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Earthworm, Lumbricus Terrestris: A Novel Microinjection Vasculature In vivo Invertebrate Model

Although vertebrates are indispensable to biomedical research, studies are often limited by factors such as cost, lengthy internal review, and ethical ...

US Food and Drug Administration

The parameters affecting the temperature rise in an insonified absorber are studied computationally. Finite-element and analytical solutions are obtained for the transient energy equation in a cylindrical absorber. When the ultrasound beam radius is less than the radius of the absorber, the temperature field is seen to be considerably more complex than when the absorber cross section is uniformly heated. Circumstances in which power predictions based upon uniform heating would result in appreciable error are identified. The rise time required to achieve equilibrium is studied as a function of operational parameters, including absorber geometry and thermal properties as well as ultrasound beamwidth and frequency. The rise time is seen to increase approximately as the square of the absorber length, while optimized temperature rise increases linearly with absorber length, demonstrating a tradeoff in ultrasound power determination via equilibrium temperature measurements: longer lengths produce higher sensitivity, but also longer times before measurements can be made. A transient technique that may bypass this tradeoff is suggested.

A theoretical assessment of a thermal technique to measure acoustic power radiated by ultrasound transducers.

The transient temperature rise at a bone/soft-tissue interface is an important quantity in the safety evaluation of procedures involving trains of high-intensity ultrasound pulses. Mathematical models based upon the time-averaged intensity of the pulse train can provide rapid estimates of the temperature rise, but are known to underestimate the temperature rise during the on-time of the pulse. This paper extends a previous analytical model to account for pulse shape, and provides error estimates for simulations employing time-averaged intensities. A simple analytic expression for the interface temperature that accounts for both bone and soft-tissue properties is provided. The analytic expression agrees well with temperature rise predictions based upon the finite-element method, when the insonation time is large compared to the pulse repetition period. In this case of large relative insonation time, the pulse shape is found to be inconsequential.

Effect of pulse characteristics on temperature rise due to ultrasound absorption at a bone/soft-tissue interface.

A method for fast numerical simulation of high-intensity focused ultrasound beams is derived. The method is based on the frequency-domain representation of the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation, and assumes for each harmonic a Gaussian transverse pressure distribution at all distances from the transducer face. The beamwidths of the harmonics are constrained to vary inversely with the square root of the harmonic number, and as such this method may be viewed as an extension of a quasilinear approximation. The technique is capable of determining pressure or intensity fields of moderately nonlinear high-intensity focused ultrasound beams in water or biological tissue, usually requiring less than a minute of computer time on a modern workstation. Moreover, this method is particularly well suited to high-gain simulations since, unlike traditional finite-difference methods, it is not subject to resolution limitations in the transverse direction. Results are shown to be in reasonable agreement with numerical solutions of the full KZK equation in both tissue and water for moderately nonlinear beams.

Gaussian representation of high-intensity focused ultrasound beams.

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.

Characterization of high intensity focused ultrasound transducers using acoustic streaming.

Two techniques are presented for noninvasively determining the intensity field of high-intensity focused ultrasound transducers in a liquid medium. The techniques are based upon the streaming velocity induced in the liquid by the absorbed ultrasound beam. The approaches are similar to an iterative streaming method previously reported, but the present approaches are "direct:" The differential operations of the Navier-Stokes equations are performed directly upon the experimentally measured streaming velocity, rather than through an iterative approach that minimizes the difference between a theoretical estimate of the streaming velocity and the one measured experimentally. As such, the direct methods are much faster than the iterative technique. The price paid for the increase in speed is smaller spatial coverage; the direct techniques are applicable only where accurate streaming velocity is available. Comparisons performed in the range 100-1000 W/cm(2) focal intensity showed differences between the direct methods and the iterative streaming technique to be less than 20%. Similar differences were observed in low-power comparisons with hydrophone measurements.

Direct methods for characterizing high-intensity focused ultrasound transducers using acoustic streaming.

