Investigation of tetrakis hydroxymethyl phosphonium chloride as an antioxidant for use in x-ray computed tomography polyacrylamide gel dosimetry

Of the antioxidants used to scavenge oxygen in polymer gel dosimeters, tetrakis (hydroxymethyl) phosphonium chloride (THPC) has been shown to hold great promise due to its rapid oxygen scavenging abilities. In this study we (a) investigate the use of THPC as an antioxidant for polyacrylamide gel (PAGAT) dosimeters used in conjunction with x-ray computed tomography (CT) and (b) work to establish the reaction mechanisms of THPC with the polymer gel constituents. We establish the dose response reproducibility of PAGAT dosimeters when imaged with CT and show that PAGAT dosimeters exhibit highly reproducible dose responses for a range of irradiation times post gel manufacture (2-6 h) and CT imaging times post gel irradiation (1-5 days). The THPC concentration within the gel leading to a maximized dose response and minimized O(2) inhibition of polymerization is found to be approximately 4.5 mM. We further assess the stability of PAGAT dosimeters by investigating the reactions of THPC with the individual gel constituents. The importance of utilizing deionized water in polymer gel manufacture is noted. We show that, while THPC remains unreactive with acrylamide and bis-acrylamide under unirradiated conditions, THPC can react with gelatin to increase the cross-linking of the gelatin matrix in unirradiated dosimeters. THPC reactions with gelatin can lead to the lower observed dose sensitivity of PAGAT (approximately 0.36 +/- 0.04 H Gy(-1)) as compared to polyacrylamide gels manufactured under anoxic conditions (approximately 0.83 +/- 0.03 H Gy(-1)). The reactions of THPC which lead to O(2) scavenging, and potential reactions of THPC with other gel constituents, are proposed.     

Investigation of the PAGAT polymer gel dosimeter using magnetic resonance imaging

Investigation of the normoxic PAGAT polymer gel dosimeter has been undertaken. The concentrations of the chemical components of the gel were varied and its response to ionizing radiation evaluated. Using MRI, the formulation to give the maximum change in the transverse relaxation rate R2 was determined to be 4.5% N, N'-methylene-bis-acrylamide (bis), 4.5% acrylamide (AA), 5% gelatine, 5 mM tetrakis (hydroxymethyl) phosphonium chloride (THPC), 0.01 mM hydroquinone (HQ) and 86% H2O. The optimal post-manufacture irradiation and post-irradiation imaging times were both determined to be 12 h. The R2-dose response was linear up to 7 Gy with R2-dose sensitivities of (0.183 +/- 0.005) s(-1) Gy(-1), (0.182 +/- 0.005) s(-1) Gy(-1) and (0.192 +/- 0.005) s(-1) Gy(-1) when imaged at 12 h, 7 days and 24 days post-irradiation, respectively. The R2-dose sensitivities were within the range of previously published values for the hypoxic PAG formulations. For the imaging parameters used in this study the optimum dose resolution was achieved for low doses. The normalized R2 edge response showed a high degree of spatial stability over a 24 day period. This study has shown that the normoxic PAGAT polymer gel has the properties of a dosimetric tool, which can be used in clinical radiotherapy. The PAGAT polymer gel has been shown to have similar qualities to the PAG polymer gel, while offering the significant advantage of simplification of the manufacturing procedure.     

