Understanding physical mechanism of low-level microwave radiation effect.

PURPOSE: This topic review aims to explain the mechanism of low-level microwave (MW) radiation effect based on published research results. The review presents the analysis of theoretical and experimental results comprising underlying physics and derived biological-physiological consequences supported by experimental data. CONCLUSIONS: The rotation of dipolar molecules causes polarization of dielectric medium and restructuring of hydrogen bonds between these molecules. The weakened hydrogen bonds decrease viscosity and enhance diffusion at constant temperature. All steps of proposed model have no critical frequency restrictions at MW frequencies and have been confirmed by electromagnetic field (EMF) theory and/or published experimental results. The synchronous cumulative impact of coherent MW electric field makes possible the field-induced effect despite the field strengths are much weaker than intermolecular fields. The rotation of dipolar molecules results in restructuring hydrogen bonds between the molecules despite the energy of MW radiation is much less than the energy of bonding. The cumulative impact of coherent MW field in a medium has been convincingly confirmed by the measurable dielectric permittivity of the medium. The described mechanism of MW field-induced effect confirms that the nature of the effect differs from the thermal effect and that the exposure by MW radiation can create the specific consequences in biology and materials not characteristic for conventional heating.

Vitamin E-stabilized highly crosslinked polyethylenes: The role and effectiveness in total hip arthroplasty.

Morphology and design of ultra-high molecular weight polyethylene (UHMWPE or simply PE) acetabular components used in total hip arthroplasty (THA) have been evolving for more than half a century. Since the late-1990s, there were two major technological innovations in PE emerged from necessity to overcome the wear-induced periprosthetic osteolysis, i.e., the development of highly crosslinked PEs (HXLPEs). There are many literature reporting that radiation crosslinked and remelted/annealed (first-generation) HXLPEs markedly reduced the incidence of osteolysis and aseptic loosening. Regardless of such clinical success in the first-generation technologies, there were some recent shifts in Japan toward the use of new second-generation HXLPEs subjected to sequential irradiation/annealing or antioxidant vitamin E (α-tocopherol) incorporation. Although the selection rate of first-generation liners still account for more than half of all the PE THAs (∼58% in 2015), the use of vitamin E-stabilized liners has been steadily growing each year since their clinical introduction in 2010. In these contexts, it is of great importance to evaluate and understand the real clinical benefits of using the new second-generation liners as compared to the first generation. This article first summarizes structural evolution and characteristic features of first-generation HXLPEs, and then provides a detailed description of second-generation antioxidant HXLPEs in regard to the role of vitamin E incorporation on their chemical and mechanical performances in THA.

A thermo-degradable hydrogel with light-tunable degradation and drug release.

The development of thermo-degradable hydrogels is of great importance in drug delivery. However, it still remains a huge challenge to prepare thermo-degradable hydrogels with inherent degradation, reproducible, repeated and tunable dosing. Here, we reported a thermo-degradable hydrogel that is rapidly degraded above 44 °C by a facile chemistry. Besides thermo-degradability, the hydrogel also undergoes rapid photolysis with ultraviolet light. By embedding photothermal nanoparticles or upconversion nanoparticles into the gel, it can release the entrapped cargoes such as dyes, enzymes and anticancer drugs in an on-demand and dose-tunable fashion upon near-infrared light exposure. The smart hydrogel works well both in vitro and in vivo without involving sophisticated syntheses, and is well suited for clinical cancer therapy due to the high transparency and non-invasiveness features of near-infrared light.

Conducting polymers with defined micro- or nanostructures for drug delivery.

Conducting polymers (CPs) are redox active materials with tunable electronic and physical properties. The charge of the CP backbone can be manipulated through redox processes, with accompanied movement of ions into and out of the polymer to maintain electrostatic neutrality. CPs with defined micro- or nanostructures have greatly enhanced surface areas, compared to conventionally prepared CPs. The resulting high surface area interface between polymer and liquid media facilities ion exchange and can lead to larger and more rapid responses to redox cycling. CP systems are maturing as platforms for electrically tunable drug delivery. CPs with defined micro- or nanostructures offer the ability to increase the amount of drug that can be delivered whilst enabling systems to be finely tuned to control the extent and rate of drug release. In this review, fabrication approaches to achieve CPs with micro- or nanostructure are outlined followed by a detailed review and discussion of recent advances in the application of the materials for drug delivery.

Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration.

Chemotherapeutic drug delivery is often ineffective within solid tumors, but increasing the drug dose would result in systemic toxicity. The use of high-intensity focused ultrasound (HIFU) has the potential to enhance penetration of small molecules. However, operation parameters need to be optimized before the use of chemotherapeutic drugs in vivo and translation to clinical trials. In this study, the effects of pulsed HIFU (pHIFU) parameters (spatial-average pulse-average intensity, duty factor and pulse repetition frequency) on the penetration as well as content of small molecules were evaluated in ex vivo porcine kidneys. Specific HIFU parameters resulted in more than 40 times greater Evans blue content and 3.5 times the penetration depth compared with untreated samples. When selected parameters were applied to porcine kidneys in vivo, a 2.3-fold increase in concentration was obtained after a 2-min exposure to pHIFU. Pulsed HIFU has been found to be an effective modality to enhance both the concentration and penetration depth of small molecules in tissue using the optimized HIFU parameters. Although, performed in normal tissue, this study has the promise of translation into tumor tissue.

A pH-Driven and photoresponsive nanocarrier: Remotely-controlled by near-infrared light for stepwise antitumor treatment.

The hollow gold nanospheres (HAuNS) have shown medicinal promise due to their inert and nontoxic properties with unique photothermal therapy capabilities. In this study, the electrostatic approach was employed to successfully absorb Chlorin e6 (Ce6) simultaneously with the pH (low) insertion peptide (pHLIP) onto surface of HAuNS, forming HAuNS-pHLIP-Ce6 with desirable pH-driven and NIR light-stimulated controlled therapeutical effect. The HAuNS-pHLIP-Ce6 experienced hyperthermia within 5 min of laser exposure, which marked the photothermal therapy (PTT) and deduced the agents release due to the reduction of electrostatic interaction. The improved strategy facilitated a stepwise photoresponsive system capable of active accumulation and retention effects, photothermal ablation of tumor cells, release of photosensitizers (PS), and subsequently photodynamic therapy (PDT) in a single light irradiation session. The smart delivery system had been proved with multi-functionalities via conjugated targeting ligand and PS. The external absorption of patient tailored medication combinations was also possible with this treatment platform.

Nano "Chocolate Waffle" for near-IR Responsive Drug Releasing System.

A majority of the photo-responsive drug-delivery systems that are currently being studied require a complicated synthesis method. Here, we prepare a near-infrared responsive, photothermally controllable, drug-delivery carrier by a simple mixing and extraction process without the incorporation of toxic chemicals. A blend of doxorubicin (DOX), an anticancer drug, and a phase-change material (PCM) are loaded onto the mesoporous structure of silica-coated graphene oxide (GO@MS) to form a waffle-like structure, which is confirmed by various physicochemical analyses. The cytotoxicity of DOX/PCM-loaded GO@MS (DOX/PCM-GO@MS) against HeLa cells is 50 times higher than that of free DOX, and this improved activity can be attributed to the photothermal effectiveness of GO@MS. Additionally, the cytotoxicity and uptake mechanism of the PCM-based material are analyzed by flow cytometry. Taken together, our results suggest an enormous potential for spatio-temporal control in photothermally responsive drug-delivery systems.

The effect of region of interest strategies on apparent diffusion coefficient assessment in patients treated with palliative radiation therapy to brain metastases.

