip, spine, humerus and femoral neck.

Development of Low Frequency (20-100 kHz) Clinically Viable Ultrasound Applicator for Chronic Wound Treatment.

This paper details the systematic approach used to develop a viable clinical prototype of a therapeutic ultrasound applicator and discusses the rationale and deliberations that led to the design strategy. The applicator was specifically devised to treat chronic wounds and-to the best of the author's knowledge-is the first truly wearable device with a proven record of reducing healing time, directly translating to a reduction of healthcare costs. The prototype operates in the kHz (20-100) range of frequencies and uses noncavitational and nonthermal levels of ultrasound energy. Hence, in the absence of inertial cavitation and temperature elevation, the tissue-ultrasound interaction is considered to be dependent on stable cavitation (if any) and radiation force. The peak acoustic output pressure amplitude is limited to 55 kPa, corresponding to a spatial peak-temporal peak intensity of 100 mW/cm2. This level of intensity is considered to be safe to apply for extended (up to 4 h) periods of time. The patch-like applicator design is suitable to be embedded in wound dressing. With its lightweight (<20 g) and circular (40 mm dia) disk-shape architecture, the applicator is well suited for chronic wound treatment. A small ( n = 8 ) pilot study on the effects of the applicator on diabetic ulcers (DUs) healing time is presented. The average time to wound closure was 4.7 weeks for subjects treated with the active ultrasound applicator, compared to 12 weeks for subjects treated with a sham applicator, suggesting that patients with DUs may benefit from the proposed treatment.

Effects of Non-thermal, Non-cavitational Ultrasound Exposure on Human Diabetic Ulcer Healing and Inflammatory Gene Expression in a Pilot Study.

The purpose of this clinical study was to assess, in a limited patient population, the potential for a novel advanced wound care treatment based on low-frequency (20 kHz) low-intensity (spatial peak temporal peak intensity <100 mW/cm2; i.e., pressure amplitude of 55 kPa) ultrasound (LFLI-US), to affect wound closure rate in human diabetic foot ulcers (DFUs) and to effect changes in the relative expression of pro-inflammatory and anti-inflammatory genes. The ratio of expression of these genes, termed the M1/M2 score because it was inspired by the transition of macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes as wound healing progresses, was previously presented as a potential healing indicator for DFUs treated with the standard of care. We previously found that non-cavitational, non-thermal LFLI-US delivered with a pulse repetition frequency of 25 Hz was effective at improving wound healing in a pilot study of 20 patients with chronic venous ulcers. In this study, we assessed the potential for weekly LFLI-US exposures to affect wound healing in patients with diabetic ulcers, and we analyzed temporal changes in the M1/M2 score in debrided diabetic wound tissue. Although this was a limited patient population of only 8 patients, wounds treated with LFLI-US exhibited a significantly faster reduction in wound size compared with sham-treated patients (p < 0.001). In addition, the value of the M1/M2 score decreased for all healing diabetic ulcers and increased for all non-healing diabetic ulcers, suggesting that the M1/M2 score could be useful as an indicator of treatment efficacy for advanced DFU treatments. Such an indicator would facilitate clinical decision making, ensuring optimal wound management and thus contributing to reduction of health care expenses. Moreover, the results presented may contribute to an understanding of the mechanisms underlying ultrasonically assisted chronic wound healing. Knowledge of these mechanisms could lead to personalized or patient-tailored treatment.

Low-intensity (400 mW/cm2, 500 kHz) pulsed transcranial ultrasound preconditioning may mitigate focal cerebral ischemia in rats.

