Development and first implementation of a novel multi-modality cardiac motion and dosimetry phantom for radiotherapy applications.

BACKGROUND: Cardiac applications in radiation therapy are rapidly expanding including magnetic resonance guided radiation therapy (MRgRT) for real-time gating for targeting and avoidance near the heart or treating ventricular tachycardia (VT). PURPOSE: This work describes the development and implementation of a novel multi-modality and magnetic resonance (MR)-compatible cardiac phantom. METHODS: The patient-informed 3D model was derived from manual contouring of a contrast-enhanced Coronary Computed Tomography Angiography scan, exported as a Stereolithography model, then post-processed to simulate female heart with an average volume. The model was 3D-printed using Elastic50A to provide MR contrast to water background. Two rigid acrylic modules containing cardiac structures were designed and assembled, retrofitting to an MR-safe programmable motor to supply cardiac and respiratory motion in superior-inferior directions. One module contained a cavity for an ion chamber (IC), and the other was equipped with multiple interchangeable cavities for plastic scintillation detectors (PSDs). Images were acquired on a 0.35 T MR-linac for validation of phantom geometry, motion, and simulated online treatment planning and delivery. Three motion profiles were prescribed: patient-derived cardiac (sine waveform, 4.3 mm peak-to-peak, 60 beats/min), respiratory (cos4 waveform, 30 mm peak-to-peak, 12 breaths/min), and a superposition of cardiac (sine waveform, 4 mm peak-to-peak, 70 beats/min) and respiratory (cos4 waveform, 24 mm peak-to-peak, 12 breaths/min). The amplitude of the motion profiles was evaluated from sagittal cine images at eight frames/s with a resolution of 2.4 mm × 2.4 mm. Gated dosimetry experiments were performed using the two module configurations for calculating dose relative to stationary. A CT-based VT treatment plan was delivered twice under cone-beam CT guidance and cumulative stationary doses to multi-point PSDs were evaluated. RESULTS: No artifacts were observed on any images acquired during phantom operation. Phantom excursions measured 49.3 ± 25.8%/66.9 ± 14.0%, 97.0 ± 2.2%/96.4 ± 1.7%, and 90.4 ± 4.8%/89.3 ± 3.5% of prescription for cardiac, respiratory, and cardio-respiratory motion profiles for the 2-chamber (PSD) and 12-substructure (IC) phantom modules respectively. In the gated experiments, the cumulative dose was <2% from expected using the IC module. Real-time dose measured for the PSDs at 10 Hz acquisition rate demonstrated the ability to detect the dosimetric consequences of cardiac, respiratory, and cardio-respiratory motion when sampling of different locations during a single delivery, and the stability of our phantom dosimetric results over repeated cycles for the high dose and high gradient regions. For the VT delivery, high dose PSD was <1% from expected (5-6 cGy deviation of 5.9 Gy/fraction) and high gradient/low dose regions had deviations <3.6% (6.3 cGy less than expected 1.73 Gy/fraction). CONCLUSIONS: A novel multi-modality modular heart phantom was designed, constructed, and used for gated radiotherapy experiments on a 0.35 T MR-linac. Our phantom was capable of mimicking cardiac, cardio-respiratory, and respiratory motion while performing dosimetric evaluations of gated procedures using IC and PSD configurations. Time-resolved PSDs with small sensitive volumes appear promising for low-amplitude/high-frequency motion and multi-point data acquisition for advanced dosimetric capabilities. Illustrating VT planning and delivery further expands our phantom to address the unmet needs of cardiac applications in radiotherapy.

Optimization of the Dose Rate Effect in Tetrazolium Gellan Gel Dosimeters.

