Journal of Physics D: Applied Physics

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Characterization of radiochromic PVA-GTA Fricke gels for dosimetry in

X-rays external radiation therapy
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Page 1 of 21 AUTHOR SUBMITTED MANUSCRIPT - JPhysD-119287.R1

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Characterization of radiochromic PVA-GTA Fricke gels for dosimetry in X-rays
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6 external radiation therapy
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10 Salvatore Gallo1,2*, Emanuele Artuso3, Maria Grazia Brambilla3, Grazia Gambarini1,2, Cristina Lenardi1,2,4,
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12 Angelo Filippo Monti3, Alberto Torresin3, Emanuele Pignoli5, Ivan Veronese1,2
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15 (1) Dipartimento di Fisica - Università degli Studi di Milano, Milano (Italy)
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17 (2) Istituto Nazionale di Fisica Nucleare (INFN) – Sezione di Milano, Milano (Italy)
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19 (3) Struttura Complessa di Fisica Sanitaria - ASST Grande Ospedale Metropolitano Niguarda, Milano (Italy)
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21 (4) Interdisciplinary Centre for Nanostructured Materials and Interfaces (CIMaINa), Milano (Italy)
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23 (5) Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milano (Italy)
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Corresponding author:

*Salvatore Gallo, Ph.D.

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31 Università degli Studi di Milano and INFN
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33 via Giovanni Celoria 16 - 20133 Milano, ITALY
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35 e-mail: [email protected]
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Abstract
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42 Quality assurance procedures required in the modern radiotherapy would greatly benefit by the development
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44 of tissue equivalent dosimeters able of rendering 3D dose profiles with high spatial resolution. In this scenario,
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46 Fricke gel (FG) dosimeters could be good candidates, but some limitations have restricted their interest in
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48 clinical practice. Recently, formulations based on gel matrices of poly(vinyl-alcohol) (PVA) chemically cross-
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50 linked with glutaraldehyde (GTA) have shown improvements as compared to FGs with natural matrices.
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52 Purpose of this study is the characterization of the dosimetric properties of radiochromic PVA-GTA Fricke gel
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54 dosimeter by means of absorption spectroscopy measurements.
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56 Xylenol Orange Fricke gel dosimeters, prepared in spectrophotometry cuvettes using 9.1 w/w of Mowiol®-
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PVA and 26.5 mM of GTA, were uniformly irradiated with a Cs source and with 6 and 15 MV X-rays
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generated by a medical linear accelerator.
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3 UV-VIS absorbance spectra collected at consecutive times post-irradiation showed that a time of
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5 approximately fifteen minutes is sufficient to reach a stable value of the absorbance, indicating the achievement
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7 of a chemical equilibrium in the complexation processes between Fe3+ and XO.
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The analysis of the change of the absorbance spectra shape with the cumulated dose demonstrated that a linear
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12 dose-response curve of PVA-GTA Fricke gel dosimeters is obtained in the entire investigated dose interval
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0.5-15 Gy by choosing properly the wavelength used for the absorbance measurements.

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16 Furthermore, PVA-GTA Fricke gel dosimeters proved to be nearly water- and tissue-equivalent and
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18 characterized by a response independent on the energies and dose rates in the investigated intervals. These
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20 findings suggested that PVA-GTA Fricke gels are promising tools for dosimetry applications in X-rays

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22 external radiation therapy.
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26 Keywords
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Fricke gel, poly(vinyl alcohol), glutaraldehyde, tissue equivalence, dosimetry
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3 1. Introduction
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5 Modulated modern radiation therapy would greatly gain from the development of reliable systems for three
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7 dimensional dose mapping with the level of accuracy and precision required for quality assurance procedures
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[1,2]. Several approaches currently studied are based on the imaging of radiation-induced chemical changes
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12 of a tracer compound suspended in a continuous medium, such as a gel, rigid or deformable plastics, or inelastic
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material [3]. This paper is focused on Fricke gel (FG) dosimetry [4]. In Fricke gel dosimeters, ionizing

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16 radiation induces radiolysis of water, followed by well-established reactions oxidizing ferrous ions (Fe2+) to
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18 ferric ions (Fe3+), with a conversion yield proportional to the absorbed dose (up to saturation) [5].
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20 The distribution of the resulting Fe3+ is used to produce a 3D image of the absorbed dose by Magnetic