The influence of cooling rate on the accuracy of normoxic polymer gel dosimeters

Polymer gel dosimeters offer a wide range of applications in the three-dimensional verification of complex radiation dose distributions such as in intensity-modulated radiotherapy (IMRT). With the release of polymer gel dosimeters that can be fabricated in normal atmospheric ('normoxic') conditions, the gel manufacturing process has been significantly simplified. Gel dosimeters are calibrated by use of a series of calibration vials irradiated with known doses or by use of a calibration phantom with a known dose distribution. The overall accuracy of the polymer gel dosimeters is determined by different dosimetric properties. In this study, we show the influence of the temperature history during storage of the gel dosimeter on the dose response curve for two gel dosimeters using the monomers acrylamide/N,N'-methylene-bis-acrylamide (nPAG) and methacrylic acid (nMAG) respectively and bis[tetrakis(hydroxymethyl)phosphonium]sulphate (THP) as antioxidant in both gel dosimeters. This study reveals that differences in temperature history after fabrication of normoxic polymer gel dosimeters may compromise the dosimetric accuracy. It was found that the acrylamide based gel dosimeter (nPAG) is less dependent on the post-manufacture temperature history than the methacrylic acid based gel dosimeter (nMAG). The importance of an equal temperature history for the gel dosimeter and calibration vials is emphasized by this study. A reproducibility study has also been performed on the nPAG gel dosimeter when additional efforts are made to control the temperature changes upon cooling.     

An experimental study of the dose response of polymer gel dosimeters imaged with x-ray computed tomography.

Changes in the linear attenuation coefficient of polymer gel dosimeters post-irradiation enable the imaging of dose distributions by x-ray computed tomography (CT). Various compositions of polymer gel dosimeters manufactured from acrylamide (AA), and N,N'-methylene-bis-acrylamide (BIS) comonomers and gelatin or agarose gelling agents were investigated. This work shows that increasing the comonomer concentration increases the CT-dose sensitivity of the polymer gel dosimeter. This can be further increased by replacing gelatin with agarose. Varying the gelatin concentration however does not significantly change the CT-dose sensitivity. Among the compositions studied, dose resolution (D(delta)95%) was found to be optimal for polymer gel dosimeters comprising 5% gelatin, 3% AA, 3% BIS and 89% water.     

The fundamental radiation properties of normoxic polymer gel dosimeters: a comparison between a methacrylic acid based gel and acrylamide based gels

Polymer gel dosimeters offer a wide range of applications in the three-dimensional verification of complex dose distributions such as in intensity-modulated radiotherapy. One of the major difficulties with polymer gel dosimeters is their sensitivity to oxygen, as oxygen inhibits the radiation-induced polymerization reaction. For several years, oxygen was removed from the gels by bubbling the sol with inert gases for several hours during the gel fabrication. Also, the gel had to be poured in containers with low oxygen permeability and solubility. Recently, it was found that these technical difficulties can easily be solved by adding an antioxidant to the gel. These gels are called 'normoxic' gels as they can be produced under normal atmospheric conditions. In this study several properties of polymer gel dosimeters have been investigated: the dose sensitivity, the temporal and spatial stability of the gel, the sensitivity of the dose response to temperature during irradiation and during MR imaging, the energy dependence and the dose-rate dependence. This study reveals that the normoxic polymer gel dosimeter based on methacrylic acid (nMAG) studied in this work has inferior radiation properties as compared to the polyacrylamide gelatine (PAG) gel dosimeters. It is shown that from the three different gel dosimeters investigated in this study, the nPAG gel dosimeter results in a less sensitive gel dosimeter but with superior radiation properties as compared to the nMAG gel dosimeter. The importance of investigating relevant radiation properties of gel dosimeters apart from the radiation sensitivity-prior to their use for dosimetric validation experiments-is illustrated and emphasized throughout this study. Other combinations of monomer and gelling agent may result in more reliable normoxic polymer gel dosimeters.     

Experimental study of attenuation properties of normoxic polymer gel dosimeters

The change in linear attenuation coefficient with absorbed dose has been investigated for aqueous polyacrylamide, gelatine and tetrakis (PAGAT) and aqueous methacrylic acid, gelatine and tetrakis (MAGAT) normoxic polymer gel dosimeters using tetrakis (hydroxy methyl) phosphonium chloride as the antioxidant. The measured linear attenuation coefficient increased linearly with absorbed dose up to 15 Gy for PAGAT gels and 10 Gy for MAGAT gels. Computerized tomography (CT) numbers or Hounsfield units (H) were calculated from the linear attenuation coefficients and compared with values obtained using a CT scanner. Both calculated and measured CT numbers followed a similar pattern when fitted with a biexponential curve. The CT numbers obtained from linear attenuation measurements were found to be greater than that obtained with the CT scanner for both PAGAT and MAGAT polymer gels. The H-dose sensitivities of the MAGAT and PAGAT polymer gel dosimeters measured on a CT scanner were calculated to be (0.85 +/- 0.08) H Gy(-1) and (0.31 +/- 0.03) H Gy(-1), respectively. The H-dose sensitivities of the MAGAT and PAGAT polymer gel dosimeters from attenuation measurements were found to be (1.10 +/- 0.66) H Gy(-1) and (0.34 +/- 0.01) H Gy(-1), respectively.     

