Numerical investigation of thermal response of laser-irradiated biological tissue phantoms embedded with gold nanoshells

The work presented in this paper focuses on numerically investigating the thermal response of gold nanoshells-embedded biological tissue phantoms with potential applications into photo-thermal therapy wherein the interest is in destroying the cancerous cells with minimum damage to the surrounding healthy cells. The tissue phantom has been irradiated with a pico-second laser. Radiative transfer equation (RTE) has been employed to model the light-tissue interaction using discrete ordinate method (DOM). For determining the temperature distribution inside the tissue phantom, the RTE has been solved in combination with a generalized non-Fourier heat conduction model namely the dual phase lag bio-heat transfer model. The numerical code comprising the coupled RTE-bio-heat transfer equation, developed as a part of the current work, has been benchmarked against the experimental as well as the numerical results available in the literature. It has been demonstrated that the temperature of the optical inhomogeneity inside the biological tissue phantom embedded with gold nanoshells is relatively higher than that of the baseline case (no nanoshells) for the same laser power and operation time. The study clearly underlines the impact of nanoshell concentration and its size on the thermal response of the biological tissue sample. The comparative study concerned with the size and concentration of nanoshells showed that 60 nm nanoshells with concentration of 5×10¹⁵ mm⁻³ result into the temperature levels that are optimum for the irreversible destruction of cancer infected cells in the context of photo-thermal therapy. To the best of the knowledge of the authors, the present study is one of the first attempts to quantify the influence of gold nanoshells on the temperature distributions inside the biological tissue phantoms upon laser irradiation using the dual phase lag heat conduction model.     

Laser-induced hyperthermia of nanoshell mediated vascularized tissue – A numerical study

Laser-induced hyperthermia treatment of tumor in a 2-D axisymmetric tissue embedded with moderate size (100–150 µm) blood vessels is studied. Laser absorption is enhanced by embedding gold–silica nanoshells in the tumor. Heat transfer in the tissue is modeled using Weinbaum–Jiji bioheat transfer equation. With laser irradiation, the volumetric radiation is accounted in the governing bioheat equation. Radiative information needed in the bioheat equation is calculated using the discrete ordinate method, and the coupled bioheat-radiation equation is solved using the finite volume method. Effects of power density, laser exposure time, beam radius, diameter of blood vessel and volume fractions of nanoshells on temperature spread in the tissue are analyzed.     

Photothermal treatment of human carcinoma cells using liposome-encapsulated gold nanoshells

We report the application of liposome-encapsulated gold nanoshells for in vitro photo-induced hyperthermia in human mammary carcinoma cells. In addition to evaluating their effects in vitro, we compared the application liposome-encapsulated gold nanoshells and free-standing gold nanoshells for NanoPhotoTherapy (NPT). NPT-induced hyperthermia was performed using a 785-nm near-infrared light from a diode laser and the in vitro effects were evaluated using nucleic acid molecular probes by fluorescence microscopy. Additionally, we monitored the effectiveness of NPT by detecting apoptosis via capase-9 activity.     

siRNA release from gold nanoparticles by nanosecond pulsed laser irradiation and analysis of the involved temperature increase

Nanosecond pulsed laser irradiation can trigger a release of nucleic acids from gold nanoparticles, but the involved nanoeffects are not fully understood yet. Here we investigate the release of coumarin labeled siRNA from 15 to 30 nm gold particles after nanosecond pulsed laser irradiation. Temperatures in the particle and near the surface were calculated for the different radiant exposures. Upon irradiation with laser pulses of 4 nanosecond duration release started for both particle sizes at a calculated temperature increase of approximately 500 K. Maximum coumarin release was observed for 15 nm particles after irradiation with radiant exposure of 80 mJ cm^?2 and with 32 mJ cm^?2 for 30 nm particles. This corresponds to a temperature increase of 815 and 900 K, respectively. Our results show that the molecular release by nanosecond pulsed irradiation is based on a different mechanism compared to continuous or femtosecond irradiation. Local temperatures are considerably higher and it is expected that bubble formation plays a crucial role in release and damage to cellular structures.      