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22 Resonance Imaging (MRI) [6-8] or by optical imaging, provided that a suitable metallic-ion indicator is
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24 employed [9-12]. The most used metallic-ion indicator is Xylenol Orange (XO). XO molecules absorb light
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26 around 430 nm. After irradiation, the generated Fe3+ ions are chelated by XO and the resulting complexes give
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light absorption above 500 nm. Therefore, it is possible to quantify the dose absorbed by Fricke gel dosimeters
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31 by evaluating the variation of their absorbance [5].
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33 Unfortunately, poor stability of Fricke gels due to the diffusion of ferric ions within natural gel matrices like
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35 gelatine and agarose, imposes constraints upon the time between the irradiation and read-out process. [13].
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37 Among the various strategies proposed for limiting this drawback [14-16], recently, formulations based on gel
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39 matrices of poly(vinyl-alcohol) (PVA) chemically cross-linked with glutaraldehyde (GTA) have shown
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41 improvements as compared to FGs with natural matrices [17,18]. Accordingly, the interest toward PVA-GTA
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Fricke gel dosimetry is gaining importance, as attested by the increasing literature about this topic [19-27].
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45 In this manuscript, driven by the results shown in Marini et al. [19], additional studies concerning the
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properties of PVA-GTA Fricke gel dosimeters have been carried out. In particular, after the analysis of the
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water- and tissue-equivalence of this gel matrix, a study of the time-formation of the dosimetry signal in PVA-
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52 GTA Fricke gels due to Fe3+ ions production and complexation was carried out. Afterwards, absorbance
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54 spectral analyses of PVA-GTA Fricke gel dosimeters were performed to characterize their response as a
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56 function of dose, dose rate and energy, in the typical intervals of interest for X-rays external radiation therapy
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3 2. Materials and methods
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7 2.1 PVA-GTA-Fricke gel dosimeters preparation
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The preparation of PVA-GTA Fricke gel dosimeters was carried out considering the procedure described in
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12 [19], but using a different PVA. The PVA Mowiol®18-88 (molecular weight 130000 Da; degree of hydrolysis
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86.7-88.7%, Sigma Aldrich) was selected for this study because of its high purity [28] and favorable properties.

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16 Indeed, complete dissolution of Mowiol®18-88 in water can be easily obtained in approximately 40 minutes
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18 at 70°C, without the use of an autoclave [19] or open vessel microwave digestion [20] as required for other
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20 PVA compounds.

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22 All batches of Fricke gel dosimeters were prepared using ultrapure water obtained by a water purification
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24 system (Milli-Q® Direct, EMD Millipore, Germany) and analytical grade reagents: 0.5 mM ferrous ammonium
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26 sulfate hexahydrate (Carlo Erba); 25.0 mM sulfuric acid (Suprapur®, Sigma Aldrich); 26.5 mM of
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glutaraldehyde (GTA, Sigma Aldrich) and 0.165 mM Xylenol Orange tetrasodium salt (XO) (Riedel-de Haën).
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31 PVA solution (final concentration 9.1 % w/w) was prepared by dissolving dry PVA in ultrapure water (80%
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33 of the total water volume, resistivity 18.2 MΩ·cm). Initially, the incorporation of PVA in water took place at
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35 room temperatures under rapid stirring (~500 rpm) for about 5 minutes to avoid the formation of aggregates
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37 of polymer granules. Next, the temperature was raised up to 70 °C with a progressive reduction of the stirring
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39 speed (~150 rpm) to limit the incorporation of oxygen into the solution. After the complete dissolution, the
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41 PVA solution was left to cool down at room temperature.
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Afterwards, Fricke-XO solution was prepared by adding sulfuric acid (two-thirds of the total amount), ferrous
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45 ammonium sulfate and Xylenol Orange sodium-salt in this order into water (10% of the total water volume)
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with moderate stirring. Finally, GTA solution was prepared by adding GTA and the remaining sulfuric acid
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into water (the remaining 10% of the total water volume).
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52 FG dosimeters were obtained by slowly incorporating Fricke solution into the PVA solution and, subsequently
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54 by adding the GTA solution. After one minute of gentle stirring to achieve homogeneity, the final solution was
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56 poured into poly(methyl methacrylate) cuvettes (10 mm optical path length) closed with polypropylene cuvette
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58 stoppers and sealed with Parafilm™. After the complete gelation, all the Fricke gel dosimeters were kept
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3 refrigerated at the controlled temperature of 6°C for one day and brought back to room temperature 1 hour
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2.2 Radiological water- and tissue-equivalence
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12 In order to verify the radiological water-equivalence [29] of the PVA-GTA-gels, the values of density, mass
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energy absorption coefficients for photons and stopping power for electrons were assessed and compared with

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16 those of water and soft tissue (ICRU 44).
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18 The PVA-GTA-gels density was measured at room temperature (25°C) by using calibrated vessels with a
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20 capillary neck and an analytical balance with precision of 0.1 mg. The uncertainty of density was obtained as

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22 the standard error of the mean value over ten different samples.
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24 The values of mass energy absorption coefficient and stopping power of PVA-GTA-gels, water and soft tissue
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26 were calculated as a weighted average of mass energy absorption coefficients and stopping powers of the
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chemical element constituents, respectively [30]. The chemical formulas and elemental compositions of the
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31 media of interest, reported in Table 1, were used for the calculations, together with the National Institute of
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33 Standards and Technology (NIST) physical reference data [31].
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37 Table 1 - Elemental compositions (% weight fractions) of water, soft tissue (ICRU 44), GTA, PVA, and PVA-
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39 GTA-gels.
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Chemical wH wO wN wC
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43 Formulas (%) (%) (%) (%)
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44 Water H2O 11.111 88.889 - -

