WO2025196255A1

WO2025196255A1 - Phantom, use and method for three-dimensional dosimetry

Info

Publication number: WO2025196255A1
Application number: PCT/EP2025/057772
Authority: WO
Inventors: Camilla LØNBORG NIELSEN; Peter Balling; Rosana MARTINEZ TURTOS; Mads LYKKE JENSEN; Brian JULSGAARD
Original assignee: Aarhus Universitet
Current assignee: Aarhus Universitet
Priority date: 2024-03-22
Filing date: 2025-03-21
Publication date: 2025-09-25
Anticipated expiration: 2026-09-22

Abstract

The present invention relates to a phantom for dosimetry comprising a composition comprising nanoparticle crystallites characterised by exhibiting optically stimulated luminescence properties, and wherein said crystallites are embedded in a hydrogel matrix. Furthermore the present invention relates to a dosimeter based on said phantom for measuring ionising radiation, and more particularly to a phantom for three-dimensional dosimetry via optically stimulated luminescence and corresponding method for preparation and use.

Description

PHANTOM, USE AND METHOD FOR THREE-DIMENSIONAL DOSIMETRY

Technical field

The present invention relates to a phantom for dosimetry comprising a composition comprising nanoparticle crystallites characterised by exhibiting optically stimulated luminescence properties, and wherein said crystallites are embedded in a hydrogel matrix. Furthermore, the present invention relates to a dosimeter based on said phantom for measuring ionising radiation, and more particularly to a phantom for three- dimensional dosimetry via optically stimulated luminescence and corresponding method for preparation and use.

Background

Radiotherapy is a treatment involving the use of radiation, in particular ionising radiation. It may for example be used to treat cancer, where high-energy radiation used during radiotherapy permanently damages the DNA of cancer cells, causing them to die.

Materials exhibiting thermoluminescence (TL) and optically stimulated luminescence (OSL) are a family of commonly used physical radiation dosimeters consisting of large- band-gap insulators. Energy deposited during irradiation excites electron-hole pairs, which may be trapped in defect-related trap states in the electronic band gap.

Subsequently, these trapped charges can be re-excited and recombine radiatively, emitting a signal that, ideally, is directly proportional to the dose deposited in the material.

Currently, 3D dosimetry has only been demonstrated using a variety of materials based on radiation-induced chemical effects, which suffer from poor temporal stability and environmental sensitivity, e.g. due to oxidation or other competing chemical reactions not originating from the radiation. The unwanted chemical processes give rise to phenomena like fading of an induced signal (e.g. reduced colouring), increased background signal (increased colouring), refractive index changes, etc. These effects lead to artefacts, not to mention batch-to-batch variations requiring extensive calibration and the inherent one-time-use nature of radio-chemical dosimeters. Such problems will be absent in dosimeters based on physical effects like TL or OSL. However, the materials exhibiting TL and/or OSL materials generally suffer from high sensitivity to environmental conditions such as moisture, which means that they can only be incorporated into moisture/water-free matrices and/or phantoms, which typically fail to mimic the human body in terms of radiation absorption.

Consequently, 3D dosimetry based on OSL have been limited to investigations of a few selected cases. 3D dosimetry and routines for performing readout of such OSL-based dosimeters is known to those skilled in the art, such as e.g. from M. L. Jensen et al., (2023), which employs YSO:Ce crystal as the OSL material. Such material is however not tissue-equivalent due to the very high atomic numbers of the involved elements and cannot currently be incorporated into a clinically relevant workflow at e.g. hospitals.

Hence, an improved three-dimensional dosimeter or phantom would be advantageous, and in particular, it would be advantageous with a three-dimensional dosimeter or phantom, which is re-usable, enables simplified readout, is not prone to delayed chemical reactions, is tissue equivalent by encompassing a large water content, has dose-rate independent response and/or has physical properties enabling avoidance of artefacts.

The present invention sets out to solve the above-identified drawbacks of current state- of-the-art OSL-based dosimeters.

Summary

Most medical radiation facilities benefit from the use and availability of large phantoms because such large phantoms (e.g. on the order of a 10 cm cube) would enclose the volume of most radiation treatment plans relevant for human radiation treatment. However in such large phantoms, even small differences in refractive index between the embedded OSL-material and the host matrix become problematic, in particular as the readout process relies on optical access to all parts of the dosimeter, which means that the OSL dosimeter needs to be sufficiently transparent. Large particles are not suitable for this purpose because large particles inherently result in more light scattering. Nanoparticles are however much more suitable for this purpose.

Thus, a first aspect of the present invention provides a phantom for dosimetry comprising a composition comprising a plurality of nanoparticle crystallites, each crystallite having a size of less than 100 nm x 100 nm x 100 nm, wherein said crystallites are characterised by exhibiting optically stimulated luminescence (OSL) properties, and wherein said crystallites are embedded in a hydrogel matrix. It is preferable that said nanoparticle crystallites comprise Cu-doped lithium fluoride crystallites (LiF:Cu).