Solid and Hollow Gold Nanostructures for Nanomedicine: Comparison of Photothermal Properties

The photothermal properties of solid and hollow gold nanostructures represented by colloidal solutions of spherical nanoparticles, nanoshells, and nanocages upon irradiation with a 100 mW 808 nm continuous-wave laser for the first time were experimentally compared under identical optical density and nanoparticle concentration conditions. Accompanying computer modeling of light absorption by the studied gold nanostructures revealed the general parameters influencing the photothermal efficiency, which is of significance for nanomedical applications. The spectral position of localized plasmonic excitations of the studied nanostructures ranged from 518 nm for solid gold nanoparticles to 718 nm for gold nanocages, which provided a possibility to observe a direct influence of the wavelength proximity between the localized surface plasmon resonance and laser line on the heat generation capability of the nanostructures. As a result, the best photothermal efficiency was registered for gold nanocages, which proves them as an efficient photothermal treatment agent and a possible candidate to build a nanocarrier platform for drug delivery with a controlled release. Light absorption modeling demonstrated an existence of optimal wall thickness for gold nanoshells that should lead to the maximum photothermal efficiency when irradiated with 808 nm light, which varied from about 0.1 to 0.4 in units of external nanoshell radius with an increase of the wall porosity. Additionally, computer modeling results show that increased wall porosity should lead to enhanced photothermal efficiency of polydisperse colloidal solutions of hollow gold nanostructures.     

Microscopic heat pulses induce contraction of cardiomyocytes without calcium transients

It was recently demonstrated that laser irradiation can control the beating of cardiomyocytes and hearts, however, the precise mechanism remains to be clarified. Among the effects induced by laser irradiation on biological tissues, temperature change is one possible effect which can alter physiological functions. Therefore, we investigated the mechanism by which heat pulses, produced by infra-red laser light under an optical microscope, induce contractions of cardiomyocytes. Here we show that microscopic heat pulses induce contraction of rat adult cardiomyocytes. The temperature increase, ΔT, required for inducing contraction of cardiomyocytes was dependent upon the ambient temperature; that is, ΔT at physiological temperature was lower than that at room temperature. Ca(2+) transients, which are usually coupled to contraction, were not detected. We confirmed that the contractions of skinned cardiomyocytes were induced by the heat pulses even in free Ca(2+) solution. This heat pulse-induced Ca(2+)-decoupled contraction technique has the potential to stimulate heart and skeletal muscles in a manner different from the conventional electrical stimulations.     

Perfused phantom models of microwave irradiated tissue

The theoretical basis, practical design considerations, and prototype testing of a perfused model suitable for simulation studies of microwave heated tissue are presented. A parallel tube heat exchanger configuration is used to simulate the internal convection effects of blood flow. The global thermal response of the phantom, on a scale of several tube spacings, is shown theoretically to be nearly identical to that predicted by Pennes' bioheat equation, which is known to give a reasonable representation of tissue under many conditions. A parametric study is provided for the relationships between the tube size, spacing and material properties and the simulated perfusion rate. A prototype with a physiologically reasonable perfusion rate was tested using a typical hyperthermia applicator. The measured thermal response of the phantom compares favorably with the numerical solution of the bioheat equation under the same irradiation conditions. This similarity sheds light on the unexpected success of the bioheat equation for modeling the thermal response of real tissue.     

Laser hyperthermia of tumors using gold nanoparticles monitored by optical coherence tomography and acoustic thermometry

Local laser hyperthermia of grafted RShM-5 tumors in mice with the use of plasmon resonant gold nanoparticles has been carried out. Accumulation of particles in the tumor was monitored in vivo noninvasively by optical coherence tomography. Thereby it was determined that the maximal content of nanoparticles in the tumor was reached within 5 h after intravenous administration, and laser hyperthermia was performed at this time. Monitoring the tumor temperature during the treatment by IR thermography and acoustic thermometry showed that the nanoparticles provided efficient temperature elevation inside the tumor as well as more selective heating. Local laser hyperthermia with gold nanoparticles, but not the laser exposure alone, substantially inhibited tumor growth in several days after a single session.     