Tetrazolium salts provide an appealing candidate for 3D gel dosimeters as they exhibit a low intrinsic color, no signal diffusion and excellent chemical stability. However, a previously developed commercial product (the ClearView 3D Dosimeter) based on a tetrazolium salt dispersed within a gellan gum matrix presented a noticeable dose rate effect. The goal of this study was to find out whether ClearView could be reformulated in order to minimize the dose rate effect by optimizing of the tetrazolium salt and gellan gum concentrations and by the addition a thickening agent, ionic crosslinkers, and radical scavengers. To that goal, a multifactorial design of experiments (DOE) was conducted in small-volume samples (4-mL cuvettes). It showed that the dose rate could be effectively minimized without sacrificing the integrity, chemical stability, or dose sensitivity of the dosimeter. The results from the DOE were used to prepare candidate formulations for larger-scale testing in 1-L samples to allow for fine-tuning the dosimeter formulation and conducting more detailed studies. Finally, an optimized formulation was scaled-up to a clinically relevant volume of 2.7 L and tested against a simulated arc treatment delivery with three spherical targets (diameter 3.0 cm), requiring different doses and dose rates. The results showed excellent geometric and dosimetric registration, with a gamma passing rate (at 10% minimum dose threshold) of 99.3% for dose difference and distance to agreement criteria of 3%/2 mm, compared to 95.7% in the previous formulation. This difference may be of clinical importance, as the new formulation may allow the quality assurance of complex treatment plans, relying on a variety of doses and dose rates; thus, expanding the potential practical application of the dosimeter.

Gellan gum gel tissue phantoms and gel dosimeters with tunable electrical, mechanical and dosimetric properties.

Gellan gum gels have been proposed as tissue- and water-mimicking materials (phantoms) applied in medical imaging and radiotherapy dosimetry. Phantoms often require ionic additives to induce desirable electrical conductivity, resistance to biological spoilage, and radical scavenging properties. However, gellan gum is strongly crosslinked by the typically used sodium salts, forming difficult-to-work with gels with reduced optical clarity. Herein we investigated lithium and tetramethylammonium chloride to induce the required electrical conductivity while maintaining optical clarity; lithium formate and methylparaben were used as a radical scavenger and antimicrobial additive, respectively. Using a multifactorial design of experiments, we studied and modeled the electrical and mechanical properties and liquid expulsion (syneresis) properties of the gels. Finally, by the addition of a radiation-sensitive tetrazolium salt, dosimeters with favorable properties were produced. The results described herein may be used to prepare tissue phantoms and dosimeters with tuned electrical, mechanical, and dosimetric properties.

On the diatomite-based nanostructure-preserving material synthesis for energy applications.

The present article overviews the current state-of-the-art and future prospects for the use of diatomaceous earth (DE) in the continuously expanding sector of energy science and technology. An eco-friendly direct source of silica and the production of silicon, diatomaceous earth possesses a desirable nano- to micro-structure that offers inherent advantages for optimum performance in existing and new applications in electrochemistry, catalysis, optoelectronics, and biomedical engineering. Silica, silicon and silicon-based materials have proven useful for energy harvesting and storage applications. However, they often encounter setbacks to their commercialization due to the limited capability for the production of materials possessing fascinating microstructures to deliver optimum performance. Despite many current research trends focusing on the means to create the required nano- to micro-structures, the high cost and complex, potentially environmentally harmful chemical synthesis techniques remain a considerable challenge. The present review examines the advances made using diatomaceous earth as a source of silica, silicon-based materials and templates for energy related applications. The main synthesis routes aimed at preserving the highly desirable naturally formed neat nanostructure of diatomaceous earth are assessed in this review that culminates with the discussion of recently developed pathways to achieving the best properties. The trend analysis establishes a clear roadmap for diatomaceous earth as a source material of choice for current and future energy applications.

Novel microscopy-based approaches to study the film formation mechanism and associated mechanical response in polymer lattices.