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46 Soft tissue (ICRU 44) - 10.117 76.183 2.600 11.100
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GTA C5H8O2 8.000 32.000 - 60.000
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49 PVA C2H4O 9.091 36.364 - 54.545
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51 PVA-GTA-gels - 10.920 83.977 - 5.103
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56 2.3 Samples irradiation
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58 Preliminary irradiations of PVA-GTA Fricke gel dosimeters were performed with an IBL 437 C 137Cs blood
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irradiator at the “Fondazione IRCCS Istituto Nazionale dei Tumori” of Milano (Italy). One FG dosimeter
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3 inside a cuvette was placed in the center of the irradiation canister to guarantee dose uniformity and irradiated
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7 Afterwards, the irradiations were carried out in a simple geometry with 6 MV and 15 MV X-rays beams
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generated by a linear accelerator (LINAC) Varian Clinac-2100 (Varian Medical Systems, CA, USA) at “ASST
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12 Grande Ospedale Metropolitano Niguarda” of Milano (Italy).
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The LINAC was calibrated following the IAEA TRS-398 code of practice (IAEA 2000) [32] using a Farmer

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16 type PTW Freiburg 30013 ionization chamber (IC) (PTW, Freiburg GmbH, Germany). For the calibration, the
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18 IC was placed in a water phantom at a depth of 10 cm, using as reference conditions a source surface distance
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20 (SSD) of 100 cm and a field size 10 cm x 10 cm, for all the X-rays beams energies.

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22 In all the experiments, at least three samples of the same batch were irradiated simultaneously. The samples
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24 were placed horizontally within a solid water slab phantom (RW3, PTW Freiburg, Goettingen, slab
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26 dimensions: 30 cm x 30 cm x 1cm) with the central plane of the cuvettes at a depth of 10 cm from the phantom
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surface. All the irradiations were performed using the source detector distance (SDD) of 100 cm (i.e. distance
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33 achieved by using a 20 cm × 20 cm field size at the position of the dosimeters and by delivering the total dose
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35 with two parallel-opposed beams. A sketch (not in scale) of the irradiation set-up with additional details is
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41 2.4 Absorbance Measurements
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In order to monitor the formation of the absorbance signal due to the Fe3+-XO complexation occurring during
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45 the first minutes after the irradiation, preliminary absorbance measurements were carried out in situ by using
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a compact thermally cooled UV-VIS spectrometer (Prime X, B&WTec Inc, USA). The sample, inside a cuvette
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holder (BCH103A, B&WTec Inc, USA), was illuminated by a halogen lamp. Silica optical fibers were used
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52 as light-guides between the various optical components (i.e. the lamp, the sample holder and the compact
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54 spectrometer). Absorbance spectrum of one sample, in the interval 460-660 nm, was collected before the
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56 irradiation with the blood irradiator. Afterwards, absorbance spectra were collected at consecutive times post-
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3 For the following dosimetric characterization, the absorbance measurements were performed in laboratory
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5 using a Cary 100 UV-Vis spectrophotometer (Agilent Technologies, Santa Clara, CA, USA) in the wavelength
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7 interval 360-720 nm. Since in the conventional gel dosimetry, the absorbed dose is correlated to absorbance
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variation of the dosimeters following irradiation, absorbance spectra were acquired using one un-irradiated
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12 sample for each batch as reference sample. The reference sample was always kept near the samples to be
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analyzed in order to reproduce the same effect of auto-oxidation inside the dosimeters. The measurements

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22 The dose response and energy dependence of the PVA-GTA Fricke gel dosimeters were studied by irradiating
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24 the samples to increasing doses in the interval 0.5-15.0 Gy, with 6 MV and 15 MV X-rays, using dose rates of
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26 208.5 cGy/min and 232.8 cGy/min, respectively. Dose-response curves for the two energies were derived by
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plotting the values of absorbance measured at different wavelengths, versus the absorbed dose.
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31 Dose rate dependence was studied by irradiating the dosimeters to a dose of 6.0 Gy with 6 MV X-rays, using
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33 different dose rates in the interval 69.5-347.5 cGy/min, by changing the LINAC pulse frequency in the range
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37 Fig. 1 - Lateral and top views of the setup used for the irradiation of PVA-GTA Fricke gel dosimeters (not in
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39 scale). Solid water (RW3) phantom in green; cuvettes filled with Fricke gel dosimeters in light yellow. The
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blue rectangles are additional cuvettes filled with ultrapure water used to ensure density uniformity over the
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3 3 Results and discussions
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The density of PVA-GTA gels was assessed equal to 1.031 ± 0.005 g/cm3, i.e. slightly higher than water and
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12 soft tissue density values (1.000 g/cm3 – [31]).
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Figure 2 shows the comparison between the mass energy absorption coefficients for photons of these media.

