Noninvasive calibrated tissue temperature estimation using backscattered energy of acoustic harmonics.

PURPOSE: A real-time and non-invasive thermometry technique is essential in thermal therapies to monitor and control the treatment. Ultrasound is an attractive thermometry modality due to its relatively high sensitivity to change in temperature and fast data acquisition and processing capabilities. A temperature-sensitive acoustic parameter is required for ultrasound thermometry in order to track the changes in that parameter during the treatment. Currently, the main ultrasound thermometry methods are based on variation in the attenuation coefficient, the change in backscattered energy of the signal (CBE), the backscattered radio-frequency (RF) echo-shift due to change in the speed of sound and thermal expansion of the medium, and change in the amplitudes of the acoustic harmonics. In this work, an ultrasound thermometry method based on second harmonic CBE (CBEh2) and combined fundamental and second harmonic CBE (CBEcomb) is used to produce 2D temperature maps, detect localized heated region generated by low intensity focused ultrasound (LIFU), and control temperature in the heated region. MATERIALS AND METHODS: Ex vivo pork muscle tissue samples were exposed to localized LIFU heating source and 2D temperature maps were produced from the RF data acquired by a 4.2 MHz linear array probe using a Verasonics Vantage™ ultrasound scanner (Verasonics Inc., Redmond, WA) after the exposure. Calibrated needle thermocouples were also placed in the ex vivo tissue sample close to the LIFU focal zone for temperature calibration purposes. The estimated temperature maps were the established echo-shift technique. A tissue motion compensation algorithm was also used to reduce the susceptibility to motion artifacts. RESULTS: 2D temperature maps were generated using CBE of acoustic harmonic and echo-shift techniques. The results show a direct correlation between the CBE of acoustic harmonics and focal tissue temperature for a range of temperatures from 37 °C (baseline) to 47 °C. CONCLUSIONS: The findings of this study show that the CBE of acoustic harmonics technique can be used to noninvasively estimate temperature change in tissue in the hyperthermia temperature range.

A novel photoacoustic-fluorescent contrast agent for quantitative imaging of lymphatic drainage.

In vivo near-infrared (NIR) photoacoustic imaging (PAI) studies using novel contrast agents require validation, often via fluorescence imaging. Bioconjugation of NIR dyes to proteins is a versatile platform to obtain contrast agents for specific biomedical applications. Nonfluorescent NIR dyes with higher photostability present advantages for quantitative PAI, compared to most fluorescent NIR dyes. However, they don't provide a fluorescence signal required for fluorescence imaging. Here, we designed a hybrid PA-fluorescent contrast agent by conjugating albumin with a NIR nonfluorescent dye (QC-1) and a visible spectrum fluorescent dye, a BODIPY derivative. The new hybrid tracer QC-1/BSA/BODIPY (QBB) had a low minimum detectable concentration (2.5µM), a steep linear range (2.4-54.4 µM; slope 3.39 E -5), and high photostability. Tracer signal was measured in vivo using PAI to quantify its drainage from eye to the neck and its localization in the neck lymph node was validated with postmortem fluorescence imaging.

The role of morphology and coupling of gold nanoparticles in optical breakdown during picosecond pulse exposures.

This paper presents a theoretical study of the interaction of a 6 ps laser pulse with uncoupled and plasmon-coupled gold nanoparticles. We show how the one-dimensional assembly of particles affects the optical breakdown threshold of its surroundings. For this purpose we used a fully coupled electromagnetic, thermodynamic and plasma dynamics model for a laser pulse interaction with gold nanospheres, nanorods and assemblies, which was solved using the finite element method. The thresholds of optical breakdown for off- and on-resonance irradiated gold nanosphere monomers were compared against nanosphere dimers, trimers, and gold nanorods with the same overall size and aspect ratio. The optical breakdown thresholds had a stronger dependence on the optical near-field enhancement than on the mass or absorption cross-section of the nanostructure. These findings can be used to advance the nanoparticle-based nanoscale manipulation of matter.

Investigating longitudinal changes in the mechanical properties of MCF-7 cells exposed to paclitaxol using particle tracking microrheology.