Also provided herein are methods for preparation of said phantom, use of said phantom in dosimetry, as well as methods of for estimating and/or determining three- dimensional dose distribution of an ionising radiation in a phantom, such as those of the present invention.

Description of Drawings

Figure 1 : Simplified working principle of a dosimeter showing an energy diagram of an OSL/TL phosphor. OSL trap states are filled by electron-hole pairs excited above the band gap by ionising radiation. When stimulated either optically (OSL) or thermally (TL), these charges recombine radiatively via luminescence traps. Also illustrated is radioluminescence (RL), where electron-hole pairs recombine during initial irradiation.

Figure 2: Irradiation and readout of the hydrogel-based LiF:Cu dosimeter.

A: Photograph (in greyscale) showing aligning of the dosimeter in the treatment room using the in-room patient alignment system lasers (more details in Example 2) prior to irradiation. While the figure is presented in greyscale, the lasers employed for the alignment are green.

B: Photograph (in greyscale) of dosimeter during readout, where the stimulating laser sheet (in this case composed of blue light) passes through the exact center of the cuvette. The camera is located off-image to the right. The laser source is placed perpendicular to the camera/dosimeter axis (seen in the upper right quadrant of the figure).

Figure 3: Projections from the readout of the cube having been irradiated with two opposing homogeneous photon fields. Readout was performed as described in section 2.1 : Optical Readout System of M. L. Jensen et al., (2023), the contents of which are incorporated by reference.

A: Sum of all depths yielding the projection along the Z direction. B: Projections along the X and Y directions showing the slightly asymmetrical distribution along X due to attenuation of the laser sheet throughout the width of the dosimeter.

C: Sum of all widths yielding a projection along the X direction similar to a side view of the dosimeter. The non-rectangular shape is partly due to the choice of readout region and partly due to internal reflections in the dosimeter. The readout region along the depth of the dosimeter (Z direction) has been slightly limited to avoid potential optical artefacts from the frontmost and backmost layers, yielding a smaller Z-range compared to the X/Y-range. The trapezoidal shape is caused by contributions from internal reflections in the dosimeter sides, which are easily accounted for as explained in M. L. Jensen et al., (2023) (Supporting information, section 1.4: internal reflections, including subsections) the contents of which are incorporated by reference.

D: Projection along the Z direction (depth) clearly showing the exponential attenuation of the signal transmitted through the volume of the dosimeter. The attenuation of signal throughout the active dosimetric volume (the Z direction) can be derived from this data, yielding an effective attenuation coefficient of <0.3 cm^-1 in the relevant spectral window. The result is a signal yield that drops to -20% from the deepest layers compared to the shallow layers, but as the signal loss is well-behaved, this effect is easily compensated for. For improved formulations of the dosimeter, this number will be higher, e.g. the data in Figure 6 correspond to 35% from the deepest layers.

Figure 4: Transmission through 1 cm cuvettes of different compositions of hydrogels. In this figure, “pure solvent” refers to a gelatine-based hydrogel produced using spectral grade glycerol (99.5+% purity, Thermo Scientific Cat. No. 184690025) as opposed to the 5%-curve or 1 %-curve wherein the hydrogel was prepared using standard reagent grade (99% purity) glycerol. As is seen from the observed transmission, choosing an alcohol-based solvent, in this case glycerol, of higher purity and/or lowering the concentration of gelatine greatly improves the transparency at UV wavelengths, where the signal from the nanoparticles is located (the OSL wavelength).

Figure 5: Comparison of the depth profile of the signal obtained from reading out back to front (in the first irradiation) and front to back (in the second irradiation).

A: The intensity has been normalized to the intensity observed at depth of 0 mm. The data shows that the intensity decay through the dosimeter is similar irrespective of back-to-front or front-to-back read-out. The sudden dip in intensity at 25 mm in the front-to-back readout is due to an optical artefact.

B: Absolute intensity showing the slightly lower signal level in the readout from front to back. The difference may stem from different exposure to light before readout and/or to the reflections of the laser sheet observed in the second readout due to the presence of an air bubble. The sudden dip in intensity at 25 mm in the front-to-back readout is due to an optical artefact.

Figure 6: Characterisation and correction of attenuation of OSL signal in the improved hydrogel, using spectral grade (+99.5%) glycerol. The hydrogel was irradiated and read out using the same irradiation plan and read-out configuration as the data presented in Figure 3.

A: A plot of the signal as a function of depth averaged over 20 x 20 mm² inside the dosimeter. The average and the statistical spread at each depth were used to fit an exponential function of the type e^{- Md}, yielding an effective attenuation length of 0.35(3) cm^-1.