In this paper, we present the results from novel microscopy-based approaches aimed at providing further insight into the mechanism of film formation and associated mechanical response in polymer lattices. Firstly, a 'simple' methodology, combining the use of variable pressure scanning electron microscopy and a recently introduced enhanced coolstage (-50 to +50°C), was successfully developed and not only used to study dynamic processes, e.g. different stages of latex film formation, but also for high-resolution imaging of 'freeze-dried' structures. By using the enhanced freeze-drying capability of the system, it was also possible to preserve the structure and features of the studied system with minimum shrinkage and distortion and in the case of polymer lattices at a desired stage of film formation. Moreover, specimens can then be readily imaged, without the need of conductive coatings and at much lower chamber gas pressures, thus minimizing the beam skirting effects and allowing higher resolutions to be achieved. The second and final part of our study consider the mechanical response of the studied latex dried under different conditions, with the particular emphasis on the effects of drying rate [% relative humidity (RH)]. Atomic force microscopy force distance curve measurements revealed that while the %RH did not have an effect on the structures formed, it did have an effect on the adhesive properties of the studied system. It is strongly believed that the methodologies developed and used here can be applied to other material systems, including biologicals and pharmaceuticals.

Gellan gum-based gels with tunable relaxation properties for MRI phantoms.

OBJECT: The research follows the analysis of gellan gum-based gels as novel MRI phantom material with the implementation of a design of experiments model to obtain tunable relaxation properties. MATERIALS AND METHODS: Gellan gum gels doped with newly synthesized superparamagnetic iron oxide nanoparticles (SPIONs) and either MnCl2 or GdCl3 were prepared and scanned from 230 µT to 3 T. Nineteen gel samples were formulated with varying concentrations of contrast agents to determine the linear, quadratic, and interactive effects of the contrast agents by a central composite design of experiment. To inhibit microbial growth in the gels and to enable long-term use, methyl 4­hydroxybenzoate (methylparaben) was utilized. RESULTS: The model containing SPIONs and metal salts relaxivity was analyzed with ANOVA, and the resulting significant coefficients were tabulated. The mathematical model was able to accurately predict the intended relaxation property from the concentration of the contrast agent with adjusted R2 values > 0.97 for longitudinal (R1) relaxation rates and 0.87 for transverse (R2) relaxation rates. CONCLUSION: The gel material maintained physical, chemical, and biological stability for at least four months and contained controllable relaxation properties while maintaining optical clarity.

Multifactorial study and kinetics of signal development in ferrous-methylthymol blue-gelatin gel dosimeters.

PURPOSE: To develop and characterize a ferrous-methylthymol blue-gelatin gel dosimeter with low optical background and appropriate additives for reduced rate of auto-oxidation and diffusion. METHODS: A mixed-level multifactorial design of experiments was used to test the effects of the concentrations of sulfuric acid, 5-nitro-1,10-phenanthroline (Nn), and glyoxal (Gx) on the background absorbance, dose sensitivity, and auto-oxidation of the tested gel dosimeter. The dosimetric properties of the proposed ferrous-methylthymol blue-gelatin dosimeter, doped with Nn and Gx, were compared with the undoped formulation and with ferrous-xylenol orange-gelatin gel dosimeters. Irradiations were performed in both small-scale cuvette samples and large 400-mL bulk samples. In addition to that, a new kinetic model for the signal development postirradiation was derived based on chemical principles and used for comparison of the different formulations. RESULTS: The new formulation showed a reduced auto-oxidation rate, while maintaining low background absorbance relative to the common ferrous-xylenol orange-gelatin gel dosimeter. Compared with undoped ferrous-xylenol orange or ferrous-methylthymol blue gels, the dose sensitivity of the new formulation is approximately 2 to 3 times lower, but remains clinically adequate. A previously unreported dose rate dependence of the dose sensitivity was observed, and a new kinetic model for the signal development postirradiation was used to investigate this effect. Similar dose rate dependences in gels containing either methylthymol blue or xylenol orange, with or without doping with Nn and Gx, were observed, suggesting that the low ferrous ammonium sulfate concentrations used in studied formulations were responsible for this effect. CONCLUSIONS: A multifactorial design of experiments and a new kinetic model for the signal development postirradiation were successfully employed to optimize the composition and characterize the properties of a new ferrous-methylthymol blue-gelatin gel dosimeter doped with 5-nitro-1,10-phenanthroline and glyoxal. Concrete recommendations were provided for precise dosimetry using the new formulation.

Controlling sensitivity and stability of ferrous-xylenol orange-gelatin 3D gel dosimeters by doping with phenanthroline-type ligands and glyoxal.

