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A real-time and non-invasive thermometry method is crucial for thermal therapies to monitor and control the treatment. Ultrasound can be used as an attractive thermometry modality for its relatively high sensitivity to change in temperature and fast data collection and processing abilities. In this work, an ultrasound thermometry method based on the change in backscattered energy (CBE) is used to control the tissue temperature using a closed-loop controller in real-time. A clinical high-frequency ultrasound scanner was used to acquire RF echo data from ex vivo porcine tissue samples while the tissue was being exposed to an interstitial laser heating source. The control system was used to rapidly increase the temperature from 37°C (baseline temperature) to 43 °C (target temperature) and maintain the target temperature for about 6 minutes. The results show that the ultrasound thermometry based on CBE generated by a high-frequency ultrasound scanner can be used to generate 2D temperature maps of a localized heating region in the hyperthermia temperature range (∼43°C). The estimated temperature varied by an average of ±0.8 °C compared to a calibrated fiber-optic measurement. Thus, a non-invasive ultrasound thermometry method based on the CBE technique can be used for real-time monitoring and control of hyperthermia treatments, using the interstitial laser heating source with acceptable accuracy.

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 (2.5 mu M), a steep linear range (2.4-54.4 mu M; 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.

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.

Plasmonic gold nanorods (AuNRs) coated with four different thickness silver shells (AuNR\Ags) were synthesized and tested for their efficiency in Surface Enhanced Raman Scattering (SERS) signal enhancement for biomedical applications. Both AuNRs and AuNR\Ags were prepared using a modified seed-mediated method and then characterized using TEM, XPS and UV-vis spectroscopy. All four bimetallic nanorods used in our experiments started from gold nanorod (AuNR) cores (of 36 nm length and 12 nm diameter) which were coated with a 0, 1, 2, 3 or 4 nm thick layer of silver. SERS spectra were obtained for each thickness of AuNR\Ag Raman agent using a Raman reporter – organic molecule p-aminothiophenol (PATP). Moreover, to confirm experimental findings a numerical model was built using COMSOL Multiphysics and solved for a single AuNR\Ag interaction with light on a silica substrate. The highest SERS signal at the incident wavelength of 784 nm, was observed for AuNR\Ags coated with a 1 nm thick silver shell. The numerical model confirmed experimental findings and predicted the highest near-field enhancement in the vicinity of nanoparticles on top of a silica substrate at 784 nm wavelength, for an AuNR\Ag with the same 1 nm silver shell thickness.

In this study, we present facile fabrication of a miniaturized remote sensing SERS platform using highly tunable Nano-Sphere Lithography (NSL) technique. Self-assembly at the air-water interface was performed and the monolayer of polystyrene spheres was transferred onto the tip of optical fibers. Various optical fibers with different numerical apertures (NAs) were used to find an optimal remote sensing setup. Using 200μm diameter optical fibers with high numerical aperture (0.5NA), the SERS enhancement of remote sensing was found to be 98% of direct sensing configuration. Standard silica optical fibers were used for remote sensing using SERS without additional need of optical filtering to mitigate fluorescence and Raman background of these fibers which allows fabrication of miniaturized remote sensing platforms that can be used for remote biochemical sensing.

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.

We perform a finite element-based numerical analysis to calculate the photoacoustic (PA) signal generated by spherical gold–silver (Au–Ag) alloy nanoparticles (NPs). These spherical particles are size-controlled and monodispersed, with tunable plasmonic resonance wavelength via change of the alloy composition. This enables their use in PA imaging as a contrast agent. This theoretical framework self-consistently solves the electromagnetic, thermodynamic and transient acoustic pressure physics using a multiphysics coupling approach. We model our system as an optically heterogeneous medium irradiated by a nanosecond laser pulse in the tissue therapeutic optical window (NIR irradiation, with wavelength of 800 nm). We calculate the PA signal generated by the photothermal expansion of both the particle and its surrounding medium. The results show the impact of the gold molar fraction (GMF) of Au–Ag alloy NPs on the PA signal for different NP sizes. We show that significantly stronger PA signals are achieved usi...

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.

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 [ $$Re \in (4,30)$$ ] 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.

Detection of radiotherapy field misalignments with electronic portal imaging devices requires the precise initial registration of the digital portal image with a reference image indicating the prescribed field alignment. Moreover, for real-time continuous detection this registration must be performed rapidly--arguably within 250 ms. The quality of this registration is sensitive to the ability of the user to accurately identify corresponding anatomical landmarks in the image pair. To improve the accuracy of the registration and, ultimately, that of the field misalignment measurement, we have developed a sequential digital portal image registration method using both user-identified anatomical matchpoints and image information. A first pass generates registration parameters from user-provided matchpoint coordinates and explicitly accounts for the uncertainty in matchpoint identification. The second pass uses both the initial registration parameters and image information to further improve the registration quality by maximizing cross correlations between segments of the image pair. As this registration method does not use massive matrix/vector computations common to other algorithms, it is inherently faster and well-suited for real-time field placement error detection. On a platform representative of those controlling many commercial electronic portal imaging devices (486 CPU), this algorithm registers portal images in times of less than 6 ms per matchpoint with errors of less than 2% in magnification, 0.5 degree in in-plane rotation, and less than 1 pixel dimension in in-plane translation. As the algorithm assumes a rigid-body geometry, it is sensitive to out-of-plane rotations. A quantitative analysis of this algorithm is presented, indicates its accuracy, and describes its sensitivity to out-of-plane rotations.