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16 Similarly, Figure 3 shows the mass collision stopping power for electrons related to gels, water, and soft tissue.
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18 The differences between the mass energy absorption coefficients for photons of PVA-GTA gels, water, and
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20 soft tissue are lower than 1.5% in the energy interval extending from 0.1 MeV to 10 MeV (Figure 2), i.e. the

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22 energy interval of interest in X-rays external radiation therapy. At lower energies the differences increase, with
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24 a maximum deviation between gels and soft tissue of approximately 7.0% around 0.03 MeV.
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PVA-GTA gels, water and soft tissue are lower than 1.0%. Slightly higher differences, within 1.6%, were
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33 As reasonably expected considering the chemical composition of PVA-GTA gels, the results of Figure 2 and
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(orange solid line), and soft tissue (green dotted line) as a function of energy. (b) Ratio between mass energy
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collisional stopping power of PVA-GTA gels and water (orange solid line), and ratio between mass collision
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3 3.2 Absorption spectra measurements
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5 Figure 4 shows the time course the absorbance at the wavelength value of 585 nm (i.e. the wavelength generally
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7 used for optical analysis of Fricke gel dosimeters [5,11,12]) related to Fe3+-XO complexation process
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monitored in the first 75 minutes after the irradiation of the PVA-GTA Fricke gel sample.
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12 After the first acquisition, performed 40 seconds post-irradiation, the absorbance increased rapidly and reached
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saturation in less than 15 minutes, indicating the achievement of the chemical equilibrium of XO-Fe3+

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16 complexation.
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18 These results obtained with the PVA-GTA matrix are in line with previous data available in the literature and
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22 therapy [33] and with a Co-60 source [34].
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44 Fig. 4 – Absorbance over time at the wavelength of 585 nm measured in PVA-GTA Fricke gel dosimeters
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The typical absorbance spectra of PVA-GTA Fricke gel dosimeters irradiated at various doses up to 15.0 Gy
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52 with 6 MV X-rays, acquired after the achievement of chemical equilibrium in the complexation processes
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21 Fig. 5 – Absorbance spectra of PVA-GTA gel dosimeters irradiated to increasing doses (up to 15.0 Gy). The
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The absorbance spectra of the studied gel dosimeters were characterized by a broad absorption peak in the

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34 5).
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36 As expected, the absorbance of PVA-GTA Fricke gel dosimeters increased with increasing the absorbed dose
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in the wavelength region between 480 nm and 660 nm. Similarly, a decrease of the absorbance around 430 nm
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with increasing the radiation dose occurred. Such features characterized also the traditional FG dosimeters
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45 glutaraldehyde does not modify either the operating principle of the dosimeters or the optical properties of
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21 Fig. 6 - Example of absorbance spectra of PVA-GTA gel dosimeters, divided by the absorbed dose. The solid
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The normalized absorbance spectra of each dosimeter showed an isosbestic point around 555 nm, suggesting

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6) whereas a decrease around 520 nm can be observed in the spectra of Figure 6 (solid black arrow in Figure
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43 Such behavior proved to have an important effect in the correct evaluation of the dose-response curve of the
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45 PVA-GTA Fricke gel dosimeters, as pointed out in the following section.
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49 3.3 Dose response curves
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51 Figure 7 shows the dose response curve of the PVA-GTA Fricke gel dosimeters irradiated at various doses in
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53 the interval 0.5-15.0 Gy with 6 MV X-rays, obtained by measuring the absorbance at 585 nm (i.e. the
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55 wavelength with the maximum absorbance value and generally used in the literature for such analyses). For
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57 doses above 5.0 Gy a linear behavior (R2=0.99982, solid orange line in Figure 7) was observed with a slope of
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the fitted straight line equal to 0.081±0.001 Gy-1 through 10 mm of optical path. Such finding is in agreement
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3 with the results recently published by Marini et al. [19] about the dose response curve of similar gel dosimeters
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5 studied in the range 5-30 Gy using 6 MV X-rays. Here, in order to investigate the dosimetric features of PVA-
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7 GTA Fricke gels for doses below 5 Gy, irradiations were performed from 0.50 Gy to 2.00 Gy in 0.25 Gy steps,
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and from 2.00 Gy to 7.00 Gy in 0.50 Gy steps.
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Fig. 7 - Absorbance at 585 nm of PVA-GTA Fricke gel irradiated at various doses in the interval 0.5-15.0 Gy
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31 using 6 MV X-rays. Each point is the mean of absorbance data from at least three samples at 585 nm. Error
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33 bars (1 standard deviation) are smaller than the plot symbols. The solid orange line is the linear fit to the
34 experimental data between 5.0 Gy and 15.0 Gy. The dashed green curve is a parabolic fit to the experimental
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36 data between 0.5 and 6.0 Gy.
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Below 5.0 Gy the results revealed a dose response curve different from the linear one obtained by considering
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42 only doses above 5.0 Gy. In fact, in the dose interval 0.5 Gy-6.0 Gy, a fit of the quadratic function to the
43
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44 experimental data y=A+xB+x2C (with A=-0.0016±0.0013, B=0.056±0.002 and C=0.023±0.001) provided a