In assessing the influence of nonlinear acoustic propagation on thermal bioeffects, approximate methods for quickly estimating the temperature rise as operational parameters are varied can be very useful. This paper provides a formula for the transient temperature rise associated with nonlinear propagation of Gaussian beams. The pressure amplitudes for the Gaussian modes can be obtained rapidly using a method previously published for simulating nonlinear propagation of Gaussian beams. The temperature-mode series shows that the nth temperature mode generated by nonlinear propagation, when normalized by the fundamental, is weaker than the nth heat-rate mode (also normalized by the fundamental in the heat-rate series) by a factor of log(n)/n, where n is the mode number. Predictions of temperature rise and thermal dose were found to be in close agreement with full, finite-difference calculations of the pressure fields, temperature rise, and thermal dose. Applications to non-Gaussian beams were made by fitting the main lobe of the significant modes to Gaussian functions.

Temperature modes for nonlinear Gaussian beams.

Experiments and computations were performed to study factors affecting thermal safety when high-intensity focused ultrasound (HIFU) beams are normally incident (i.e., beam axis normal to the interface) upon a bone/soft-tissue interface. In particular, the temperature rise and thermal dose were determined as a function of separation between the beam focus and the interface. Under conditions representative of clinical HIFU procedures, it was found that the thermal dose at the bone surface can exceed the threshold for necrosis even when the beam focus is more than 4 cm from the bone. Experiments showed that reflection of the HIFU beam from the bone back into the transducer introduced temperature fluctuations of as much as +/-15% and may be an important consideration for safety analyses at sufficiently high acoustic power. The applicability of linear propagation models in predicting thermal dose near the interface was also addressed. Linear models, while underpredicting thermal dose at the focus, provided a conservative (slight overprediction) estimate of thermal dose at the bone surface. Finally, temperature rise due to absorption of shear waves generated by the HIFU beam in the bone was computed. Modeling shear-wave propagation in the thermal analysis showed that the predicted temperature rise off axis was as much as 30% higher when absorption of shear waves is included, indicating that enhanced heating due to shear-wave absorption is potentially important, even for normally incident HIFU beams.

Thermal effects generated by high-intensity focused ultrasound beams at normal incidence to a bone surface.

In the characterization of high-intensity focused ultrasound (HIFU) systems, it is desirable to know the intensity field within a tissue phantom. Infrared (IR) thermography is a potentially useful method for inferring this intensity field from the heating pattern within the phantom. However, IR measurements require an air layer between the phantom and the camera, making inferences about the thermal field in the absence of the air complicated. For example, convection currents can arise in the air layer and distort the measurements relative to the phantom-only situation. Quantitative predictions of intensity fields based upon IR temperature data are also complicated by axial and radial diffusion of heat. In this paper, mathematical expressions are derived for use with IR temperature data acquired at times long enough that noise is a relatively small fraction of the temperature trace, but small enough that convection currents have not yet developed. The relations were applied to simulated IR data sets derived from computed pressure and temperature fields. The simulation was performed in a finite-element geometry involving a HIFU transducer sonicating upward in a phantom toward an air interface, with an IR camera mounted atop an air layer, looking down at the heated interface. It was found that, when compared to the intensity field determined directly from acoustic propagation simulations, intensity profiles could be obtained from the simulated IR temperature data with an accuracy of better than 10%, at pre-focal, focal, and post-focal locations.

Theoretical framework for quantitatively estimating ultrasound beam intensities using infrared thermography.

In the event of a public-health threat involving bioaerosols, such as a terrorist attack or pandemic, options for devices to protect the pediatric population are limited. One strategy involves deployment of facemasks meant for the pediatric population, although protection against bioaerosols was not an intended use of such masks and little is known about their effectiveness.

Effectiveness of facemasks for pediatric populations against submicron-sized aerosols.

Ultrasound-enhanced drug delivery through the cornea has considerable therapeutic potential. However, our understanding of how ultrasound enhances drug transport is poor, as is our ability to predict the increased level of transport for given ultrasound parameters. Described here is a computational model for quantifying changes in corneal porosity during ultrasound exposure. The model is calibrated through experiments involving sodium fluorescein transport through rabbit cornea. Validation was performed using nylon filters, for which the properties are known. It was found that exposure to 800-kHz ultrasound at an intensity 2 W/cm for 5 min increased the porosity of the epithelium by a factor of 5. The model can be useful for determining the extent to which ultrasound enhances the amount of drug transported through biological barriers, and the time at which a therapeutic dose is achieved at a given location, for different drugs and exposure strategies.

Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery.