B: Attenuation lengths from absorption (p_a) and scattering (p_s) of the hydrogel as determined using a spectrophotometer. Also shown are the transmission window of the read-out setup, and the OSL emission band of the LiF:Cu nanoparticles.

C: Three-dimensional plot of the read-out from the homogenously irradiated hydrogel (Example 2) corrected for attenuation using the attenuation length (from the fit in subfigure 6a)).

Figure 7: Computed tomography (CT) scan of the hydrogel manufactured using the improved recipe (i.e. using spectral grade glycerol) in a quartz cuvette. The figure shows a histogram of the radiodensity in the innermost 60 x 60 x 60 mm³ enclosing the dosimeter and cuvette. The inset shows a similar histogram of the centermost 40 x 40 x 40 mm³ of only the hydrogel, outlined in white on the 3D representation. As is evident from the histogram, the radiodensity of the dosimeter is predominantly in the range of 100 to 200 HU which is comparable to normal soft tissue (-300 to +200 HU).

Figure 8: Three-dimensional dose distributions for three intersecting photon beams. A: measured; and B: planned. The measured data have been corrected for the attenuation of light through the dosimeter. The 3D distribution has been cut out along three axes to show the dose distribution along planes intersecting the centre of the distribution for both measurement and plan.

Detailed description

Composition

The present invention provides a composition which is advantageous for providing a phantom (i.e., a model of a part of the human body), which can be subjected to radiation and which phantom can subsequently be subjected to examination revealing the resulting amount of deposited radiation (dose) and its spatial distribution. This may for example be relevant for validating radiation plans (before actually subjecting a patient to a planned radiation treatment), such as to verify that a dose distribution of radiation does in fact correspond to the volume requiring treatment, while leaving healthy tissue as unaffected as possible.

Within the present invention, a phantom for dosimetry, preferably for three-dimensional dosimetry, may be provided as comprising a composition comprising a plurality of particles embedded in a hydrogel matrix, wherein said particles comprise optically stimulated luminescence material or exhibit optically stimulated luminescence properties. It is preferred that said matrix is a hydrogel matrix to best mimic human tissue for the purpose of medical dosimetry.

Refractive index mismatching

In an embodiment of the presently disclosed phantom, the nanoparticle crystallites are characterised by a first refractive index (n_Crystai), the hydrogel matrix is characterised by a second refractive index (nhydrogei) , wherein the difference between n_Crystai and hydrogei (A_n) is no more than 2.0%, preferably no more than 1.0%, more preferably no more than 0.5%. A_n may be determined according to the following formula:

In one embodiment of the present disclosure, A_n is no more than 2%, preferably no more than 1.0%, more preferably no more than 0.5% over the wavelength region corresponding to the optically stimulated luminescence (OSL) wavelength and/or A„ is no more than 2%, preferably no more than 1.0%, more preferably no more than 0.5% over the wavelength region corresponding to the optically stimulating wavelength or excitation wavelength.

In one embodiment of the present disclosure, A„ is no more than 2%, such as preferably no more than 1.0%, such as preferably no more than 0.5% in the region from 300 nm to 500 nm, more preferably in the region from 300 nm to 450 nm, such as from in the region from 325 nm to 450 nm.

In one embodiment of the present disclosure, A„ is no more than 2%, in the region from 310 nm to 450 nm, such as in the region from 320 nm to 450 nm, such as in the region from 325 nm to 450 nm, such as in the region from 325 nm to 445 nm.

In one embodiment of the present disclosure, A„ is no more than 2% at 325 nm and/or is no more than 2% at 445 nm.

One embodiment of the present disclosure is a phantom wherein a ratio between the refractive indices of the hydrogel matrix and the nanoparticle crystallites at a wavelength, where optical stimulation of the particles can be carried out and/or at a wavelength where stimulated luminescence takes place, is equal to or less than 1.10, such as equal to or less than 1.05, such as equal to or less than 1.04, such as equal to or less than 1.03, such as equal to or less than 1.02, such as equal to or less than 1 .015, such as equal to or less than 1 .01 , optionally with the proviso that the ratio is larger than 0.9, such as 0.95, such as 1.0. Such ratio may be determined as (nhydrogei/ncrystai) using conventional refractometry analytical methods known in the art for determining refractive indices at a specified wavelength. For very small particles such as nanoparticles, the refractive index of such particles may alternatively be measured by dispersing a known amount of nanoparticles into a solution of known refractive index and measuring the transparency and/or transmission at the wavelength in question, such as the OSL wavelength in order to determine the refractive index of the nanoparticles at the OSL wavelength. Such methodology is known from e.g. C. L. Nielsen et al., (2023), the contents of which are incorporated by reference. In one embodiment of the present disclosure, the ratio nhydrogei/flcrystai may be between 0.90 and 1.10 at the OSL wavelength, such as between 0.92 and 1.08, such as between 0.95 and 1 .05, such as between 0.98 and 1 .02 at the OSL wavelength. In one embodiment of the present disclosure, the OSL material is LiF:Cu and the OSL light has a peak emission at 325 nm, corresponding to the OSL wavelength. Comprehensive databases such as refractiveindex.info can be consulted for refractive index information on a vast selection of common materials.