Plasmonic Heating-Assisted Transformation of SiO2/Au Core/Shell Nanospheres (Au Nanoshells): Caveats and Opportunities for SERS and Direct Laser Writing

The selective modification of silica/gold nanospheres (gold nanoshells) driven by plasmonic heating is demonstrated. Direct laser writing and reshaping of nanoshell assemblies can be easily controlled and exploited for nanofabrication purposes. The modified nanoshells exhibit improved surface enhanced Raman scattering, allowing to settle most of the issues related to nanoshell stability under working conditions.

Psychoactive-drug response is affected by acute low-level microwave irradiation

The effects of various psychoactive drugs were studied in rats exposed for 45 min in a circularly polarized, pulsed microwave field (2450 MHz; SAR 0.6 W/kg; 2-microseconds pulses, 500 pps). Apomorphine-induced hypothermia and stereotypy were enhanced by irradiation. Amphetamine-induced hyperthermia was attenuated while stereotypy was unaffected. Morphine-induced catalepsy and lethality were enhanced by irradiation at certain dosages of the drug. Since these drugs have different modes of action on central neural mechanisms and the effects of microwaves depend on the particular drug studied, these results show the complex nature of the effect of microwave irradiation on brain functions.     

RGD/FA双靶纳米金棒的制备及其在肿瘤细胞协同靶向成像与光热治疗中的应用

目的:通过制备RGD/FA双靶纳米金考察其与高表达整合素与叶酸受体B16细胞的协同靶向成像与热疗作用;方法:采用功能化PEG分子将靶向小分子RGD与叶酸通过强健Au-S键连接至纳米金棒表面,利用激光共聚焦与808 nm近红外激光器评价修饰纳米金的协同靶向作用;结果:RGD与叶酸分子被成功连接于纳米金表面,且双靶纳米金对小鼠黑色素瘤细胞具有较好的协同靶向作用;结论:同时靶向同一肿瘤细胞的不同表位,可克服单一靶向功能化纳米粒子难以在肿瘤位点有效积累的问题,本研究为多功能纳米金棒在临床肿瘤早期诊断与光热治疗中的应用提供研究基础。     

Determination of the 3D temperature distribution during ferromagnetic hyperthermia under the influence of blood flow

A numerical simulation of tissue heating during thermo-seed ferromagnetic hyperthermia was performed to determine the temperature distribution of treated tumor tissues under the influence of three large blood vessels at different locations. The effects of the blood velocity waveform, blood vessel size, Curie point of the thermo-seeds and the thermo-seed number on temperature distributions were analyzed. The results indicate that the existence of a blood vessel inside the tumor has a significant cooling effect on the temperature distribution in a treated tumor tissue, which is enhanced with an increase in blood velocity. However, the pulsatile blood flow does not have apparently different effects on the outcomes of uniformly heating target tissues in comparison with the steady blood flow during the hyperthermia process. It is also concluded that a higher Curie point temperature and an increase in the number of thermo-seeds can result in profound increases in the temperature variations of the tumor tissue. In addition, tissue-equivalent phantom experiments were conducted to confirm the cooling effects of the blood vessels, and to validate the effectiveness and accuracy of the proposed heat transfer model for the ferromagnetic hyperthermia.     

3D in silico study of magnetic fluid hyperthermia of breast tumor using Fe3O4 magnetic nanoparticles

Modeling and simulation of the temperature distribution, the mass concentration, and the heat transfer in the breast tissue are hot issues in magnetic fluid hyperthermia treatment of cancer. The breast tissue can be visualized as a porous matrix with saturated blood. In this paper, 3D in silico study of breast cancer hyperthermia using magnetic nanoparticles (MNPs) is conducted. The 3D FEM models are incorporated to investigate the infusion and backflow of nanofluid in the breast tumor, the diffusion of nanofluid, temperature distribution during the treatment, and prediction of the fraction of tumor necrosis while dealing with the thermal therapy. All the hyperthermia procedures are simulated and analyzed on COMSOL Multiphysics. The sensitivity of frequency and amplitude of the applied magnetic field (AMF) is investigated on the heating effect of the tumor. The mesh dependent solution of Penne's bioheat model is also analyzed. The simulated results demonstrate successful breast cancer treatment using MNPs with minimum side effects. Validation of current simulations results with experimental studies existing in literature advocates the success of our therapy. The increase in the amplitude and frequency of the AMF increases of the temperature in the tumor. The variation of mesh from coarser to finer increased the temperature through small fractions. We have also simulated the magnetic induction problem where the magnetic field is generated by current-carrying coil conductors induce heat in nearby breast tumors due to excitation of MNPs by magnetic flux. This research will aid treatment protocols and real-time clinical breast cancer treatments.     