BACKGROUND: Although diffusion-weighted magnetic resonance imaging (DW-MRI) is widely used in radiation therapy (RT) response studies, no standard of delineating the region of interest (ROI) exists. In this retrospective study, we evaluate the effect of four ROI strategies on the apparent diffusion coefficients (ADC) in patients receiving palliative RT to brain metastases. MATERIAL AND METHODS: Twenty-two metastases from nine patients, treated with whole-brain irradiation (30 Gy in 10 fractions) were analyzed. Patients were scanned with a 1T MR system to acquire DW- (eight b-values), T2*W-, T2W- and T1W scans, before start of RT (pre-RT) and at the 9th/10th fraction (end-RT). The following ROI strategies were applied. ROIb800 and ROIb0: Entire tumor volume visible on DW(b = 800 s/mm(2)) and DW(b = 0 s/mm(2)) images, respectively. ROIb800vi: Viable tumor volume based on DW(b = 800 s/mm(2)). ROIb800rep: ROIb800 from pre-RT scan replicated to end-RT scan. Delineations were aided by co-registered T1W, T2W and T2*W images. ADC was estimated with two mono-exponential fits and one bi-exponential fit. RESULTS: Differences in absolute ADC values were non-significant across ROI strategy independent of fitting method, while significantly different between fitting methods. Evaluation of individual metastases showed that ROI strategies disagreed on the relative ADC change (from pre-RT to end-RT) in 13 of the 22 metastases when all fitting methods were added up. CONCLUSION: The ROI strategies have an effect on the relative ADC change, which may be important for the assessment of individual patient's response to RT and the interpretation of the current literature.

Diffusion-weighted magnetic resonance imaging during radiotherapy of locally advanced cervical cancer--treatment response assessment using different segmentation methods.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) and the derived apparent diffusion coefficient (ADC) value has potential for monitoring tumor response to radiotherapy (RT). Method used for segmentation of volumes with reduced diffusion will influence both volume size and observed distribution of ADC values. This study evaluates: 1) different segmentation methods; and 2) how they affect assessment of tumor ADC value during RT. MATERIAL AND METHODS: Eleven patients with locally advanced cervical cancer underwent MRI three times during their RT: prior to start of RT (PRERT), two weeks into external beam RT (WK2RT) and one week prior to brachytherapy (PREBT). Volumes on DW-MRI were segmented using three semi-automatic segmentation methods: "cluster analysis", "relative signal intensity (SD4)" and "region growing". Segmented volumes were compared to the gross tumor volume (GTV) identified on T2-weighted MR images using the Jaccard similarity index (JSI). ADC values from segmented volumes were compared and changes of ADC values during therapy were evaluated. RESULTS: Significant difference between the four volumes (GTV, DWIcluster, DWISD4 and DWIregion) was found (p < 0.01), and the volumes changed significantly during treatment (p < 0.01). There was a significant difference in JSI among segmentation methods at time of PRERT (p < 0.016) with region growing having the lowest JSIGTV (mean± sd: 0.35 ± 0.1), followed by the SD4 method (mean± sd: 0.50 ± 0.1) and clustering (mean± sd: 0.52 ± 0.3). There was no significant difference in mean ADC value compared at same treatment time. Mean tumor ADC value increased significantly (p < 0.01) for all methods across treatment time. CONCLUSION: Among the three semi-automatic segmentations of hyper-intense intensities on DW-MR images implemented, cluster analysis and relative signal thresholding had the greatest similarity to the clinical tumor volume. Evaluation of mean ADC value did not depend on segmentation method.

Ultrasonically Assisted Polysaccharide Microcontainers for Delivery of Lipophilic Antitumor Drugs: Preparation and in Vitro Evaluation.

High toxicity, poor selectivity, and severe side effects are major drawbacks of anticancer drugs. Various drug delivery systems could be proposed to overcome these limitations. The aim of this study was to fabricate polysaccharide microcontainers (MCs) loaded with thymoquinone (TQ) by a one-step ultrasonication technique and to study their cellular uptake and cytotoxicity in vitro. Two MC fractions with a mean size of 500 nm (MC-0.5) and 2 µM (MC-2) were prepared and characterized. Uptake of the MCs by mouse melanoma M-3 cells was evaluated in both 2D (monolayer culture) and 3D (multicellular tumor spheroids) models by confocal microscopy, flow cytometry, and fluorimetry. The higher cytotoxicity of the TQ-MC-0.5 sample than the TQ-MC-2 fraction was in good correlation with higher MC-0.5 accumulation in the cells. The MC-0.5 beads were more promising than the MC-2 particles because of a higher cellular uptake in both 2D and 3D models, an enhanced antitumor effect, and a lower nonspecific toxicity.

Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood-brain barrier.

PURPOSE: The present study examines the use of an external magnetic field in combination with the disruption of tight junctions to enhance the permeability of iron oxide nanoparticles (IONPs) across an in vitro model of the blood-brain barrier (BBB). The feasibility of such an approach, termed magnetic field enhanced convective diffusion (MFECD), along with the effect of IONP surface charge on permeability, was examined. METHODS: The effect of magnetic field on the permeability of positively (aminosilane-coated [AmS]-IONPs) and negatively (N-(trimethoxysilylpropyl)ethylenediaminetriacetate [EDT]-IONPs) charged IONPs was evaluated in confluent monolayers of mouse brain endothelial cells under normal and osmotically disrupted conditions. RESULTS: Neither IONP formulation was permeable across an intact cell monolayer. However, when tight junctions were disrupted using D-mannitol, flux of EDT-IONPs across the bEnd.3 monolayers was 28%, increasing to 44% when a magnetic field was present. In contrast, the permeability of AmS-IONPs after osmotic disruption was less than 5%. The cellular uptake profile of both IONPs was not altered by the presence of mannitol. CONCLUSIONS: MFECD improved the permeability of EDT-IONPs through the paracellular route. The MFECD approach favors negatively charged IONPs that have low affinity for the brain endothelial cells and high colloidal stability. This suggests that MFECD may improve IONP-based drug delivery to the brain.

High-frequency (20 to 40 MHz) acoustic response of liquid-filled nanocapsules.

Liquid-core nanoparticles are promising candidates for targeted ultrasound-controlled therapy, but their acoustic detection remains challenging. High-frequency (20 to 40 MHz) tone burst sequences were implemented with a programmable ultrasound biomicroscope to characterize acoustic response from perfluorooctyl bromide-core nanoparticles with thick poly(lactide-coglycolide) (PLGA) shells. Radio-frequency signals were acquired from flowing solutions of nanoparticles with two different shell-thickness-to-particle-radius ratios, solid PLGA nanoparticles, and latex nanobeads (linear controls). Normalized fundamental (20 MHz) and second-harmonic power spectral density (PSD) increased with particle concentration and was highest for the thinnest shelled particles. The second- harmonic PSD was detectable from the nanoparticles for peak rarefactional pressures (PRP) from 0.97 to 2.01 MPa at 23 cycles and for tone bursts from 11 to 23 cycles at 2.01 MPa. Their second-harmonic¿to¿fundamental ratio increased as a function of PRP and number of cycles. Within the same PRP and cycle ranges, the second-harmonic¿to¿fundamental ratios from matched concentration solutions of latex nanobeads and solid PLGA nanoparticles was more weakly detectable but also increased with PRP and number of cycles. Nanoparticles were detectable under flow conditions in vitro using the contrast agent mode of a high-frequency commercial scanner. These results characterize linear acoustic response from the nanoparticles (20 to 40 MHz) and demonstrate potential for their highfrequency detection.

In vitro localized release of thermosensitive liposomes with ultrasound-induced hyperthermia.

Localized drug delivery with ultrasound-induced hyperthermia can enhance the therapeutic index of chemotherapeutic drugs by improving efficacy and reducing systemic toxicity. A novel in vitro method for the activation of drug-loaded thermosensitive liposomes is described. In particular, a dual-compartment, acoustically transparent container is used in which thermosensitive liposomes suspended in cell culture medium are immersed in a thermally absorptive medium, glycerol. Hyperthermia is induced with ultrasound in the glycerol, which in turn heats the culture medium by thermal conduction. The method approximately mimics the in vivo scenario of thermosensitive liposomes collected in the interstitial spaces of tumors, where ultrasound induces hyperthermia in the tumor tissue, which in turn heats the thermosensitive liposomes by conduction and induces release of the encapsulated drug. The acoustic conditions for the desired hyperthermia are derived theoretically and validated experimentally. Eighty percent release of doxorubicin from thermosensitive liposomes is achieved.

