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.

A finite-element model of wave propagation using COMSOL Multiphysics (COMSOL Inc., Burlington, MA) was developed to solve the problem of high frequency ultrasound scattering from spheres. This model is used to predict ultrasound backscatter from cells for ultrasound tissue characterization. In this work, the backscatter from an elastic sphere was used to validate the computational model against analytical solutions (Faran theory). Agreements between analytical and finite element solutions were found in the scattered far-field over a range of frequencies of interest (10 - 70 MHz). Oscillations of the elastic sphere at various resonance frequencies (peaks in the power spectrum) were also investigated. The resonance frequencies predicted by the analytical solutions corresponded to surface modes. A systematic relationship between the resonance frequency and its corresponding surface mode was found. The oscillations of the elastic sphere were visualized at these resonances. 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 the prediction of ultrasound backscatter from cells, and on ultrasound tissue characterization techniques are discussed.

Thermal dose models are metrics that quantify the thermal effect on tissues based on the temperature and the time of exposure. These models are used to predict and control the outcome of hyperthermia (up to 45 degrees C) treatments, and of thermal coagulation treatments at higher temperatures (>45 degrees C). The validity and accuracy of the commonly used models (CEM43) are questionable when heating above the hyperthermia temperature range occurs, leading to an over-estimation of the accumulation of thermal damage. A new CEM43 dose model based on an Arrhenius-type, Vogel-Tammann-Fulcher, equation using published data, is introduced in this work. The new dose values for the same damage threshold that was produced at different in-vivo skin experiments were in the same order of magnitude, while the current dose values varied by two orders of magnitude. In addition, the dose values obtained using the new model for the same damage threshold in 6 lesions in ex-vivo liver experiments were more consistent than the current model dose values. The contribution of this work is to provide new modeling approaches to inform more robust thermal dosimetry for improved thermal therapy modeling, monitoring, and control.

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 (TM) 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 degrees C (baseline) to 47 degrees C. Conclusions: The findings of this study show that the CBE of acoustic harmonics technique can be used to non-invasively estimate temperature change in tissue in the hyperthermia temperature range.

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.

Objective: This work aims to determine whether photoacoustic (PA) thermometry from a commercially available PA imaging system can be used to control the temperature in nanoparticle-mediated thermal therapies. Methods: The PA imaging system was interfaced to obtain PA images while scanning ex-vivo tissue. These images were then used to obtain temperature maps in real-time during heating. Validation and calibration of the PA thermometry were done using a fluoroptic thermometer. This thermometer was also used to develop and tune a software-based proportional integral derivative (PID) controller. Finally, a PA-based PID closed-loop controller was used to control gold nanorod (GNR) mediated laser therapy. Results: The use of GNRs substantially enhanced laser heating; the temperature rise increased 7-fold by injecting a GNR solution with a concentration of 0.029 mg/mL. The control experiments showed that the desired temperature could be achieved and maintained at a targeted location in the ex-vivo tissue. The steady-state mean absolute deviations (MAD) from the targeted temperature during control were between 0.16 $^\circ {\kern-0.70007pt}\text{C}$ and 0.5 $^\circ {\kern-0.70007pt}\text{C}$ , depending on the experiment. Conclusion: It was possible to control hyperthermia treatments using a software-based PID controller and a commercial PA imaging system. Significance: The monitoring and control of the temperature in thermal-based therapies are important for assuring a prescribed temperature to the target tissue while minimizing the temperature of the surrounding healthy tissue. This easily implemented non-invasive control system will facilitate the realization of a broad range of hyperthermia treatments.

In this study, we present facile fabrication of a miniaturized remote sensing SERS platform using highly tunable Nano-Sphere Lithography (NSL) technique. Using 200 μm 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.

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.