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46 satisfactory description of the dose-response curve (R2=0.99976, dashed green curve in Figure 7).
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48 It must be pointed that the signal of an ideal dosimeter should be linearly proportional to the absorbed dose
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50 over the entire dose range of interest. As a matter of principle, in PVA-GTA Fricke gel dosimeters such
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52 condition can be obtained by integrating the absorbance over the broad spectral interval 480-680 nm, as shown
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54 in Figure 8. Indeed, the fitted straight line in Figure 8 (slope = 8.87±0.05 Gy-1, intercept = -0.05±0.30) provided
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56 a good (R2=0.9998) description of the experimental data over the entire dose interval 0.5-15 Gy. However, this
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approach is not practical for measuring 3D images of the absorbed dose distributions in gel dosimeters. Indeed,
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3 of lasers or LEDs as light sources [37,38], do not cover the whole absorbance spectral interval required to
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15.0 Gy using 6 MV X-rays. Each point is the mean of absorbance data from at least three samples. Error bars
(1 standard deviation) are smaller than the plot symbols. The dashed blue line is the linear fit to the
30 experimental data.
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35 the radiation dose (Figure 6), and reconstructing the dose-response curve using the absorbance values
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37 measured at the wavelength of the isosbestic point. Indeed, the dose-response curve obtained by using the
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absorbance values at 555 nm showed a linear trend over the entire investigated dose interval, as illustrated in
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42 Figure 9.
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44 Figure 9a shows the experimental data together with the linear fit. The random pattern of the residual plot
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46 (Figure 9b) together with the R2 value (0.99987) demonstrate the reliability of the linear model. The values of
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48 -0.004 ± 0.003 and 0.071±0.002 Gy-1 were found for the intercept and the slope of the fitted straight line,
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50 respectively. It can be noted that the intercept is comparable with the zero value, demonstrating the direct
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52 proportionality between the absorbance and the absorbed dose. Furthermore, the slope of the linear regression
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54 indicated a sensitivity of the studied PVA-GTA Fricke gel dosimeters higher than that previously obtained in
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56 gelatine-based Fricke gel dosimeters using the same wavelength for the analysis (0.058 ± 0.001 Gy-1) [15].
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Figure 9c shows the relative standard deviation (RSE, i.e. the ratio of the standard deviation to the mean) vs
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the absorbed dose. The RSE value decreased with increasing the dose: for doses higher than 6.0 Gy, the RSE
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3 was lower than 1.5%. However, for doses lower than 2.0 Gy the RSE was higher than 4.5%. These data suggest
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5 that, currently, the investigated PVA-GTA FG are mostly promising in quality assurance procedures of
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7 hypofractionated radiation treatments, i.e. treatments characterized by a dose per fraction much higher than 2
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Gy. In fact, these treatments typically require suitable patient specific quality assurance practices. Conversely,
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12 further improvements in the dosimetric performances of the PVA-GTA FG dosimeters are still required for
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their use in conventional treatments regimes (2 Gy per fraction).

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44 Fig. 9 - (a) Absorbance at 555 nm of PVA-GTA Fricke gel irradiated at various doses in the interval 0.5-15
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46 Gy using 6 MV photon beams. Each point is the mean of measurements at 555 nm on at least three samples.
47 Error bars (1 standard deviation) are smaller than the plot symbols. The dashed green line is the linear fit to
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49 the experimental data. (b) Residual plot (c) Relative Standard Errors (RSE) vs absorbed dose.
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53 3.4 Dose-rate and energy dependence
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55 The dose-response curves of the PVA-GTA Fricke gel dosimeters irradiated with 6 MV and 15 MV X-rays
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were evaluated from the absorbance spectra at main absorption peak (585 nm) and at the isosbestic absorbance
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59 point (555 nm). The results are shown in Figure 10. No differences between the dose-response curve at 6 MV
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and 15 MV were observed, independently of the wavelength used for the absorbance evaluation. As previously
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3 pointed out, linearity over the entire dose interval was achieved by considering the absorbance values at 555
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5 nm, for both the investigated energies.
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7 Figure 11 shows typical absorbance spectra of PVA-GTA Fricke gel dosimeters irradiated to the same dose of
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6 Gy with 6 MV X-rays using different dose-rates in the interval 69.5-347.5 cGy/min. The differences among
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12 the absorbance values were lower than 1.5% over the entire spectral region, i.e. of the same order of magnitude
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of the observed intra-batch sample variability (Figure 9c).