Evidence suggests that compression and shear wave elastography are sensitive to the mechanical property changes occuring in dying cells following chemotherapy, and can hence be used to monitor cancer treatment response. A qualitative and quantitative understanding of the mechanical changes at the cellular level would allow to better infer how these changes affect macroscopic tissue mechanical properties and therefore allow the optimization of elastographic techniques (such as shear wave elastography) for the monitoring of cancer therapy. We used intracellular particle tracking microrheology (PTM) to investigate the mechanical property changes of cells exposed to paclitaxol, a mitotic inhibitor used in cancer chemotherapy. The average elastic and viscous moduli of the cytoplasm of treated MCF-7 breast cancer cells were calculated for frequency ranges between 0.2 and 100 rad s(-1) (corresponding to 0.03 and 15.92 Hz, respectively). A significant increase in the complex shear modulus of the cell cytoplasm was detected at 12 h post treatment. At 24 h after drug exposure, the elastic and viscous moduli increased by a total of 191.3 Pa (>8000×) and 9 Pa (∼9×), respectively for low frequency shear modulus measurements (at 1 rad s(-1)). At higher frequencies (10 rad s(-1)), the elastic and viscous moduli increased by 188.5 Pa (∼60×) and 1.7 Pa (∼1.1×), respectively. Our work demonstrates that PTM can be used to measure changes in the mechanical properties of treated cells and that cell elasticity significantly increases by 24 h after chemotherapy exposure.

Steady flow through a constricted cylinder by multiparticle collision dynamics.

The flow characterization of blood through healthy and diseased flow geometries is of interest to researchers and clinicians alike, as it may allow for early detection, and monitoring, of cardiovascular disease. In this paper, we use a numerically efficient particle-based flow model called multiparticle collision dynamics (MPC for short) to study the effect of compressibility and slip of flow of a Newtonian fluid through a cylinder with a local constriction. We use a cumulative averaging method to compare our MPC results to the finite-element solution of the incompressible no-slip Navier-Stokes equations in the same geometry. We concentrate on low Reynolds number flows [[Formula: see text]] and quantify important differences observed between the MPC results and the Navier-Stokes solution in constricted geometries. In particular, our results show that upstream recirculating zones can form with the inclusion of slip and compressibility, which are not observed in the flow of an incompressible Newtonian fluid using the no-slip assumption, but have been observed experimentally for blood. Important flow features are also presented that could be used as indicators to observe compressibility and slip in experimental data where near-wall data may be difficult to obtain. Finally, we found that the cumulative averaging method used is ideal for steady particle-based flow methods, as macroscopic no-slip is readily obtained using the MPC bounce-back rule. Generally, a small spurious slip is seen using other averaging methods such as weighted spatial averages or averages over several runs, and the bounce-back rule has to be modified so as to achieve macroscopic no-slip. No modifications of the bounce-back rule were required for our simulations.

Surface modes and acoustic scattering of microspheres and ultrasound contrast agents.

Surface modes of spherical objects subject to ultrasound excitation have been recently proposed to explain experimental measurements of scattering from microspheres and ultrasound contrast agents (UCAs). In this work, the relationship between surface modes and resonance frequencies of microspheres and UCAs is investigated. A finite-element model, built upon the fundamentals of wave propagation and structural mechanics, was introduced and validated against analytical solutions (error <5%). Numerical results showed the existence of a systematic relationship between resonance frequencies and surface modes of a 30 µm microsphere driven at 1-70 MHz. On the contrary, for a 100 nm shelled, 4 µm diameter UCA, no clear relationship between the resonance frequencies and the surface modes was found in the frequency range examined. Instead, the UCA exhibited a collection of complex oscillations, which appear to be a combination of various surface modes and displacements. A study of the effects of varying the shell properties on the backscatter showed the presence of peaks in the backscatter of thick-shelled UCAs, which are not predicted by previous models. In summary, this work presents a systematic effort to examine scattering and surface modes from ultrasound contrast agents using finite-element models.

A quantitative study of the environmental effects on the optical response of gold nanorods.

The effects of the dielectric environment on the optical extinction spectra of gold nanorods were quantitatively studied using individual bare and silica-coated nanorods. The dispersion and amplitude of their extinction cross-section, dominated by absorption for the investigated sizes, were measured using spatial modulation spectroscopy (SMS). The experimental results were compared to calculations from a numerical model that included environmental features present in the measurements and the morphology and size of the corresponding nanorods measured by transmission electron microscopy. The combination of these experimental and theoretical tools permits a detailed interpretation of the optical properties of the individual nanorods. The measured optical extinction spectra and the extinction cross-section amplitudes were well reproduced by the numerical model for silica-coated gold nanorods, for which the silica shell provides a controlled environment. In contrast, additional environmental factors had to be assumed in the model for bare nanorods, stressing the importance of controlling and characterizing the experimental conditions when measuring the optical response of bare surface-deposited single metal nanoparticles.

The measurement of ultrasound scattering from individual micron-sized objects and its application in single cell scattering.