Synthetic aperture focusing techniques (SAFT) make the lateral spatial resolution of the conventional ultrasound imaging from a single-element focused transducer more uniform. In this work, two new frequency-domain SAFT (FD-SAFT) algorithms are proposed, which are based on 2D matched filtering techniques. The first algorithm is the FD-SAFT virtual disk source (FD-VDS) that treats the focus of a focused transducer as a finite sized virtual source and the diffraction effect in the far-field is accounted for in the image reconstruction. The second algorithm is the FD-SAFT deconvolution (FD-DC) that uses the simulated point spread function of the imaging system as a matched filter kernel in the image reconstruction. These algorithms were implemented for pulsed and linear frequency modulated chirp excitations. The performance of these algorithms was studied using a series of simulations and experiments, and it was compared with the conventional B-mode and time-domain virtual point source SAFT (TD-VPS) imaging techniques. The image quality was analyzed in terms of spatial resolution, sidelobe level, signal-to-noise ratio (SNR), contrast resolution, contrast-to- speckle ratio, and ex vivo tissue image quality. The results showed that the FD-VDS had the highest spatial resolution and FD-DC had the second highest spatial resolution. In addition, FD-DC had generally the highest SNR. The computation run time of the proposed methods was significantly lower than the TD-VPS. Furthermore, chirp excitation improves the SNR of all methods by about 8 dB without significantly affecting the spatial resolution and sidelobe level. Thus, the FD-VDS and FD-DC methods offer efficient solutions to make the spatial resolution of conventional B-mode imaging more uniform.

Raman spectroscopy (RS) can provide a molecular vibrational fingerprint of an analyte. In this study, RS was used to distinguish normal tissues from tumor tissues using ex-vivo and deparaffinized breast tissues.

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.

Our group has recently developed a finite element model of a nanoparticle-mediated optical breakdown phenomena. Previously, this model was used to analyze the role of the nanoparticle morphology and the wavelength dependence of a nanoparticle-mediated optical breakdown threshold during near-infrared ps and fs pulse exposures. In this study, we provide a theoretical insight into the optoporation efficiency of live cells and bubble formation threshold during nanoparticle-mediated optical breakdown. It was done by the calculation of maximum temperature and free electron density in the vicinity of a single gold nanoshell in water during 70 femtosecond single pulse exposure and comparison against published experimental data.

Synthetic aperture focusing techniques (SAFT) mathematically synthesize an effective large aperture by scanning a single-element transducer to improve the lateral spatial resolution and extend the depth of field. In this work, two frequency-domain SAFT algorithms are proposed, which are based on the synthetic aperture radar’s wavenumber algorithm. Both algorithms use 2D matched filtering for the image reconstruction. The first algorithm (FD-SAFT-VS) treats the focus of the transducer as a virtual source of finite-sized, where the diffraction effects in the far-field is taken into account in the image reconstruction. The second algorithm (FD-SAFT-DE) uses the simulated point spread function of the imaging system as a filter kernel in the image reconstruction. The performances of the proposed SAFT algorithms were evaluated using a series of simulations for a 25 MHz single-element focused transducer. The image quality was measured in terms of spatial resolution, electronic signal-to-noise ratio (SNR e ), and contrast-to-speckle ratio (CSR) and it was compared with conventional B-mode and time-domain SAFT (TD-SAFT-VPS) imaging methods. The results showed that the FD-SAFT-VS had the smallest spatial resolution and FD-SAFT-DE had the second smallest spatial resolution. In addition, FD-SAFT-DE generally had the higher SNR e and CSR values compared to other methods. Furthermore, the computation run times of FD-SAFT-VS and FD-SAFT-DE methods were similar and they were 4 to 190 times smaller compared to TD-SAFT-VPS.

This paper investigates the wavelength dependence of the threshold of gold nanorod-mediated optical breakdown during picosecond and femtosecond near infrared optical pulses. It was found that the wavelength dependence in the picosecond regime is governed solely by the changes of a nanorod's optical properties. On the other hand, the optical breakdown threshold during femtosecond pulse exposure falls within one of two regimes. When the ratio of the maximum electric field from the outside to the inside of the nanorod is less then 7 (the absorption regime) the seed electrons are initiated by photo-thermal emission, and the wavelength dependence in the threshold of optical breakdown is the result of optical properties of the nanoparticle. When the ratio is greater than 7 (the near-field regime) more seed electrons are initiated by multiphoton ionization, and the wavelength dependence of the threshold of optical breakdown results from a combination of nanorod's optical properties and transitions in the order of multiphoton ionization. The findings of this study can guide the design of nanoparticle based optical breakdown applications. This analysis also deepens the understanding of nanoparticle-mediated laser induced breakdown for picosecond and femtosecond pulses at near infrared wavelengths.