BACKGROUND: Preconditioning methods, which could increase tolerance of brain to subsequent ischemic injuries with a small dose of non-injury stimuli, have gained attention. Capitalizing on noninvasiveness and safety of ultrasound modality, the pulsed transcranial ultrasound stimulation (pTUS) approach may provide a novel treatment for patients with high risk of stroke. OBJECTIVE: This study's goal was to investigate whether the risk of stroke could be minimized or eliminated by prior exposure to low-intensity, pulsed transcranial ultrasound stimulation (pTUS). METHODS: Rats were randomly assigned to control (n = 12) and pTUS preconditioning (pTUS-PC) groups (n = 14). The animals in pTUS-PC group were exposed to transcranial ultrasound stimulation before the induction of photothrombotic stroke, whereas control animals were handled identically but without the ultrasound stimulation. Cerebral blood flow was monitored using laser speckle imaging in both groups during stroke induction, as well as 24 and 48 h after stroke, respectively. Also, infarct volumes and edema were measured at 48 h after stroke. RESULTS: pTUS-PC rats had smaller ischemic areas during stroke induction, and 24 and 48 h after the stroke, and smaller infarct volume (1.770 ± 0.169%) than the controls (3.215 ± 0.401%) (p < 0.01). Moreover, the pTUS-PC group experienced lower volume of brain edema than the control group (pTUS-PC rats: 6.658 ± 1.183%; control rats: 12.48 ± 1.386%, p < 0.01). CONCLUSION: These results support the hypothesis that transcranial ultrasound stimulation applied before photothrombosis could provide neuroprotection by increasing the brain's tolerance to subsequently induced focal ischemic injury.

In vitro ultrasound experiments: Standing wave and multiple reflections influence on the outcome.

The purpose of this work was to determine the influence of standing waves and possible multiple reflections under the conditions often encountered in examining the effects of ultrasound exposure on the cell cultures in vitro. More specifically, the goal was to quantitatively ascertain the influence of ultrasound exposure under free field (FF) and standing waves (SW) and multiple reflections (MR) conditions (SWMR) on the biological endpoint (50% cell necrosis). Such information would help in designing the experiments, in which the geometry of the container with biological tissue may prevent FF conditions to be established and in which the ultrasound generated temperature elevation is undesirable. This goal was accomplished by performing systematic, side-by-side experiments in vitro with C6 rat glioma cancer cells using 12 well and 96 well plates. It was determined that to obtain 50% of cell viability using the 12 well plates, the spatial average, temporal average (ISATA) intensities of 0.32W/cm2 and 5.89W/cm2 were needed under SWMR and FF conditions, respectively. For 96 well plates the results were 0.80W/cm2 and 2.86W/cm2 respectively. The corresponding, hydrophone measured pRMS maximum pressure amplitude values, were 0.71MPa, 0.75MPa, 0.75MPa and 0.73MPa, respectively. These results suggest that pRMS pressure amplitude was independent of the measurement set-up geometry and hence could be used to predict the cells' mortality threshold under any in vitro experimental conditions or even as a starting point for (pre-clinical) in vivo tests. The described procedure of the hydrophone measurements of the pRMS maximum pressure amplitude at the λ/2 distance (here 0.75mm) from the cell's level at the bottom of the dish or plate provides the guideline allowing the difference between the FF and SWMR conditions to be determined in any experimental setup. The outcome of the measurements also indicates that SWMR exposure might be useful at any ultrasound assisted therapy experiments as it permits to reduce thermal effects. Although the results presented are valid for the experimental conditions used in this study they can be generalized. The analysis developed provides methodology facilitating independent laboratories to determine their specific ultrasound exposure parameters for a given biological end-point under standing waves and multiple reflections conditions. The analysis also permits verification of the outcome of the experiments mimicking pre- and clinical environment between different, unaffiliated teams of researchers.

Investigating the spatial extent of acoustically activated echogenic liposomes.

The purpose of this work was to investigate the ability of bubbles entrapped within echogenic liposomes (ELIP) to serve as foci for cavitational events that would cause leakage in neighboring non-echogenic liposomes (NELIP). Previous studies have shown that entrapping bubbles into liposomes increases ultrasound-mediated leakage of hydrophilic components at ultrasound settings known to induce inertial cavitation, specifically 20kHz and 2.2W/cm2. Using tone-burst approach and pulse repetition frequency of 10Hz would bring this intensity level to the one accepted (220mW/cm2) in clinical imaging. Mixed populations of ELIP and NELIP were simultaneously exposed to ultrasound at varying ratios to examine the effect of ELIP concentration on release of a hydrophilic dye, calcein, from NELIP. Calcein release from NELIP was observed to be independent of ELIP concentration, suggesting that the release enhancement from echogenicity is strictly a localized event. Additionally, it was observed that the release mechanisms independent of echogenicity were active for the duration of experiment whereas those associated with echogenicity were active for only the initial 1-2min.