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16 Therefore, it can be concluded that the PVA-GTA Fricke gel dosimeters maintain the desired properties of
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18 independence of the response of the dose rate and of radiation energy characterizing the Fricke gel dosimeters
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20 based on traditional gelling agents [33,39-41], at least in the investigated intervals.

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42 Fig. 10 – Absorbance at 585 nm and 555 nm of PVA-GTA Fricke gel irradiated at various doses in the interval
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44 0.5-15.0 Gy using 6 MV and 15 MV X-rays. Each point is the mean of measurements on at least three samples.
45 Error bars (1 standard deviation) are smaller than the plot symbols. Lines connecting points are for guiding the
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the dose rate from 69.5 cGy/min to 347.5 cGy/min. An un-irradiated sample was used as reference.
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4. Conclusions
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The dosimetric properties of Fricke gel dosimeters based on poly(vinyl alcohol) as gelling agent and
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glutaraldehyde as cross-linker were studied by spectrophotometry. The results suggested that a time of
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34 approximately fifteen minutes after the irradiation is sufficient to reach a stable value of the absorbance,
35
36 indicating the achievement of a chemical equilibrium in the complexation processes between Fe3+ and XO.
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38 The analysis of the change of the absorbance spectra shape with the cumulated dose demonstrated that a linear
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40 dose-response curve of PVA-GTA Fricke gel dosimeters can be obtained in the entire investigated dose
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42 interval 0.5-15.0 Gy by optimizing the choice of wavelength to be used for the absorbance measurements. This
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44 finding could be exploited for the improvement of the optical computed tomography scanners used for 3D
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46 dose mapping in gel dosimeters, alternative to the MRI.
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As expected because of their chemical composition, PVA-GTA Fricke gel dosimeters proved to be nearly
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water- and tissue-equivalent and characterized by a response independent of the energies and dose rates in the
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53 investigated intervals.
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55 Such features, together with the low Fe3+ diffusion rate characterizing the PVA-GTA gel networks, [19-21],
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57 make these dosimeters promising tools in X-rays external radiation therapy applications. Further studies are
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59 currently in progress with the aim to improve the precision of the optical response of PVA-GTA FG dosimeters
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3 irradiated to low doses (i.e. < 2 Gy), element required for the possible transition of these systems in the clinical
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5 practice.
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Acknowledgments
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12 The authors wish to thank Daniela Bettega, and Paola Calzolari for their useful comments and suggestions.
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The authors are also grateful to Ester Mazzarella for the irradiation of the samples at the “Fondazione IRCCS

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16 Istituto Nazionale dei Tumori”.
17
18
19
20 Reference

us
21
22 [1] Alber M, Broggi S, De Wagter C, Eichwurzel I, Engström P, Fiorino C, Georg D, Hartmann G, Knöös T,
23 et al. (2008) Guidelines for the verification of IMRT, Booklet No. 9, ESTRO (Brussels, Belgium).
24
25 [2] Kron T, Lehmann J, Greer P (2016) Dosimetry of ionising radiation in modern radiation oncology
26 Physics in Medicine and Biology 61(14) 167-205.
27
28
29
an
[3] Doran S (2009) The history and principles of chemical dosimetry for 3-D radiation fields: Gels, polymers
and plastics Applied Radiation and Isotopes 67 393–398.
30
[4] Olsson L, Appleby A and Sommer I (1991) A new dosimeter based on ferrous sulphate solution and
31
32 agarose gel Applied Radiation and Isotopes 42 1081-1086.
dM
33
[5] Davies J and Baldock C (2008) Sensitivity and stability of the Fricke-gelatin-xylenol orange gel
34
35 dosimeter Radiation Physics and Chemistry 77(6) 690–696.
36 [6] Marrale M, Brai M, Gagliardo C, Gallo S, Longo A, Tranchina L, Abbate B, Collura G, Gallias K,
37
38 Caputo V et al. (2014) Correlation between ferrous ammonium sulfate concentration, sensitivity and stability
39 of Fricke gel dosimeters exposed to clinical X-ray beams Nuclear Instruments and Methods in Physics
40 Research Section B 335 54–60.
41
42 [7] Galante A, Cervantes H, Cavinato C, Campos L and Rabbani S (2008) MRI study of radiation effect on
43 Fricke gel solutions Radiation Measurements 43 (2) 550–553.
pte

44
45 [8] Marrale M, Brai M, Longo A, Gallo S, Tomarchio E, Tranchina L, Gagliardo C and d’Errico F (2014)
46 NMR relaxometry measurements of Fricke gel dosimeters exposed to neutrons Radiation Physics and
47 Chemistry 104 424-428.
48
49 [9] Eyadeh M, Rabaeh K, Hailat T and Aldweri F (2018) Evaluation of ferrous Methylthymol blue gelatin
50 gel dosimeters using nuclear magnetic resonance and optical techniques Radiation Measurements 108 26-33.
51
ce