An advantage of this may be that the ratio close to unity ensures a relatively low amount of refraction and scattering at the boundaries between the matrix material and the particles. It may be seen as an insight of the inventors, that the optical properties of the phantom, such as the attenuation coefficient, may depend not only on the (isolated) optical properties of the matrix as such and/or the optical properties of the OSL particles as such, but also on the relation between the optical properties of the matrix and the particles, such as the ratio of their refractive indices, since tuning this ratio may alter the attenuation coefficient of the phantom, regardless of the respective attenuation coefficients of the matrix and the particles.

In a simplistic description, particles exhibiting optically stimulated luminescence properties are those particles comprising electrons characterised by being radiation excitable, such as by ionising radiation, such as the electrons in the particles may be brought into excited states of higher energy than the valence band via ionising radiation and are capable of emitting optically stimulated luminescence (i.e. emit light of a certain OSL material-dependent wavelength) via stimulation by electromagnetic radiation, such as light. These excited states are also herein referred to as OSL trap states or simply trap states. For a more detailed technical description of OSL materials and the underlying physical principles, the inventors refer to E. G. Yukihara et al., (2008), the contents of which is incorporated by reference.

Within the present invention, a phantom may be provided as a composition comprising a plurality of nanoparticle crystallites, each crystallite having a size of less than 100 nm x 100 nm x 100 nm, wherein said crystallites are characterised by exhibiting optically stimulated luminescence properties, and wherein said crystallites are embedded in a matrix, such as a hydrogel matrix.

In one embodiment of the present disclosure, said nanoparticle crystallites consist of or comprise lithium fluoride (LiF) nanoparticles. Lithium fluoride is preferable due to its low effective atomic number, which makes it close to tissue-equivalent. In a further embodiment, said lithium fluoride nanoparticles are doped with small amounts of dopant atoms X (LiF:X). In one embodiment of the present disclosure, X may be a combination of different dopant elements X1, X2, X3...Xn, wherein n may take a value op to 10.

Screening experiments by the present inventors have found observable optically stimulated luminescence (OSL) response in undoped lithium fluoride nanoparticles as well as lithium fluoride nanoparticles doped with magnesium (Mg), copper (Cu), or phosphorous (P) as well as combinations thereof. Additionally, lithium fluoride nanoparticles doped with silver (Ag), cerium (Ce), europium (Eu), sodium (Na), ytterbium (Yb), and zinc (Zn) have shown observable optically stimulated luminescence (OSL) responses as has lithium fluoride nanoparticles doped with magnesium (Mg) combined with titanium (Ti).

The optically stimulated luminescence (OSL) response from Cu-doped lithium fluoride nanoparticles (LiF:Cu) was shown to be superior to the alternative dopants and combinations thereof.

In one embodiment of the present disclosure, said lithium fluoride nanoparticles comprise copper-doped lithium fluoride nanoparticles (LiF:Cu).

LiF:Cu

LiF:Cu is a known OSL material, however as it is comprised of mainly lithium fluoride (LiF) which is known to be highly hygroscopic its usefulness in moisture-rich matrixes such as hydrogels has long been considered non-existing, in particular due to the known instability of LiF in contact with moisture (B. Fleming et al., (2017), incorporated by reference).

The present inventors have however demonstrated that as opposed to what could be expected, LiF:Cu nanoparticle crystallites show highly surprising stability both in terms of preserving OSL properties but also re-usability is preserved despite the high watercontent of the hydrogel matrix. In addition, the present inventors have demonstrated that unexpectedly, despite the assumed incompatibility of LiF:Cu with water and/or moisture, the LiF:Cu nanoparticle crystallites can be suspended in pure demineralised water and incorporated into a hydrogel in a simple and efficient manufacturing method without any detrimental effects observable in the OSL properties of LiF:Cu.

In one embodiment of the present disclosure, the nanoparticle crystallites comprise Cu- doped lithium fluoride crystallites denoted herein as LiF:Cu, more preferably said Cu- doped lithium fluoride crystallites are single-crystal crystallites. In one embodiment said single crystal crystallites have a cube morphology and/or shape. In some further embodiments, said single-crystal crystallites are characterised by a cubic Bravais crystal lattice.