The potential of ultrasound in cardiac pacing and rhythm modulation.

INTRODUCTION: This review examines the potential for ultrasound to induce or otherwise influence cardiac pacing and rhythm modulation. AREAS COVERED: Of particular interest is the possibility of developing new, truly non-invasive, nonpharmacological, acute and chronic, ultrasound-based arrhythmia treatments. Such approaches would not depend upon implanted or indwelling devices of any kind and would use ultrasound at diagnostic exposure levels (so as not to harm the heart or surrounding tissues). It is known that ultrasound can cause cardiomyocyte depolarization and a variety of underlying mechanisms have been proposed. Expert commentary: Questions still remain regarding the effect of exposure parameters and work will also be necessary to identify the optimal target regions within the heart if ultrasound energy is to be used to induce safe and reliable pacing in a clinical setting.

Determining temperature distribution in tissue in the focal plane of the high (>100 W/cm(2)) intensity focused ultrasound beam using phase shift of ultrasound echoes.

In therapeutic applications of High Intensity Focused Ultrasound (HIFU) the guidance of the HIFU beam and especially its focal plane is of crucial importance. This guidance is needed to appropriately target the focal plane and hence the whole focal volume inside the tumor tissue prior to thermo-ablative treatment and beginning of tissue necrosis. This is currently done using Magnetic Resonance Imaging that is relatively expensive. In this study an ultrasound method, which calculates the variations of speed of sound in the locally heated tissue volume by analyzing the phase shifts of echo-signals received by an ultrasound scanner from this very volume is presented. To improve spatial resolution of B-mode imaging and minimize the uncertainty of temperature estimation the acoustic signals were transmitted and received by 8 MHz linear phased array employing Synthetic Transmit Aperture (STA) technique. Initially, the validity of the algorithm developed was verified experimentally in a tissue-mimicking phantom heated from 20.6 to 48.6 °C. Subsequently, the method was tested using a pork loin sample heated locally by a 2 MHz pulsed HIFU beam with focal intensity ISATA of 129 W/cm(2). The temperature calibration of 2D maps of changes in the sound velocity induced by heating was performed by comparison of the algorithm-determined changes in the sound velocity with the temperatures measured by thermocouples located in the heated tissue volume. The method developed enabled ultrasound temperature imaging of the heated tissue volume from the very inception of heating with the contrast-to-noise ratio of 3.5-12 dB in the temperature range 21-56 °C. Concurrently performed, conventional B-mode imaging revealed CNR close to zero dB until the temperature reached 50 °C causing necrosis. The data presented suggest that the proposed method could offer an alternative to MRI-guided temperature imaging for prediction of the location and extent of the thermal lesion prior to applying the final HIFU treatment.

Experimental observation of acoustic emissions generated by a pulsed proton beam from a hospital-based clinical cyclotron.

PURPOSE: To measure the acoustic signal generated by a pulsed proton spill from a hospital-based clinical cyclotron. METHODS: An electronic function generator modulated the IBA C230 isochronous cyclotron to create a pulsed proton beam. The acoustic emissions generated by the proton beam were measured in water using a hydrophone. The acoustic measurements were repeated with increasing proton current and increasing distance between detector and beam. RESULTS: The cyclotron generated proton spills with rise times of 18 µs and a maximum measured instantaneous proton current of 790 nA. Acoustic emissions generated by the proton energy deposition were measured to be on the order of mPa. The origin of the acoustic wave was identified as the proton beam based on the correlation between acoustic emission arrival time and distance between the hydrophone and proton beam. The acoustic frequency spectrum peaked at 10 kHz, and the acoustic pressure amplitude increased monotonically with increasing proton current. CONCLUSIONS: The authors report the first observation of acoustic emissions generated by a proton beam from a hospital-based clinical cyclotron. When modulated by an electronic function generator, the cyclotron is capable of creating proton spills with fast rise times (18 µs) and high instantaneous currents (790 nA). Measurements of the proton-generated acoustic emissions in a clinical setting may provide a method for in vivo proton range verification and patient monitoring.