Attenuation of diagnostic energy photons by polymer gel dosimeters

Post-irradiation changes in the linear attenuation coefficient, mu, of polymer gel dosimeters give rise to a change which can be measured with x-ray computed tomography. Polymer gel dosimeters were manufactured consisting of 3% (by weight) acrylamide and 3% N,N'-methylene-bis-acrylamide comonomers dissolved in aqueous gelatin (5% gelatin by total weight and 89% de-ionized distilled water). Mu was measured in a collimated radiation beam of photons from an 241Am source. Density, rho, of polymer gel dosimeters was measured using volumetric flasks with capillary stoppers. The measured post-irradiation data of mu was plotted against the data of rho for different batches, and linear least squares fits gave r2 values of 0.99605 and 0.99953, with P values of less than 0.001. This confirms that the post-irradiation change in mu is proportional to that of rho. The change in rho implies a change in volume regardless of the evaluation modality of the polymer gel dosimeter.     

Modelling of post-irradiation events in polymer gel dosimeters.

The nuclear magnetic resonance (NMR) spin-spin relaxation time (T2) is related to the radiation-dependent concentration of polymer formed in polymer gel dosimeters manufactured from monomers in an aqueous gelatin matrix. Changes in T2 with time post-irradiation have been reported in the literature but their nature is not fully understood. We investigated those changes with time after irradiation using FT-Raman spectroscopy and the precise determination of T2 at high magnetic field in a polymer gel dosimeter. A model of fast exchange of magnetization taking into account ongoing gelation and strengthening of the gelatin matrix as well as the polymerization of the monomers with time is presented. Published data on the changes of T2 in gelatin gels as a function of post-manufacture time are used and fitted closely by the model presented. The same set of parameters characterizing the variations of T2 in gelatin gels and the increasing concentration of polymer determined from FT-Raman spectroscopy are used successfully in the modelling of irradiated polymer gel dosimeters. Minimal variations in T2 in an irradiated PAG dosimeter are observed after 13 h.     

Three dimensional radiation dosimetry in lung-equivalent regions by use of a radiation sensitive gel foam: proof of principle

A polymer hydrogel foam is proposed as a potential three dimensional experimental dosimeter for radiation treatment verification in low-density tissue such as the lung. A gel foam is created by beating a radiation sensitive polymer gel mixture in an anoxic atmosphere. The mass density of the gel foam is in the order of 0.25-0.35 kg/dm3. Both nuclear magnetic resonance (NMR) spin-spin relaxation rate (R2) and magnetization transfer ratio (MTR) have been used to map the dose distribution from the gel dosimeter. It is found that MTR has significant advantages compared to R2 for mapping the dose distribution in the polymer gel foam dosimeters. The magnetization transfer ratio is found to be less dependent on the density and microstructure of the gel foam dosimeter while spin-spin relaxation dispersion has been observed making the spin-spin relaxation rate dependent on the interecho time interval. Optical microscopy reveals a microstructure that shows great similarity with human lung tissue. It is also shown how NMR hydrogen proton density measurements can be used to map the density distributions in gel dosimeters.     