52 [10] Alves A, de Almeida S, Sussuchi M, Lazzeri L, d'Errico F and de Souza S (2018) Investigation of
53 chelating agents/ligands for Fricke gel dosimeters Radiation Physics and Chemistry 150 151-156.
54
55 [11] Babic S, Battista J and Jordan K (2008) An apparent threshold dose response in ferrous xylenol-orange
56 gel dosimeters when scanned with a yellow light source Physics in Medicine and Biology 53(6) 1637-1650.
Ac

57
58
[12] Gambarini G, Veronese I, Bettinelli L, Felisi M, Gargano M, Ludwig L, Lenardi C, Carrara M, Collura
59 G, Gallo S, et al. (2017) Study of optical absorbance and MR relaxation of Fricke xylenol orange gel
60 dosimeters Radiation Measurements 106 622-627.

19
 AUTHOR SUBMITTED MANUSCRIPT - JPhysD-119287.R1 Page 20 of 21

1
2
3 [13] de Oliveira L, de Almeida A and Caldas L (2014) Fricke gel diffusion coefficient measurements for
4 applications in radiotherapy level dosimetry Radiation Physics and Chemistry 98 42–45.
5
6 [14] Maeyama T, Fukunishi N, Ishikawa K, Furuta T, Fukasaku K, Takagi S, Noda N, Himeno R and
7 Fukuda S (2014) A diffusion free and linear-energy-transfer-independent nanocomposite Fricke gel
8
dosimeter Radiat. Phys. Chem. 96 92−96.

pt
9
10 [15] Gallo S, Cremonesi L, Gambarini G, Ianni L, Lenardi C, Argentiere S, Bettega D, Gargano M, Ludwig
11
N and Veronese I (2018) Study of the effect of laponite on Fricke xylenol orange gel dosimeter by optical
12
13 techniques Sensors and Actuators B: Chemical 272C 618-625.

cri
14 [16] Babu S, Peace S, Rafic K, Raj E, Christopher S and Ravindran P (2019) Escalation of optical
15
16 transmittance and determination of diffusion co-efficient in low-bloom strength gelatin-based Fricke gel
17 dosimeters Radiation Physics and Chemistry 156 300-306.
18
[17] Jin C, Chen J, Yang L, Luo W, Wu G and Zha Z (2012) Effect of DMSO on the sensitivity and
19
20 diffusion of FPGX gel dosimeter Radiation Physics and Chemistry 81 879–883.

us
21
[18] Ruijia X, Liming Y, Jie C, Qiang Q, Liang R, Fangqi C, Wenyun L, Xiaoqing D, Yuanzi Z and Guohua
22
23 W (2010) Preparation and characterization of FPGX hydrogel dosimeters Nuclear Science and Techniques
24 21 60–62.
25
26
[19] Marini A, Lazzeri L, Cascone M, Ciolini R, Tana L and d’Errico F (2017) Fricke gel dosimeters with
27
28
29
106 618-621.
an
low-diffusion and high-sensitivity based on a chemically cross-linked PVA matrix Radiation Measurements

30 [20] Marrale M, Collura G, Gallo S, Nici S, Tranchina L, Abbate B, Marineo S, Caracappa S and d’Errico F
31 (2017) Analysis of spatial diffusion of ferric ions in PVA-GTA gel dosimeters analyzed via magnetic
32 resonance imaging Nuclear Instruments and Methods in Physics Research Section B 396 50–55.
dM
33
34 [21] Smith S, Masters K, Hosokawa K and Blincol B (2015) Technical Note: Preliminary investigations into
35 the use of a functionalized polymer to reduce diffusion in Fricke gel dosimeters Medical Physics 42(12)
36 6798-6803.
37
38 [22] Gallo S, Gambarini G, Veronese I, Argentiere S, Gargano M, Ianni L, Lenardi C, Ludwig N, Pignoli E
39 and d’Errico F (2019) Influence of gelation temperature and amount of sulfuric acid on the dosimetric
40 properties of PVA-GTA Fricke gels Radiation Physics and Chemistry (In preparation).
41
42 [23] d’Errico F, Lazzeri L, Dondi D, Mariani M, Marrale M, Souza S and Gambarini G (2017) Novel GTA-
43
pte

PVA Fricke gels for three-dimensional dose mapping in radiotherapy Radiation Measurements 106 612-617.
44
45 [24] Collura G, Gallo S, Tranchina L, Abbate B, Bartolotta A, d’Errico F and Marrale M (2018) Analysis of
46 response of PVA-GTA Fricke-gel dosimeters through clinical magnetic resonance imaging Nuclear
47
Instruments and Methods in Physics Research Section B 414 146-153.
48
49 [25] Gallo S, Collura G, Longo A, Bartolotta A, Tranchina L, Iacoviello G, d’Errico F and Marrale M (2017)
50 Preliminary MR relaxometric analysis of Fricke-gel dosimeters produced with Poly-vinyl alcohol and
51
ce

52 glutaraldehyde Nuclear Technology & Radiation Protection 32(3) 242-249.