The measurement of the ultrasound backscatter from individual micron-sized objects such as cells is required for various applications such as tissue characterization. However, performing such a measurement remains a challenge. For example, the presence of air bubbles in a suspension of cells during the measurements may lead to the incorrect interpretation of the acoustic signals. This work introduces a technique for measuring the ultrasound backscatter from individual micron-sized objects by combining a microinjection system with a co-registered optical microscope and an ultrasound imaging device. This allowed the measurement of the ultrasound backscatter response from a single object under optical microscope guidance. The optical and ultrasonic data were used to determine the size of the object and to deduce its backscatter responses, respectively. In order to calibrate the system, the backscatter frequency responses from polystyrene microspheres were measured and compared to theoretical predictions. A very good agreement was found between the measured backscatter responses of individual microspheres and theoretical predictions of an elastic sphere. The backscatter responses from single OCI-AML-5 cells were also investigated. It was found that the backscatter responses from AML cells are best modeled using the fluid sphere model. The advantages, limitations, and future applications of the developed technique are discussed.

A study of high frequency ultrasound scattering from non-nucleated biological specimens.

The high frequency backscatter from cells with a nucleus to cell volume ratio of 0.50 cannot be adequately modeled as a homogeneous sphere. It was hypothesized that the cytoplasm of such cells is of fluid nature. This work attempts to model the ultrasound backscatter (10-62 MHz) from some non-nucleated biological specimens. This was done by measuring the backscatter response from individual sea urchin oocytes and comparing it to theoretical predictions in both the time and frequency domains. A good agreement was found between the experimental and theoretical results suggesting that the non-nucleated oocytes are of fluid nature.

Feasibility of salvage interstitial microwave thermal therapy for prostate carcinoma following failed brachytherapy: studies in a tissue equivalent phantom.

Thermal therapy is an experimental treatment to destroy solid tumours by heating them to temperatures ranging from 55 degrees C to 90 degrees C, inducing thermal coagulation and necrosis of the tumour. We are investigating the feasibility of interstitial microwave thermal therapy as a salvage treatment for prostate cancer patients with local recurrence following failed brachytherapy. Due to the electrical and thermal conductivity of the brachytherapy seeds, we hypothesized that the seeds could scatter the microwave energy and cause unpredictable heating. To investigate this, a 915 MHz helical antenna was inserted into a muscle-equivalent phantom with and without brachytherapy seeds. Following a 10 W, 5 s input to the antenna, the temperature rise was used to calculate absorbed power, also referred to as specific absorption rate (SAR). Plane wave models based on Maxwell's equations were also used to characterize the electromagnetic scattering effect of the seeds. In addition, the phantom was heated with 8 W for 5 min to quantify the effect of the seeds on the temperature distribution during extended heating. SAR measurements indicated that the seeds had no significant effect on the shape and size of the SAR pattern of the antenna. However, the plane wave simulations indicated that the seeds could scatter the microwave energy resulting in hot spots at the seed edges. Lack of experimental evidence of these hot spots was probably due to the complex polarization of the microwaves emitted by the helical antenna. Extended heating experiments also demonstrated that the seeds had no significant effect on the temperature distributions and rates of temperature rise measured in the phantom. The results indicate that brachytherapy seeds are not a technical impediment to interstitial microwave thermal therapy as a salvage treatment following failed brachytherapy.

Optimization of a beam shaping bolus for superficial microwave hyperthermia waveguide applicators using a finite element method.

Temperature inhomogeneity in hyperthermia treatments often limits the total thermal dose that can be delivered to the tumour region. To reduce such inhomogeneities, a prototype dynamically modifiable square array of saline-filled patches which attenuate microwave energy was developed for superficial treatments that use external microwave applicators. The array was situated inside the coupling water bolus that is often used with external applicators. The prototype has been previously tested clinically with promising results. A more complete theoretical analysis of the performance of this new bolus design and improvements to its design by modelling are presented here. The analysis was performed by performing five iterative simulations of the SAR pattern produced inside a tissue structure by a waveguide applicator with a water bolus containing the dynamic patch array attached. Between iterations the patch array configuration was modified in an attempt to improve the ability of the bolus to confine heating to an 'L'-shaped tumour region. These simulations were performed using the finite element method. The steady-state temperature profile was then computed using a finite element method based simulation of heat transfer that assumed a given applicator power level and water bolus temperature. Several iterations of these heat transfer simulations were performed with varying applicator power level and water bolus temperature to improve the confinement of heating to the target region. The analysis showed that the dynamic patch array should be capable of conforming heating to an 'L'-shaped target tumour region while limiting the heating to the surrounding normal tissue to an acceptable level.