International audience; 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 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.

The measurement of the ultrasound backscatter from individual micron-sized objects is required to gain an understanding of the behavior of both weak (cells) and strong (contrast agents) scatterers for applications ranging from tissue characterization to molecular imaging. However, obtaining such a response remains a challenge. For instance, the presence of air bubbles in a suspension of cells during measurements of cell backscatter may lead to the incorrect interpretation of the backscattered signals. In addition, the size and shape of the single object that produces an ultrasound backscatter signal are critical input parameters to theoretical models, yet hard to be measured experimentally. In this work, a novel technique combining a Xenoworks microinjection system (Sutter, Inc., Los Angeles, CA) with co-registered Olympus IX71 inverted microscope (Olympus America, Inc., Center Valley, PA) and a VEVO770 Ultrasound imaging device (VisualSonics, Inc., Toronto, ON) was developed in which the ultrasound backscatter response from a single object was obtained under optical microscope guidance. This technique provides accurate information about the size and shape of the object. Two transducers of central frequencies of 25 and 55 MHz were used (for a total spectrum of 12–57 MHz). The foci of the optical lens and the transducer were aligned to obtain optical and ultrasonic images of the same region. The object of interest was attached to the micropipette (using negative pressure) and then released from the micropipette (using positive pressure and/or tapping on the micropipette) while imaging it both optically and ultrasonically. In order to calibrate the system, a micropipette was used to grab a 20 µm polystyrene microsphere from a suspension of microspheres in degassed water by applying a pressure of −18.9 kPa. The microsphere was released by applying a pressure of +35.0 kPa. During the release, optical and ultrasonic raw RF lines were obtained. These lines were then used to obtain the power spectral plot of individual microspheres which were compared to analytical solutions. A very good agreement was found (error of 1%) between the measured backscatter response of microspheres and that of a Faran model of an elastic sphere. Extension of this method to prostate carcinoma (PC-3) cells showed a good agreement (error of 5%) when compared to the Anderson fluid sphere model. This technique is capable of providing accurate measurements of the backscatter from individual objects and is currently being used to deduce the backscatter response from other cell lines of different sizes and from ultrasound contrast agents either in isolation or when attached to a cell. The advantages of the technique along with its future applications are discussed.

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.

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.

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.

High‐frequency ultrasound is a novel method to detect cell death based on changes in cell morphology that cause alterations in the acoustic properties of cell ensembles in tissues. In previous work, our group has suggested that for cells with a nucleus to cell volume ratio of 0.33, the backscatter response from single cells was best modeled as a fluid sphere. However, for cells with a larger nucleus, neither the fluid nor the elastic sphere models showed a good agreement. We hypothesize that cells with a large nucleus ratio (> 0.33) may be modeled as an elastic sphere surrounded by a fluid shell. In this work, the backscatter response from non‐nucleated cells (Strongylocentrotus purpuratus oocytes) was measured Experimental RF lines were acquired using the VisualSonics VS40B ultrasound biomicroscope using 20 and 40 MHz transducers. A finite‐element model of wave propagation was developed to solve high‐frequency ultrasound scattering from spheres. A very good agreement was found suggesting that the cytopla...

A finite‐element model of wave propagation using COMSOL Multiphysics (COMSOL Inc., Burlington, MA) was developed to solve the problem of high‐frequency ultrasound (10–70 MHz) scattering from spheres. This model is being used to predict ultrasound backscatter from cells for ultrasound tissue characterization. In this work, backscatter from an elastic (polystyrene) microsphere was used to validate the computational model against experimental results. Agreement between experimental results and finite‐element solutions were found in the frequency domain solutions. Moreover, conversion of the theoretical solutions to time‐domain backscatter data showed good agreement with experimental time domain measurements. To develop a better understanding of the interactions of the incident pressure field with the scattering object, oscillations of the elastic microsphere at various resonance frequencies were also investigated. A systematic relationship between the resonance frequency and its corresponding surface mode was found. An ultrasound scattering model by a single cell is also presented. The model treats the cell as an elastic sphere (nucleus) surrounded by a fluid shell (cytoplasm). Comparison of the theoretical backscatter predicted by the model and experimental measurements for acute Myeloid Leukemia (AML) cell is also shown. Finally, the implications of these results on ultrasound tissue characterization techniques are discussed.