Fabrication and characterization of photoluminescent silicon nanoparticles for drug delivery applications.

Photoluminescent silicon nanoparticles containing camptothecin (CPT) were fabricated by using a CPT-derivatized porous silicon (PSi). PSi samples displaying red photoluminescence (PL) were prepared by an electrochemical etch of n-type silicon under the illumination with a 300 W tungsten filament bulb for the duration of etch. For the drug-derivatized PSi, luminescent PSi was oxidized and derivatized with CPT. Silicon nanoparticles containing CPT were obtained by fracturing of luminescent PSi with ultrasono-method. Optical characteristic of drug-derivatized silicon particles were investigated in aqueous buffer solution. The release of CPT was measured by UV-vis spectrometer. The intensity of fluorescence of the silicon nanoparticles was measured with a drug release. The concentration of released drug exhibited non-linear relationship with a release time.

Analytical model of chemical phase and formation of DSB in chromosomes by ionizing radiation.

Mathematical analytical model of the processes running in individual radical clusters during the chemical phase (under the presence of radiomodifiers) proposed by us earlier has been further developed and improved. It has been applied to the data presented by Blok and Loman characterizing the oxygen effect in SSB and DSB formation (in water solution and at low-LET radiation) also in the region of very small oxygen concentrations, which cannot be studied with the help of experiments done with living cells. In this new analysis the values of all reaction rates and diffusion parameters known from literature have been made use of. The great increase of SSB and DSB at zero oxygen concentration may follow from the fact that at small oxygen concentrations the oxygen absorbs other radicals while at higher concentrations the formation of oxygen radicals prevails. It explains the double oxygen effect found already earlier by Ewing. The model may be easily extended to include also the effects of other radiomodifiers present in medium during irradiation.

Microbubble-induced sonoporation involved in ultrasound-mediated DNA transfection in vitro at low acoustic pressures.

In the present work, human breast cancer cells MCF-7 mixed with polyethylenimine: deoxyribonucleic acid complex and microbubbles were exposed to 1-MHz ultrasound at low acoustic driving pressures ranging from 0.05 to 0.3 MPa. The sonoporation pores generated on the cell membrane were examined with scanning electron microscopy. The transfection efficiency and cell viability were evaluated with flow cytometry. The results showed that ultrasound sonication under the current exposure condition could generate cell pores with mean size ranging from about 100 nm to 1.25 µm, and that larger sonoporation pores would be generated with the increasing acoustic pressure or longer treatment time, leading to the enhancement of transfection efficiency and the reduction of cell viability. The simulations based on the Marmottant model were performed to test the hypothesis that the microstreaming-induced shear stress might be involved in the mechanisms of the low-intensity ultrasound induced sonoporation. The calculated shear stress resulting from the micro-streaming ranged from 15 to 680 Pa corresponding to the applied acoustic pressures 0.05-0.3 MPa, which is sufficient to induce reversible sonoporation. This study indicates that the shear stress related bio-effects may provide a base for strategies aimed at targeted drug delivery.

Synergetic effect between photocatalytic degradation and adsorption processes on the removal of phenolic compounds from olive mill wastewater.