Enhanced therapeutic anti-inflammatory effect of betamethasone on topical administration with low-frequency, low-intensity (20 kHz, 100 mW/cm(2)) ultrasound exposure on carrageenan-induced arthritis in a mouse model.

The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm(2), spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery-powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose. The outcome of the experiments indicated that the combination of ultrasound exposure and topical application of 0.1% (w/w) betamethasone gel resulted in statistically significantly (p < 0.05) enhanced anti-inflammatory activity in comparison with drug or ultrasound treatment alone. The present study underscores the potential benefits of low-frequency, low-intensity ultrasound-assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, tolerable low-frequency, low-intensity ultrasound-promoted non-invasive drug delivery.

Ultrasound-induced modulation of cardiac rhythm in neonatal rat ventricular cardiomyocytes.

Isolated neonatal rat ventricular cardiomyocytes were used to study the influence of ultrasound on the chronotropic response in a tissue culture model. The beat frequency of the cells, varying from 40 to 90 beats/min, was measured based upon the translocation of the nuclear membrane captured by a high-speed camera. Ultrasound pulses (frequency = 2.5 MHz) were delivered at 300-ms intervals [3.33 Hz pulse repetition frequency (PRF)], in turn corresponding to 200 pulses/min. The intensity of acoustic energy and pulse duration were made variable, 0.02-0.87 W/cm(2) and 1-5 ms, respectively. In 57 of 99 trials, there was a noted average increase in beat frequency of 25% with 8-s exposures to ultrasonic pulses. Applied ultrasound energy with a spatial peak time average acoustic intensity (Ispta) of 0.02 W/cm(2) and pulse duration of 1 ms effectively increased the contraction rate of cardiomyocytes (P < 0.05). Of the acoustic power tested, the lowest level of acoustic intensity and shortest pulse duration proved most effective at increasing the electrophysiological responsiveness and beat frequency of cardiomyocytes. Determining the optimal conditions for delivery of ultrasound will be essential to developing new models for understanding mechanoelectrical coupling (MEC) and understanding novel nonelectrical pacing modalities for clinical applications.

Probing acoustic fields of clinically relevant transducers: the effect of hydrophone probes' finite apertures and bandwidths.

The influence of finite aperture and frequency response of piezoelectric ultrasonic hydrophone probes on the free-field pulse intensity integral (PII) and mechanical index (MI) was investigated using a comprehensive acoustic wave propagation model. The model developed was capable of predicting the true pressure-time waveforms at virtually any point in the field. The input to the model used pressure amplitude data measured in the immediate vicinity of the acoustic source or transducer considered. The experimental verification of the model was obtained using a commercially available, 8 MHz, dynamically focused linear array and a single element, 5 MHz, focused rectangular source. The verification was performed at low and high excitation levels, corresponding to linear and nonlinear acoustic wave propagation, respectively. The pressure-time waveforms were recorded using piezoelectric polymer hydrophone probes that had different sensitivities, frequency responses, bandwidths, and active element diameters. The nominal diameters of the probes ranged from 50 to 500 microm, and their useable bandwidths varied between 55 and 100 MHz. The PII, used to calculate the thermal index (TI), was found to increase with increasing bandwidth and decreasing effective aperture of the probes. The MI, another safety indicator, also was affected, but to a lesser extent. The corrections predicted using the model were used to reduce discrepancies as large as 30% in the determination of PII. The results of this work indicate that, by accounting for hydrophones' finite aperture and correcting the value of PII, all intensities derived from the PII can be corrected for spatial averaging error. The results also point out that caution should be exercised when comparing acoustic output data. In particular, hydrophone's frequency characteristics of the effective diameter and sensitivity are needed to correctly determine the MI, TI, and the total acoustic output power produced by an imaging transducer.