In one embodiment of the present disclosure, the Cu-doped lithium fluoride crystallites are characterised by a Cu-doping of 0.01 mol% to 2.0 mol%, such as 0.01 mol% to 0.025 mol%, such as 0.025 mol% to 0.05 mol%, such as 0.05 mol% to 0.075 mol%, such as 0.075 mol% to 0.1 mol%, such as 0.1 mol% to 0.25 mol%, such as 0.25 mol% to 0.5 mol%, such as 0.5 mol% to 0.75 mol%, such as 0.75 mol% to 1.0 mol%, such as 1.0 mol% to 1.5 mol%, such as 1.5 mol% to 2.0 mol%. In one embodiment, the Cu- doping is 0.05 mol% to 0.1 mol%. In one embodiment, the Cu-doping is 0.05 mol%.

For practical applications in the field of dosimetry using medical phantoms, ionising radiation is used for the purpose of exciting the electrons in the OSL material from the ground state to the excited OSL trap-states. Ionising radiation is characterised by having an energy above 10 - 50 eV, but is for most real-world applications in the order of 1 - 250 MeV. In the field of medically relevant applications, the ionizing radiation may be in the form of high-energy photons (1-25 MV beam quality), electrons (4-20 MeV) and protons (70-250 MeV). Upon exposure to optical stimulation with light of the material-specific excitation wavelength, luminescence is triggered which results in the emission of light of a second material-specific wavelength referred to as the OSL wavelength.

The present inventors have found that for LiF:Cu as the OSL material, the wavelength where optical stimulation takes place, i.e. the first material-specific excitation wavelength, is preferably around 400 nm to approximately 580 nm, which covers the spectrum of blue to yellow light, most preferably around 445 nm ± 20 nm, such as 445 nm corresponding to blue light. Optically stimulated luminescence of LiF:Cu has been achieved with a variety of light sources, such as light of 532 nm (green light) and 460 nm (blue light). Thus, in one embodiment of the present disclosure, the excitation wavelength is from 400 nm to 580 nm, more preferably from 400 nm to 530 nm. In one embodiment of the present disclosure, the excitation wavelength is 455 ± 10 nm. LiF:Cu presents a further advantage for OSL-based dosimetry purposes, in that the temporal lifetime of the OSL trap states is at least several minutes, such as the OSL trap state temporal lifetime and/or stability is more than 10 minutes, such as more than 60 minutes, such as more than 1 day, such as more than 2 days, such as more than a week, as long as the material is not heated up and/or stored in a dark container or a container which only allows light of a wavelength above 600 nm to enter the internal space of the container.

Similarly, it has been found that the wavelength of the optically stimulated luminescence originating from LiF:Cu has a wavelength spanning from approximately 280 nm to 400 nm with its peak intensity around 325 nm. Thus in one embodiment, the OSL emission is characterized by a peak emission at 325 nm ± 10 nm. In one embodiment of the present disclosure, the OSL wavelength is preferably 325 nm ± 35 nm, with the ± 35 nm representing the full-width half-maximum of the OSL emissions band.

It is thus an embodiment of the presently disclosed phantom, wherein the wavelength were optical stimulation takes place is 450 ± 50 nm, and/or wherein said stimulated luminescence wavelength is 325 ± 35 nm.

In one embodiment of the present disclosure the nanoparticle crystallites are present in the hydrogel matrix in an amount corresponding to from 0.1 wt.% to 10.0 wt.% by weight of the phantom composition, such as from 0.1 wt.% to 0.5 wt.%, such as from 0.5 wt.% to 1.0 wt.%, such as from 1.0 wt.% to 2.0 wt.%, such as from 2.0 wt.% to 3.0 wt.%, such as from 3.0 wt.% to 4.0 wt.%, such as from 4.0 wt.% to 5.0 wt.%, such as from 5.0 wt.% to 6.0 wt.%, such as from 6.0 wt.% to 7.0 wt.%, such as from 7.0 wt.% to 8.0 wt.%, such as from 8.0 wt.% to 9.0 wt.%, such as from 9.0 wt.% to 10.0 wt.% by weight of the phantom composition, including any 0.5 wt.% incremental value therein between.

In one embodiment, the nanoparticle crystallites are present in the hydrogel matrix in an amount corresponding to from 5 wt.% to 10 wt.% by weight of the phantom composition. In one embodiment, the nanoparticle crystallites are present in the hydrogel matrix in an amount corresponding to from 5.0 ± 2.0 wt.% by weight of the phantom composition. In one embodiment, the nanoparticle crystallites are present in the hydrogel matrix in an amount corresponding to 1 , 2, 3, 4 or 5 wt.% by weight of the phantom composition. In one embodiment of the present disclosure, substantially all exposed facets and/or faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}. In one embodiment, all exposed facets and/or faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}.