53 [26] Eyadeh M, Rabaeh K, Hailat T, Al-Shorman M, Aldweri F, Kanan H and Awad S (2018) Investigation
54
of a novel chemically cross-linked fricke-Methylthymol bluesynthetic polymer gel dosimeter with
55
56 glutaraldehyde cross-linker Radiation Measurements 118 77–85.
Ac

57
[27] Rabaeh K, Eyadeh M, Hailat T, Aldweri F, Alheet S, Eid R (2018) Characterization of ferrous-
58
59 methylthymol blue-polyvinyl alcohol gel dosimeters using nuclear magnetic resonance and optical
60 techniques Radiation Physics and Chemistry 148 25–32.

20
Page 21 of 21 AUTHOR SUBMITTED MANUSCRIPT - JPhysD-119287.R1

1
2
3 [28] SIGMA Product Specification of Mowiol® 18-88 Mw
4 https://www.sigmaaldrich.com/catalog/product/aldrich/81365?lang=it&region=IT (last access at 20
5
6 November 2018).
7 [29] Un A (2013) Water and tissue equivalency of some gel dosimeters for photon energy absorption,
8
Applied Radiation and Isotopes 82 258–263.

pt
9
10 [30] Attix F H (2008) Introduction to Radiological Physics and Radiation Dosimetry John Wiley & Sons.
11
12 [31] Hubbell H and Seltzer S M Tables of x-ray mass attenuation coefficients and mass energy-absorption
13 coefficients 1 keV to 20 MeV for elements Z= 1 to 92 and 48 additional substances of dosimetric interest,

cri
14 (1995) Tech. rep., National Inst. of Standards and Technology-PL, Gaithersburg, MD (United States).
15
16 Ionizing Radiation Div. https://physics.nist.gov/PhysRefData/XrayMassCoef/tab2.html (last access at 30
17 November 2018).
18
[32] Andreo P, Burns D, Hohlfeld K, Huq M, Kanai T, Laitano F, Smyth V and Vynckier S (2000) Absorbed
19
20 dose determination in external beam radiotherapy: an international Code of Practice for dosimetry based on

us
21 standards of absorbed dose to water IAEA Technical Reports Series 398 International Atomic Energy
22 Agency.
23
24 [33] Soliman Y, El Gohary M, Garad M, Amin E and Desouky O (2017) Fricke gel dosimeter as a tool in
25 quality assurance of the radiotherapy treatment plans Applied Radiation and Isotopes 120 126-132.
26
27
28
29
Radiological Protection 20 287–294.
an
[34] Bero M, Gilboy W and Glover O (2000) An optical method for three-dimensional dosimetry Journal of

30 [35] Liosi G, Dondi D, Vander Griend G, Lazzaroni S, d’Agostino and Mariani M (2017) Fricke-gel
31 dosimeter: overview of Xylenol Orange chemical behavior Radiation Physics and Chemistry 140 74-77.
32
dM
33 [36] Bou R, Codony R, Tres A, Decker E and Guardiola F (2008) Review: Determination of hydroperoxides
34 in foods and biological samples by the ferrous oxidation–xylenol orange method: A review of the factors that
35 influence the method’s performance Analytical Biochemistry 377 1–15.
36
37 [37] Colnot J, Huet C, Gschwind R and Clairand I (2018) Characterisation of two new radiochromic gel
38 dosimeters TruView™ and ClearView™ in combination with the vista™ optical CT scanner: A feasibility
39 study Physica Medica 52 154–164.
40
41 [38] Olding T, Holmes O and Schreiner L (2010) Cone beam optical computed tomography for gel
42 dosimetry I: scanner characterization Physics in Medicine and Biology 55 2819–2840.
43
pte

44 [39] Leong L, Kandaiya S and Seng N (2007) Characterisation of a Ferrous Agarose Xylenol (FAX) gel for
45 radiotherapy dose measurement Australasian Physical & Engineering Sciences in Medicine 30(2) 135-140.
46
47 [40] Moussous O, Khoudri S and Benguerba M (2011) Characterization of a Fricke dosimeter at high energy
48 photon and electron beams used in radiotherapy Australasian Physical & Engineering Sciences in Medicine
49 34(4) 523-528.
50
51 [41] Cavinato C and Campos L (2010) Energy dependent response of the Fricke gel dosimeter prepared with
ce

52 270 Bloom gelatine for photons in the energy range 13.93 keV–6 MeV Nuclear Instruments and Methods in
53 Physics Research Section A 619 198-202.
54
55
56
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57
58
59
60

21