Gold nanoparticles (GNP) have been shown to highly absorb ionizing radiation compared to tissue. GNPs have also been shown to be high absorbers of non-ionizing radiation with a peak absorbance at a wavelength dependent on their shape and size. This study investigated radiation dose enhancement in PC3 cells when in the presence of gold nanorods (NR) and near infrared light (IR). The PC3 cells were incubated with either PEGylated NRs (PNR) or anti prostate stem cell antigen antibody with nuclear localization sequence peptide conjugated NRs (AbNR). They were exposed to near infrared light at a wavelength of 810 nm to achieve a temperature of 42 ºC to 43 ºC for 60 minutes. They were also exposed to 160 kVp x-rays. It was found that both targeted and non-targeted GNPs when exposed to radiation and near infrared light synergistically enhanced radiation dose. It was also found that AbNRs provide greater dose enhancement than PNRs.

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.

Optical spectroscopy/imaging has been one of the techniques, which has a major impact in the field of medical diagnostics. The degree of multiplexing (e.g. detecting multiple analytes through a single spectral acquisition) and versatility of spectral techniques in molecular sensing domain has been well established in the literature. Raman spectroscopy detects individual molecules and is independent of excitation wavelength, allowing selection of application specific wavelengths while using the same data library measured at a fixed wavelength, making RS a prime candidate for label-free sensing and imaging. Raman spectra are very sensitive biochemical markers due to the unique vibrational fingerprint spectra of the tissue. Raman spectroscopy is also very sensitive towards small molecular/chemical changes, such as an increased nucleus-to-cytoplasm ratio, disordered chromatin, higher metabolic activity, and changes in lipid and protein levels. We have collected Raman spectral libraries for obtaining operator independent diagnostics under ex-vivo and in-vivo conditions and we have tested this approach using multivariate analysis on known solutions with Raman active components. The ultimate successful classification architecture is a blend of multivariate analysis of the spectral data as well as their transformation into feature space with prominent features defined as peak location, peak widths and relative peak-peak ratios.

We perform a finite element-based numerical analysis to calculate the photoacoustic (PA) signal generated by spherical gold silver (Au-Ag) alloy nanopartides (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 using Au-Ag alloy NPs (GMF = 0.55) in comparison with pure AuNPs (GMF = 1) and pure AgNPs (GMF = 0) of the same size and shape.

Over the last decade, Photoacoustic (PA) imaging has been applied to the biomedical research field and matured into a new clinical modality for tissue imaging and functional cancer cell research. PA imaging uses a pulsed laser to irradiate a region of interest and generate a thermally induced acoustic pressure wave that can be collected by an ultrasound transducer to form an image. The combination of ultrasound imaging and high optical contrast of the biological tissues is used in PA for in-vivo and in-vitro imaging of tissue and cells. The optical absorption/PA contrast of the region of interest can be enhanced by the use of plasmonic nanoparticles due to their high optical absorption. Optical properties of nanoparticles are governed by their plasmon resonance a collective oscillation of free electrons confined by the surface of the nanoparticle. The nanoparticles can be tuned to resonate at the excitation wavelength by changing their size and shape. The PA wave from plasmonic nanoparticles depends on their local environment. Chen et. al. [1] experimentally observed an enhancement of the PA signal from silica-coated gold nanoparticles that depends on the silica thickness and the refractive index of the surrounding medium. The current work aims to develop a solid theoretical understanding of these observations, which can be used for optimization of the use of plasmonic nanoparticles during PA imaging. A theoretical understanding of the PA processes can be obtained through the use of computational modeling. The finite element analysis software COMSOL Multiphysics® is being used to model PA behavior of plasmon nanoparticles, including the effect of their local environment. The COMSOL Multiphysics model is being set up to couple the following physics modes into a single model: the electromagnetic (RF) wave equation (to obtain the optical properties of bare and silica-coated gold nanoparticles), transient heat transfer (HT) with a heat source that incorporates the characteristics of the laser pulse and the optical properties of the particle (coupling parameter to RF), and an acoustic pressure wave propagation that was generated by thermal expansion of the particle's surrounding (coupling to HT). The computational model has been validated against an analytical model produced by Diebold [2] (see Figure 1). With the help of numerical methods such as finite element analysis, we will be able to understand the physics behind PA signal enhancement and provide optimized nanoparticle designs for use in PA imaging.