Hydrogel

In one embodiment of the present disclosure, the hydrogel matrix is in the form of a solid, such as a solid cube, comprising OSL-active nanoparticle crystallites distributed therein, further wherein said solid has a size along each of its sides of at least 10 mm, such as at least 15 mm, such as at least 20 mm, such as at least 50 mm, such as at least 100 mm, such as at least 150 mm, such as at least 200 mm.

In one embodiment of the present disclosure, the hydrogel matrix is in the form of a solid, such as a solid cube, comprising OSL-active nanoparticle crystallites distributed therein, further wherein said solid has a size along each of its sides of at 10 mm to 200 mm, such as 10 mm to 15 mm, such as 15 mm to 20 mm, such as 20 mm to 50 mm, such as 50 mm to 100 mm, such as 100 mm to 150 mm, such as 150 mm to 200 mm. Preferably, each side if of the solid cube is 50 mm to 100 mm.

In one embodiment of the present disclosure, said hydrogel matrix is based on natural or synthetic polymers.

Natural polymers are well known in the art and may in one embodiment of the present disclosure refer to at least one polymer selected from the group consisting of gelatine, collagen, starch, alginate, agarose, agar, hyaluronic acid, chitosan, heparin, pectin, fibrin, and/or mixtures thereof.

Similarly, synthetic polymers are also well known in the art and may in one embodiment of the present disclosure refer to at least one polymer selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium polyacrylate, and/or mixtures thereof. In one embodiment of the present disclosure, said hydrogel matrix is based on gelatine as the natural polymer. It would be readily understandable to the skilled person having regard to the entirety of the present disclosure that any embodiment of the present disclosure making reference to a hydrogel matrix could equally be seen as a reference to a gelatine-based hydrogel matrix.

In one embodiment of the present disclosure, the natural polymer, preferably gelatine, makes up 1.0 to 10.0% by weight of the hydrogel composition, preferably 3.0 to 6.0% by weight of the hydrogel composition.

In one embodiment of the present disclosure, said hydrogel further comprises an alcohol. In one embodiment, said alcohol is selected from the group consisting of glycerol, ethylene glycol, propylene glycol, ethanol and isopropyl alcohol.

A ratio between the refractive index of the hydrogel and the nanocrystal material (nhydrogei/ncrystai) close to unity can be obtained by optimizing the constituents of the hydrogel matrix. Specifically, it is well-known to those skilled in the art that any liquid consisting of a mixture of two (or more) miscible base liquids of different refractive indices will exhibit an effective refractive index of a value between that of the base liquids, depending on the implemented mixing ratio. This means that the mixing ratio can be used as a chemical handle to adjust the effective refractive index of the mixed liquid such that it matches that of the nanocrystals over a given wavelength range, said wavelength range being determined by the dispersion of the nanocrystals and the liquids.

Within the scope of the present disclosure, the alcohol is chosen such as to provide a chemical handle for bridging any discrepancies between the matrix and the OSL material thereby bringing the refractive index ratio (nhydrogei/flcrystai) closer to unity. Therefore by choosing the relevant alcohol and admixing it in a relevant amount with e.g. water and gelatine, a hydrogel can be formed which has approximately the same refractive index as the OSL material, here exemplified with LiF:Cu nanoparticles. This procedure ensures a dosimeter which can be tuned to be transparent at the relevant wavelengths such as the excitation wavelength and/or OSL wavelength. In one embodiment of the present disclosure, said alcohol is glycerol or ethylene glycol, preferably glycerol.

In one embodiment of the present disclosure, the alcohol, preferably glycerol, makes up 30 to 70% by weight of the hydrogel composition, such as 30%, such as 40%, such as 50%, such as 60%, such as 70% by weight of the hydrogel composition and any 5.0% value therein between.

In one embodiment of the present disclosure, water makes up 30 to 70% by weight of the hydrogel composition, such as 30%, such as 40%, such as 50%, such as 60%, such as 70% by weight of the hydrogel composition and any 5.0% value therein between.

An embodiment provided within the scope of the present disclosure also provides a method of manufacturing a phantom, comprising at least the steps: a. Admixing in a first container at least water, glycerol and a natural polymer such as gelatine thereby obtaining a first container mixture, optionally wherein said admixing is done at a temperature above room temperature, such as at 50-65 °C; b. Providing an OSL active material, such as LiF:Cu nanoparticle crystallites, and adding said OSL active material to the first container mixture, thereby obtaining a liquid mixture of OSL active material and hydrogel, optionally wherein said OSL active material is provided in the form of an aqueous suspension; and c. Allowing said liquid mixture of OSL active material and hydrogel to solidify, thereby obtaining a solid hydrogel comprising OSL active material embedded therein, such as in the form of a phantom within the scope of the present invention;

In one embodiment of the present disclosure, step b of said phantom production method comprises letting the first container mixture cool to below 40 °C, such as below 30 °C, such as to room temperature or below 25 °C.