The ferrous-xylenol orange-gelatin (FXG) dosimeter is widely used for three-dimensional ionizing radiation field mapping through optical scanning. Upon irradiation, the ferrous iron (Fe(2+)) is oxidized to ferric iron (Fe(3+)), which forms an intensely coloured complex with xylenol orange (XO). XO also acts as a diffusion-limiting additive; however, its presence may cause rapid auto-oxidation of Fe(2+) during storage and low stability of the dose response. In this work, phenanthroline-type ligands were added to FXG system in a bid to bind the ferrous iron in a stable complex and minimize the rate of the auto-oxidation, whereas glyoxal was used as a chemical cross-linker, aiming to minimize the ferric iron diffusion. It was found that addition of either 1,10-phenanthroline or 5-nitro-1,10-phenanthroline can improve the auto-oxidation behaviour of the gels. However, the initial background absorbance was slightly increased, and the sensitivity of the dosimeters was decreased. Doping with glyoxal led to a moderate decrease of the diffusion only in those gels that also contained a phenanthroline-type ligand, and did not affect the initial dose response. Glyoxal also afforded an extended period of stable background absorbance level after an initial period of bleaching of the gel. Following re-irradiation, most glyoxal-containing dosimeters showed an excellent linearity of the dose response, albeit at a decreased sensitivity. We recommend further testing of FXG dosimeters, doped with phenanthroline-type ligands and glyoxal as a means for controlling the dose response and improving the long-term storage properties of the gels and the potential for dose fractionation.

Cracking of drying latex films: an ESEM experiment.

In this study environmental scanning electron microscopy was used to observe the cracking of drying latex films below their glass-transition temperature. By controlling the relative humidity so that it decreases linearly with time, a critical level of humidity at which cracking occurs can be determined and this is measured as a function of film thickness. It was found that the cracking humidity decreases with increases in film thickness for thicknesses in the range of 30 to 100 mum and then remains almost unchanged. A scaling argument can be used to fit the data very well and indicates that cracking occurs as soon as the entire film is consolidated into close packing.

A new tensile stage for in situ electron microscopy examination of the mechanical properties of "superelastic" specimens.

We have developed a novel tensile stage that can be used for in situ electron microscopy examination of the mechanical properties of "superelastic" materials. In our stage, one of the specimen clamps is replaced by a cylindrical roller, which when driven by a motor can easily stretch ("roll on") any specimen irrespective of its plastic properties. We have used the so-called Roll-o-meter in the study of the tensile behavior of two different film formed latex formulations, here referred to as standard and novel. We find that the values of the tensile strength and extension to break of the studied systems, measured by using the Roll-o-meter, are similar to those measured by a Hounsfield tensile testing machine outside the microscope chamber. Further, in situ environmental scanning electron microscopy examination of the deformation and failure of the lattices revealed that the standard specimens exhibit a more ductile behavior, compared to the novel ones.

Evaluation of the ligase chain reaction (LCR) for the detection of point mutations.

The ligase chain reaction (LCR) was evaluated as an amplification method for an in vivo mutation assay. Specifically, the ligase was tested for its ability to selectively amplify a DNA sequence mutated at a single base, in the presence of an excess of wild-type DNA. As a model template a 370-bp DNA fragment of the mouse Ha-ras protooncogene containing an A to T mutation at the second position of codon 61 was used. With the commercially available ligase Ampligase (Epicenter), 250 molecules of mutant fragments could be detected by an enzyme-linked immunoassay with digoxigenin marker (giving a theoretical detection limit of 1 target gene per 10(4) copies of genome). In the analysis of mixtures with corresponding wild-type DNA fragments, a 1:1 mixture resulted in a clearly stronger signal than control samples lacking wild-type and mutant DNA. However, the signal obtained from a 100-fold dilution of the mutant DNA with wild-type DNA could not be distinguished from the background noise. In this particular form, LCR lacks sufficient selectivity to be applied to an in vivo situation, where the ratio of mutant to wild-type DNA sequences might be expected to lie around 1:10(6).