Immunonanoshells for targeted photothermal ablation of tumor cells

Consisting of a silica core surrounded by a thin gold shell, nanoshells possess an optical tunability that spans the visible to the near infrared (NIR) region, a region where light penetrates tissues deeply. Conjugated with tumor-specific antibodies, NIR-absorbing immunonanoshells can preferentially bind to tumor cells. NIR light then heats the bound nanoshells, thus destroying the targeted cells. Antibodies can be consistently bound to the nanoshells via a bifunctional polyethylene glycol (PEG) linker at a density of approximately 150 antibodies per nanoshell. In vitro studies have confirmed the ability to selectively induce cell death with the photothermal interaction of immunonanoshells and NIR light. Prior to incubation with anti-human epidermal growth factor receptor (HER2) immunonanoshells, HER2-expressing SK-BR-3 breast carcinoma cells were seeded alone or adjacent to human dermal fibroblasts (HDFs). Anti-HER2 immunonanoshells bound to HER2-expressing cells resulted in the death of SK-BR-3 cells after NIR exposure only within the irradiated area, while HDFs remained viable after similar treatment since the immunonanoshells did not bind to these cells at high levels. Control nanoshells, conjugated with nonspecific anti-IgG or PEG, did not bind to either cell type, and cells continued to be viable after treatment with these control nanoshells and NIR irradiation.     

Comparison of neutron organ and effective dose coefficients for PIMAL stylized phantom in bent postures in standard irradiation geometries

Neutron dose coefficients for standard irradiation geometries have been reported in International Commission on Radiological Protection (ICRP) Publication 116 for the ICRP Publication 110 adult reference phantoms. In the present work, organ and effective dose coefficients have been calculated for a receptor in both upright and articulated (bent) postures representing more realistic working postures exposed to a mono-energetic neutron radiation field. This work builds upon prior work by Dewji and co-workers comparing upright and bent postures for exposure to mono-energetic photon fields. Simulations were conducted using the Oak Ridge National Laboratory’s articulated stylized adult phantom, “Phantom wIth Moving Arms and Legs” (PIMAL) software package, and the Monte Carlo N-Particle (MCNP) version 6.1.1 radiation transport code. Organ doses were compared for the upright and bent (45° and 90°) phantom postures for neutron energies ranging from 1 × 10^??9 to 20 MeV for the ICRP Publication 116 external exposure geometries—antero-posterior (AP), postero-anterior (PA), and left and right lateral (LLAT, RLAT). Using both male and female phantoms, effective dose coefficients were computed using ICRP Publication 103 methodology. The resulting coefficients for articulated phantoms were compared to those of the upright phantom. Computed organ and effective dose coefficients are discussed as a function of neutron energy, phantom posture, and source irradiation geometry. For example, it is shown here that for the AP and PA irradiation geometries, the differences in the organ coefficients between the upright and bent posture become more pronounced with increasing bending angle. In the AP geometry, the brain dose coefficients are expectedly higher in the bent postures than in the upright posture, while all other organs have lower dose coefficients, with the thyroid showing the greatest difference. Overall, the effective dose estimated for the upright phantom is more conservative than that for the articulated phantom, which may have ramifications in the estimation or reconstruction of radiation doses.     