In one embodiment of the present disclosure, step c of said phantom production method comprises minimizing solvent evaporation during solidification, such as e.g., by covering the liquid mixture with a water and/or moisture impermeable sheet, such as parafilm, glass or similar for the duration of the process.

In one embodiment of the present disclosure, said method comprises the admixing of gelatine (4-6 wt.%), glycerol (30-40 wt.%) and water (50-60 wt.%). In a further embodiment, said hydrogel is obtained by the admixing of gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%), wherein said wt.% refers to the total weight of the final solid hydrogel.

In one embodiment of the present disclosure, said method comprises the admixing of gelatine, glycerol and water in a 1 : 7(±1) : 10(±2) ratio by mass, preferably in a 1 : 7(±0.5) : 11 (±0.5) ratio by mass.

In one embodiment of the present disclosure, said method comprises the admixing of gelatine, glycerol and water in a 1 : 7(±1) : 9(±1) ratio by mass, preferably in a 1 : 7(±0.5) : 9(±0.5) ratio by mass.

In one embodiment, said hydrogel matrix is prior to solidification further admixed with LiF:Cu nanoparticle crystallites and allowed to solidify, such as solidify upon cooling. In one embodiment of the present disclosure, said phantom comprises a composition comprising a plurality of LiF:Cu nanoparticle crystallites embedded in a gelatine-based hydrogel matrix, wherein said LiF:Cu particles make up 2 to 5 wt.% of the total composition, the remaining being gelatine-based hydrogel comprised of gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%).

In one embodiment of the present disclosure, said method comprises admixing of gelatine, glycerol and water at 40-80 °C, preferably at 50-65 °C.

In one embodiment of the present disclosure, the hydrogel matrix is transparent.

In one embodiment of the present disclosure, the phantom is characterised by an attenuation coefficient equal to or less than 10 cm^-1 at the excitation wavelength and/or at the OSL wavelength, such as equal to or less than 6.9 cm^-1, such as equal to or less than 5.0 cm^-1, such as equal to or less than 2.0 cm^-1, such as equal to or less than 1 .4 cm^-1, such as equal to or less than 1.0 cm^-1, such as equal to or less than 0.9 cm^-1 , such as equal to or less than 0.6 cm^-1, such as equal to or less than 0.5 cm^-1 at the excitation wavelength and/or at the OSL wavelength. In some embodiments of the present disclosure, the attenuation coefficient may be as low as 0.3 cm^-1 at the excitation wavelength and/or at the OSL wavelength. An advantage of this may be that it enables getting photons in to and/or out of an interior voxel, such as a voxel lying at least 1 cm from an outer interface of the phantom, while still carrying information regarding their initial position.

By 'attenuation coefficient' may be understood Napierian attenuation coefficient u, such as wherein transmission T through a material is given as: — _e~ u(z)dz where the integral is taken over the length of the material, where e denotes the exponential function, where z denotes a corresponding axis through the material and the corresponding coordinate.

The attenuation coefficient may be obtained as is common in the art, such as via measurement in a standard spectrophotometer, which measures the absorption through, e.g. a 1 cm cuvette, accounting for any reflections from the cuvette surfaces. The measured absorbance, denoted by A, is in a standard spectrophotometer apparatus determined as A = log(/o//), where log is the base-10 logarithm, /o is the incident intensity before the cuvette and I the intensity after the cuvette. The measured absorbance is thus related to the Napierian attenuation coefficient as:

A = log(e) int(u(z)dz) with e denoting the base number for the natural logarithm (2.71828). Any reflectance caused by the cuvette material may be accounted for by either a reference measurement of a blank cuvette, or any other methodology available and known to those skilled in art.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at the excitation wavelength as measured using LIV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at the optically stimulating wavelength or excitation wavelength, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at the excitation wavelength, as measured using LIV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at 455 nm, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at 445 nm, as measured using LIV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at the OSL wavelength as measured using LIV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at the optically stimulated luminescence (OSL) wavelength, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at the optically stimulated luminescence (OSL) wavelength, as measured using UV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix has a light transmission above 30% per centimetre at 325 nm, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at 325 nm, as measured using UV-VIS spectroscopy.

In one embodiment of the present disclosure, the hydrogel matrix is essentially colourless.

In one embodiment of the present disclosure, said hydrogel is obtained by the admixing of gelatine, glycerol and water.

In one embodiment of the present disclosure, said hydrogel is obtained by the admixing of gelatine (4-6 wt.%), glycerol (30-40 wt.%) and water (50-60 wt.%). In a further embodiment, said hydrogel is obtained by the admixing of gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%). In one embodiment, said hydrogel matrix is prior to solidification further admixed with LiF:Cu nanoparticle crystallites and allowed to solidify upon cooling. In one embodiment of the present disclosure, said phantom comprises a composition comprising a plurality of LiF:Cu nanoparticle crystallites embedded in a gelatine-based hydrogel matrix, wherein said LiF:Cu particles make up 2 to 5 wt.% of the composition, the remaining being gelatine hydrogel comprised of gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%).