A "credible" computational fluid dynamics (CFD) model has the potential to provide a meaningful evaluation of safety in medical devices. One major challenge in establishing "model credibility" is to determine the required degree of similarity between the model and experimental results for the model to be considered sufficiently validated. This study proposes a "threshold-based" validation approach that provides a well-defined acceptance criteria, which is a function of how close the simulation and experimental results are to the safety threshold, for establishing the model validity. The validation criteria developed following the threshold approach is not only a function of Comparison Error, E (which is the difference between experiments and simulations) but also takes in to account the risk to patient safety because of E. The method is applicable for scenarios in which a safety threshold can be clearly defined (e.g., the viscous shear-stress threshold for hemolysis in blood contacting devices). The applicability of the new validation approach was tested on the FDA nozzle geometry. The context of use (COU) was to evaluate if the instantaneous viscous shear stress in the nozzle geometry at Reynolds numbers (Re) of 3500 and 6500 was below the commonly accepted threshold for hemolysis. The CFD results ("S") of velocity and viscous shear stress were compared with inter-laboratory experimental measurements ("D"). The uncertainties in the CFD and experimental results due to input parameter uncertainties were quantified following the ASME V&V 20 standard. The CFD models for both Re = 3500 and 6500 could not be sufficiently validated by performing a direct comparison between CFD and experimental results using the Student's t-test. However, following the threshold-based approach, a Student's t-test comparing |S-D| and |Threshold-S| showed that relative to the threshold, the CFD and experimental datasets for Re = 3500 were statistically similar and the model could be considered sufficiently validated for the COU. However, for Re = 6500, at certain locations where the shear stress is close the hemolysis threshold, the CFD model could not be considered sufficiently validated for the COU. Our analysis showed that the model could be sufficiently validated either by reducing the uncertainties in experiments, simulations, and the threshold or by increasing the sample size for the experiments and simulations. The threshold approach can be applied to all types of computational models and provides an objective way of determining model credibility and for evaluating medical devices.

Use of the FDA nozzle model to illustrate validation techniques in computational fluid dynamics (CFD) simulations.

Blenderized diets are gaining increasing popularity among enteral tube users. Connectors in gastrostomy tubes (G-tubes) are undergoing standardization to reduce misconnections. These standardized G-tubes are referred to as ENFit G-tubes. This study was performed to quantify the in vitro performance of existing (legacy) G-tubes and compare them with ENFit G-tubes for blenderized diets.

Article	Year
A theoretical assessment of a thermal technique to measure acoustic power radiated by ultrasound transducers. IEEE transactions on ultrasonics, ferroelectrics, and frequency control\| PubMed ID: 12046932	2002
Effect of pulse characteristics on temperature rise due to ultrasound absorption at a bone/soft-tissue interface. The Journal of the Acoustical Society of America\| PubMed ID: 15957794	2005
Gaussian representation of high-intensity focused ultrasound beams. The Journal of the Acoustical Society of America\| PubMed ID: 18189543	2007
Characterization of high intensity focused ultrasound transducers using acoustic streaming. The Journal of the Acoustical Society of America\| PubMed ID: 18345858	2008
Direct methods for characterizing high-intensity focused ultrasound transducers using acoustic streaming. The Journal of the Acoustical Society of America\| PubMed ID: 19045669	2008
Temperature modes for nonlinear Gaussian beams. The Journal of the Acoustical Society of America\| PubMed ID: 19603899	2009
Thermal effects generated by high-intensity focused ultrasound beams at normal incidence to a bone surface. The Journal of the Acoustical Society of America\| PubMed ID: 20059000	2010
Theoretical framework for quantitatively estimating ultrasound beam intensities using infrared thermography. The Journal of the Acoustical Society of America\| PubMed ID: 21682428	2011
Effectiveness of facemasks for pediatric populations against submicron-sized aerosols. American journal of infection control\| PubMed ID: 26022658	2015
Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery. Ultrasound in medicine & biology\| PubMed ID: 28335999	2017
Use of the FDA nozzle model to illustrate validation techniques in computational fluid dynamics (CFD) simulations. PloS one\| PubMed ID: 28594889	2017
Impact of Design Changes in Gastrostomy Tube (G-tube) Devices for Patients Who Rely on Home-Based Blenderized Diets for Enteral Nutrition. Journal of the American College of Nutrition\| PubMed ID: 30821589	2019

Matthew R. Myers

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