On the relation between the spatial dose integrity and the temporal instability of polymer gel dosimeters

When irradiating a polymer gel dosimeter to relatively high doses, edge enhancing effects (overshoots) may be noticed near dose gradients, resulting in a loss of spatial dose integrity. These overshoots are believed to be a consequence of monomers diffusing into the high-dose region, where they react with long-living macroradicals. Macroradicals may also be responsible for the temporal chemical instability of post-irradiation polymerization that occurs in the polymer gel dosimeter. In this study, a mathematical model is proposed that simulates the edge enhancing effect. The model is based on the hypothesis that the macroradicals are responsible for both the temporal instability and loss of spatial dose integrity. All input parameters for the model are obtained from independent experiments. The edge enhancing effect is studied both experimentally and theoretically for polymer gel dosimeters with various gelatin concentrations. The change in the edge enhancement is also investigated over post-irradiation time. Comparisons between polymer gel measurements and simulations confirm the hypothesis that there is a strong relation between the spatial and temporal instabilities.     

Cosolvent-free polymer gel dosimeters with improved dose sensitivity and resolution for x-ray CT dose response

This study reports new N-isopropylacrylamide (NIPAM) polymer gel recipes with increased dose sensitivity and improved dose resolution for x-ray CT readout. NIPAM can be used to increase the solubility of N, N'-methylenebisacrylamide (Bis) in aqueous solutions from approximately 3% to 5.5% by weight, enabling the manufacture of dosimeters containing up to 19.5%T, which is the total concentration of NIPAM and Bis by weight. Gelatin is shown to have a mild influence on dose sensitivity when gels are imaged using x-ray CT, and a stronger influence when gels are imaged optically. Phantoms that contain only 3% gelatin and 5 mM tetrakis hydroxymethyl phosphonium chloride are sufficiently stiff for dosimetry applications. The best cosolvent-free gel formulation has a dose sensitivity in the linear range (~0.88 H Gy(-1)) that is a small improvement compared to the best NIPAM-based gels that incorporate isopropanol as a cosolvent (~0.80 H Gy(-1)). This new gel formulation results in enhanced dose resolution (~0.052 Gy) for x-ray CT readout, making clinical applications of this imaging modality more feasible.     

Dose-response stability and integrity of the dose distribution of various polymer gel dosimeters

In this study the stability of different polymer gel dosimeters is investigated. Further to a previous chemical stability study on a (6%T, 50%C) PAG gel, the change in slope and intercept of the linear part of the R2-dose plot is recorded with time for different gel formulations. In addition to this R2-dose-response stability study, the dose edge of a half-blocked field was recorded with time. Three different PAG type polymer gels, a hydroxyethyl acrylate (HEA) gel and two different normoxic polymer gels were investigated. In the PAG type polymer gels, the relative concentration of gelatin and comonomers was varied in order to study the influence of the different components, that constitute the dosimeter, on the stability. It is shown that the R2-dose-response stability is largely determined by the chemical composition of the gel dosimeters. All the PAG gel dosimeters and the normoxic gel dosimeters are found to preserve the integrity of the dose distribution up to 22 days after irradiation. The half-life of the change in dose sensitivity of a MAGIC gel is found to be 18 h compared to 5.7 h for a (6%T, 50%C) PAG gel. A maximum relative decrease in dose sensitivity of 21% was noted for the MAGIC gel compared to an increase of 50% for a (6%T, 50%C) PAG gel. A loss of integrity of the dose distribution was found in the HEA gel.     

Severe dose inaccuracies caused by an oxygen-antioxidant imbalance in normoxic polymer gel dosimeters

Two oxygen scavengers have been successfully tested to produce normoxic polymer gel dosimeters under normal atmospheric conditions. The first is ascorbic acid and the second is a chloride (also sulfate) salt of tetrakis (hydroxymethyl) phosphonium. These antioxidants, added to the dosimeter during gel preparation, chemically remove dissolved oxygen that otherwise inhibits propagation of the polymerization reaction during irradiation of the dosimeter. These gel dosimeters are radiosensitive after manufacture under normoxic conditions. However, we show herein that the accuracy of the dosimetric measurement is compromised due to chemical reactions of the antioxidant with radicals. In addition, we provide evidence that both antioxidant and oxygen act as radical scavengers that affect the amount of polymer formed in the gel dosimeter. This can result in important dose inaccuracies in both methacrylic acid-based and acrylamide-based normoxic dosimeter gels.     