The photocatalytic degradation of two phenolic compounds, p-coumaric acid and caffeic acid, was performed with a suspended mixture of TiO(2) and powdered activated carbon (PAC) (at pH=3.4 and 8). Adsorption, direct photolysis and photocatalytic degradation were studied under different pH and UV light sources (sunlight vs. 365nm UV lamps). The potential for reusing this catalyst mixture in sequential photocatalytic runs was examined as well. Quantum yields for the direct photolysis of caffeic acid under solar and artificial 365nm light were calculated (for the first time) as 0.005 and 0.011, respectively. A higher removal rate of contaminants by either adsorption or photocatalysis was obtained at a low pH (pH 4). Furthermore, the addition of PAC increased the removal efficiency of the phenolic compounds. Fast removal of the pollutants from the solution over three sequential runs was achieved only when both TiO(2) and PAC were present. This suggests that at medium phenolic concentrations, the presence of PAC as a co-sorbent reduces surface poisoning of the TiO(2) catalyst and hence improves photocatalysis degradation of phenolic pollutants. The adsorption equilibrium of caffeic acid or p-coumaric acid on TiO(2), PAC and the combined mixture of TiO(2) and PAC follows the Langmuir isotherm model. Experiments with PAC TiO(2) mixture and olive mill wastewater (anaerobically treated and diluted by a factor of 10) showed higher removal of polyphenols than of chemical oxygen demand (COD). 87% removal of total polyphenols, compared to 58% of COD, was achieved after 24h of exposure to 365nm irradiation (7.6W/m(2)) in the presence of a suspended mixture of TiO(2) and PAC, indicating "self-selectivity" of polyphenols.

Degradation mechanism of 4-chlorophenol with electrogenerated hydrogen peroxide on a Pd/C gas-diffusion electrode.

Using a self-made Pd/C gas-diffusion electrode as the cathode and a Ti/IrO2/RuO2 anode, the degradation of 4-chlorophenol has been investigated in an undivided electrolysis device by the electrochemical oxidation processes. The result indicated that the neutral aqueous solutions can accelerate 4-chlorophenol degradation during electrolysis. The removal efficiency of 4-chlorophenol and COD reached about 89.6% and 62.0% after 120 min electrolysis, respectively. It suggested that most of 4-chlorophenol was oxidised to intermediates using the Pd/C gas-diffusion electrode. Furthermore, the biodegradation ability of the solution was increased significantly during the electrolysis. The degradation of 4-chlorophenol was attributed to the cooperative oxidation processes including electrochemical oxidation at the anode and H2O2 and hydroxyl radical (HO·) produced by the reduction of oxygen at the cathode. Finally, main aromatic intermediates (e.g., hydroquinone and benzoquinone) and main aliphatic carboxylic intermediates (e.g., oxalic, malonic, maleic, succinic, fumaric, and dodecanoic acids) were identified by GC-MS. Moreover, a reaction scheme involving all these intermediates was proposed.

The reaction process of firefly bioluminescence triggered by photolysis of caged-ATP.

The reaction process of firefly bioluminescence was studied by photolyzing caged-ATP to adenosine triphosphate (ATP) within 100 ms. The intensity of luminescence increases markedly to reach a maximum within 1 s, maintains almost the same intensity up to 5 s and then decays monotonically. The rise γ(1) and decay γ(2) rate constants were determined to be about 5 s(-1) and 1 × 10(-2) s(-1), respectively, so as to phenomenologically fit the time course. A second luminescence peak appears after around 350 s. The dependence of the rate constants on the concentrations of reactants and a viscous reagent revealed that two kinds of reaction contribute the observed time course: (1) an intrinsic reaction by ATP photolyzed from caged-ATP that is already trapped in luciferase; and (2) a diffusion-controlled reaction by free ATP in the buffer solution outside luciferase. Numerical analysis based on reaction kinetics related γ(1) and γ(2) to the rate constants of a three-step reaction model, and accurately described the effects of concentration of reactants and a viscous reagent on the time courses of bioluminescence. Thus, it has been clearly concluded that the binding mode of caged-ATP at the catalytic center of luciferase is very different from that of ATP.

Detection of weak and large electric fields through the transient dynamics of a Brownian particle in an electromagnetic field.

In this work we present a mechanism to detect the presence of an external electric field of either weak or large amplitude by means of the decay process from an unstable state, described by a bistable potential, of an electrically charged Brownian particle embedded in a uniform electromagnetic field. Since the detection process takes place around the initial unstable state of the bistable potential, our theoretical description is given in the linear approximation of the aforementioned potential. The decay process is characterized through the statistics of the passage time distribution calculated by means of two theoretical approaches relying on the overdamped Langevin equation: one is the quasideterministic approach valid for large times and used for the detection of weak signals, whereas the other one is the rotational approach, valid for intermediate times and adequate for the detection of large electric-field amplitudes.