Simulation of images of CDMAM phantom and the estimation of measurement uncertainties of threshold gold thickness

PurposeTo demonstrate a method of simulating mammography images of the CDMAM phantom and to investigate the coefficient of variation (CoV) in the threshold gold thickness (t_T) measurements associated with use of the phantom.MethodsThe noise and sharpness of Hologic Dimensions and GE Essential mammography systems were characterized to provide data for the simulation. The simulation method was validated by comparing the t_T results of real and simulated images of the CDMAM phantom for three different doses and the two systems. The detection matrices produced from each of 64 images using CDCOM software were randomly resampled to create 512 sets of 8, 16 and 32 images to estimate the CoV of t_T. Sets of simulated images for a range of doses were used to estimate the CoVs for a range of diameters and threshold thicknesses.ResultsNo significant differences were found for t_T or the CoV between real and simulated CDMAM images. It was shown that resampling from 256 images was required for estimating the CoV. The CoV was around 4% using 16 images for most of the phantom but is over double that for details near the edge of the phantom.ConclusionsWe have demonstrated a method to simulate images of the CDMAM phantom for different systems at a range of doses. We provide data for calculating uncertainties in t_T. Any future review of the European guidelines should take into consideration the calculated uncertainties for the 0.1 mm detail.     

Development of a four-dimensional Monte Carlo dose calculation system for real-time tumor-tracking irradiation with a gimbaled X-ray head

PurposeTo develop a four-dimensional (4D) dose calculation system for real-time tumor tracking (RTTT) irradiation by the Vero4DRT.MethodsFirst, a 6-MV photon beam delivered by the Vero4DRT was simulated using EGSnrc. A moving phantom position was directly measured by a laser displacement gauge. The pan and tilt angles, monitor units, and the indexing time indicating the phantom position were also extracted from a log file. Next, phase space data at any angle were created from both the log file and particle data under the dynamic multileaf collimator. Irradiation both with and without RTTT, with the phantom moving, were simulated using several treatment field sizes. Each was compared with the corresponding measurement using films. Finally, dose calculation for each computed tomography dataset of 10 respiratory phases with the X-ray head rotated was performed to simulate the RTTT irradiation (4D plan) for lung, liver, and pancreatic cancer patients. Dose-volume histograms of the 4D plan were compared with those calculated on the single reference respiratory phase without the gimbal rotation [three-dimensional (3D) plan].ResultsDifferences between the simulated and measured doses were less than 3% for RTTT irradiation in most areas, except the high-dose gradient. For clinical cases, the target coverage in 4D plans was almost identical to that of the 3D plans. However, the doses to organs at risk in the 4D plans varied at intermediate- and low-dose levels.ConclusionsOur proposed system has acceptable accuracy for RTTT irradiation in the Vero4DRT and is capable of simulating clinical RTTT plans.     

The Lack of Toxic Effect of High-Power Short-Pulse 101 GHz Millimeter Waves on Healthy Mice

Irradiation of cancer cells by non-ionizing millimeter waves (MMW) causes increased cell mortality. We examined if MMW have toxic effects on healthy mice. To that end, the skin of healthy C57BL/6 mice was irradiated locally at the right flank with 101 GHz MMW in a pulsed (5–10 µs) regime using a free electron laser. Irradiation was performed in a dose-dependent manner, with 20–50 pulses and a power range of 0.5–1.5 kW. Physical, physiological, and pathological parameters as well as behavior were examined before and after irradiation. Our results showed that all parameters were within normal range for all experimental mice groups and for the control group. No significant changes were noted in the physical, physiological, or behavioral status of the mice following irradiation as compared with the control group. In addition, no significant changes were found in locomotor, exploratory behavior, or anxiety of the irradiated mice and no pathological changes were noted following the hematological and biochemical blood analysis. Our results indicate that irradiation of healthy mice with MMW does not cause any general toxic effects. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.     

Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment

PurposeTo determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment.MethodsSimulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78–147 MeV and 177–223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations.ResultsOut-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5–151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%.ConclusionsThe agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.     

EphrinA I-targeted nanoshells for photothermal ablation of prostate cancer cells

Gold-coated silica nanoshells are a class of nanoparticles that can be designed to possess strong absorption of light in the near infrared (NIR) wavelength region. When injected intravenously, these nanoshells have been shown to accumulate in tumors and subsequently mediate photothermal treatment, leading to tumor regression. In this work, we sought to improve their specificity by targeting them to prostate tumor cells. We report selective targeting of PC-3 cells with nanoshells conjugated to ephrinA I, a ligand for EphA2 receptor that is overexpressed on PC-3 cells. We demonstrate selective photo-thermal destruction of these cells upon application of the NIR laser.