Clinical application of the OneDose Patient Dosimetry System for total body irradiation

The OneDose Patient Dosimetry System (Sicel Technologies) is a new dosimeter based on metal oxide semiconductor field-effect transistor technology and designed for the in vivo measurement of patient dose during radiotherapy. In vivo dosimetry for total body irradiation (TBI) is challenging due to the extended treatment distance, low dose rates and beam spoilers. Phantom results confirm the suitability of the dosimeter for TBI in terms of inherent build-up, post-irradiation fading, accuracy, reproducibility, linearity and temperature dependence. Directional dependence is significant and should be taken into account. The OneDose dosimeters were also trialed in vivo for two TBI patients and the dose measured compared to conventional dosimeter measurements using an ionization chamber and thermoluminescent dosimeters (TLD), with agreement to within 2.2% and 3.9%, respectively. Phantom and patient results confirm that the OneDose patient dosimetry system is a practical and convenient alternative to TLDs for TBI in vivo dosimetry. For increased confidence in results with this dosimeter, we recommend that two dosimeters be used for each site of interest.     

The relationship between radiation-induced chemical processes and transverse relaxation times in polymer gel dosimeters

The effects of ionizing radiation in different compositions of polymer gel dosimeters are investigated using FT-Raman spectroscopy and NMR T2 relaxation times. The dosimeters are manufactured from different concentrations of comonomers (acrylamide and N,N'-methylene-bis-acrylamide) dispersed in different concentrations of an aqueous gelatin matrix. Results are analysed using a model of fast exchange of magnetization between three proton pools. The fraction of protons in each pool is determined using the known chemical composition of the dosimeter and FT-Raman spectroscopy. Based on these results, the physical and chemical processes in interplay in the dosimeters are examined in view of their effect on the changes in T2. The precipitation of growing macroradicals and the scavenging of free radicals by gelatin are used to explain the rate of polymerization. The model describes the changes in T2 as a function of the absorbed dose up to 50 Gy for the different compositions. This is expected to aid the theoretical design of new, more efficient dosimeters, since it was demonstrated that the optimum dosimeter (i.e, with the lowest dose resolution) must have a range of relaxation times which match the range of T2 values which can be determined with the lowest uncertainty using an MRI scanner.     

Dose resolution in radiotherapy polymer gel dosimetry: effect of echo spacing in MRI pulse sequence

In polymer gel dosimetry using magnetic resonance imaging, the uncertainty in absorbed dose is dependent on the experimental determination of T2. The concept of dose resolution (Dpdelta) of polymer gel dosimeters is developed and applied to the uncertainty in dose related to the uncertainty in T2 from a range of T4 encountered in polymer gel dosimetry. Dpdelta is defined as the minimal separation between two absorbed doses such that they may be distinguished with a given level of confidence, p. The minimum detectable dose (MDD) is Dpdelta as the dose approaches zero. Dpdelta and the minimum detectable dose both give a quantifiable indication of the likely practical limitations and usefulness of the dosimeter. Dpdelta of a polyacrylamide polymer gel dosimeter is presented for customized 32-echo and standard multiple-spin-echo sequences on a clinical MRI scanner. In evaluating uncertainties in T2, a parameter of particular significance in the pulse sequence is the echo spacing (ES). For optimal results, ES should be selected to minimize Dpdelta over a range of doses of interest in polymer gel dosimetry.     

Dose-response curve slope improvement and result reproducibility of ferrous-sulphate-doped gels analysed by NMR imaging

Ferrous sulphate gel analysed by relaxation time measurements with NMR imaging is considered a useful dosimeter for 3D determinations of absorbed dose. A protocol for the gel preparation with agarose SeaPlaque that leads to a dosimeter with very high dose sensitivity is described. The dose-response curve slope is about 0.2 s(-1) Gy(-1) and the G factor turns out to be approximately 185 ions per 100 eV of absorbed energy. A method for making the measurements and analysing the results that brings about good result reproducibility is suggested. A thorough experimental study of the dependence of the dosimeter response on the elapsed time from preparation to irradiation and from irradiation to NMR measurement has revealed good reproducibility. The above characteristic of the gel system is very interesting, because it shows the possibility of utilizing the dosimeter for absolute dose determinations with satisfactory reliability.     

Dose resolution optimization of polymer gel dosimeters using different monomers.

Polymer gel dosimeters of different formulations were manufactured from different monomers of acrylamide, acrylic acid, methacrylic acid, 1-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and 2-hydroxyethyl acrylate. Gelatin and agarose were used as the gelling agents and N,N'-methylene-bis-acrylamide was used as a co-monomer in each polymer gel dosimeter. The T2 dependence of each dosimeter was analysed using a model of fast exchange of magnetization. The influence of the half-dose and the apparent T2 of the polymer-proton pool on the dose resolution (Dpdelta) were examined. Comparisons are made with the commonly employed R2-dose sensitivity. Differences exist suggesting that experiments reported in the literature using what were thought to be more optimal dosimeters may not actually be so. Based on Dpdelta of each formulation, conclusions are drawn on the optimal formulation required for a specific range of absorbed doses. In addition, information about the extent of polymerization of the monomers used along with some characteristics of the polymer network formed are reported. The influence of the concentration of monomers and gelling agent was subsequently evaluated using a model of fast exchange of magnetization. Based on these calculations, further improvement in Dpdelta can be expected.     

A preliminary study of the novel application of normoxic polymer gel dosimeters for the measurement of CTDI on diagnostic x-ray CT scanners

Computer tomography dose index (CTDI) is a measurement undertaken during acceptance testing and subsequent quality assurance measurements of diagnostic x-ray CT scanners for the determination of patient dose. Normoxic polymer gel dosimeters have been used for the first time to measure dose and subsequently CTDI during acceptance testing of a CT scanner and compared with the conventional ionization chamber measurement for a range of imaging protocols. The normoxic polymer gel dosimeter was additionally used to simultaneously determine slice-width dose profiles and CTDI in the transaxial plane, the measurements of which are usually determined with thermoluminescent dosimetry or film. The resulting CTDI for all slice widths calculated from the normoxic polymer gel dosimeter were within corresponding ionization chamber CTDI values. Slice-width dose-profiles full-width half-maximum values from the normoxic polymer gel dosimeter were compared to the slice sensitivity profiles and were within the tolerances of the manufacturer. Normoxic polymer gel dosimeters have been shown to be a useful device for determining CTDI and dose distributions for CT equipment, and provide additional information not possible with just the use of an ionization chamber.     

Preliminary studies on the role and reactions of tetrakis(hydroxymethyl)phosphonium chloride in polyacrylamide gel dosimeters

A major source of dosimetric inaccuracy in normoxic polymer gel dosimeters is local variations in the concentration of oxygen scavenger. Currently, a phosphorus compound, tetrakis(hydroxymethyl)phosphonium chloride (THPC), is the oxygen scavenger of choice in most polymer gel dosimetry studies. Reactions of THPC in a gel dosimeter are not limited to oxygen. It can possibly be consumed in reacting with gelling agent, water free-radicals and polymer radicals before, during and after irradiation, hence affecting the dose response of the dosimeter in several ways. These reactions are not fully known or understood. It is our hypothesis that THPC not only scavenges radical species but also modifies the morphology of the gelatin network and of the polymer, possibly by intervening in the polymerization of monomers. These hypotheses are investigated in an anoxic acrylamide-based gel dosimeter. Scanning electron microscopy results indicate gelatin pores decreasing from 70 to 40?μm and a very different radiation-induced polymer structure in samples containing THPC; Fourier-transform Raman spectroscopy shows a two-fold reduction in the dose constants of monomer consumption; however, a significant change in the relative dose constants of monomer consumption as a function of dose could not be detected.