In one embodiment of the present disclosure, said admixing of gelatine, glycerol and water is carried out at 40-80 °C, preferably at 50-65 °C.

In one embodiment of the present disclosure, the density of LiF:Cu crystallites in said hydrogel is within 1 ■ 10'⁶ to 1 ■ 10'³ g/mm³, such as within 6.0- 10'⁶ to 3.0- 10'⁵ g/mm³, such as within 1.0- 10’⁵ to 3-1 O'⁵ g/mm³, such as within 4.0- 10'⁵ to 9.0- 10'⁵ g/mm³, such as within 1 ■ 10’⁵ to 1 ■ 10’⁴ g/mm³, such as within 1 ■ 10’⁴ to 5 10'⁴ g/mm³, such as within 5 1 O'⁴ to 1 ■ 10’³ g/mm³. An advantage of this may be that it enables providing a good OSL signal (such as sufficient number of photons emitted from the particles) while at the same time providing good optical properties (i.e. , low attenuation coefficient), which in turn enables that a good number of optically stimulated luminescence photons can reach a detector, even if originating from voxels within the phantom.

In one embodiment of the present disclosure, said hydrogel does not comprise silicone. In one embodiment of the present disclosure, said hydrogel does not comprise synthetic polymers.

Closable container

To improve prolonged phantom stability, reduce any loss of water content from the hydrogel, and to preserve against any physical impact, the phantom of the present invention may in one embodiment preferably further comprise an external casing in the form of a closable container.

For improved thermal and temporal stability, it is preferred that said container is not only closable but also sealable to prevent exchange of e.g. moisture with the environment outside the container. Therefore in one embodiment, the container may be reversibly- or irreversibly sealable. In one embodiment, said container and/or seal is gas impermeable.

In one embodiment, said container and/or seal is liquid impermeable.

In one embodiment, said container and/or seal is moisture impermeable.

In one embodiment, said container and/or seal is water impermeable.

In one embodiment, said container and/or seal is gas- and/or liquid impermeable or water and/or moisture impermeable.

In one embodiment, said container and/or seal is UV transparent, such as transparent to electromagnetic radiation having a wavelength from 150 nm to 400 nm, more preferably from 250 to 400 nm.

In one embodiment, said container is made essentially of quartz. In one embodiment of the present disclosure, said container is characterised by a refractive index (n_COntainer) which is 1.45 ± 0.1 at the OSL wavelength, such as at 325 nm.

In one embodiment of the present disclosure, said container is made essentially of quartz, and is further characterised by a refractive index (n_COntainer) which is 1.45 ± 0.1 at the OSL wavelength, such as 1 .48 ± 0.02 at the OSL wavelength, such as at 325 nm.

In one embodiment of the present disclosure, the maximum refractive index mismatch in terms of numerical value between the container (n_COntainer) and the hydrogel (nhydrogei) is 0.1 at the OSL wavelength.

Use and methods

The phantom of the present disclosure is suitable for use as a dosimeter in dosimetry. Embodiments falling under such use are also comprised within the scope of the present disclosure. In one embodiment of the present disclosure, such use may be either two-dimensional (2D) dosimetry or three-dimensional (3D) dosimetry.

In one embodiment of the present disclosure, the phantom and/or dosimeter of the present disclosure is in the form of an external dosimeter, such as a dosimeter which is in use outside of the human body. In one embodiment, said phantom and/or dosimeter is characterised by being reversible and/or re-usable.

Re-usable dosimeters and/or phantoms are of particular interest because this requires less resources for production and calibration. Any calibration would only need to be done once for each dosimeter, and multiple sequential read-outs may be performed in the life-time of the OSL dosimeter which also supports an environmental- and less waste-oriented use. In particular, OSL dosimeters such as the one of the present disclosure may be optically bleached using stimulation by green, blue or UV light following read-out to empty all OSL trap-states. Thereby the OSL material is ready for a new cycle of irradiation and re-population of excited OSL trap-states which may subsequently be read-out by optical stimulation at the excitation wavelength.

In one embodiment of the present disclosure, the use of the phantom and/or dosimeter described herein comprises irradiation with ionising radiation, such as photons, electrons and/or protons to populate excited OSL trap-states. In one embodiment, the use comprises irradiation with photons. In one embodiment, the use comprises irradiation with protons.

In one embodiment of the present disclosure, the use comprises at least the steps: a. irradiation of the dosimeter and/or phantom of the present disclosure using a medically relevant source of radiation such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter, optionally wherein said medically relevant source of radiation is ionising radiation; b. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter; and c. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step b, to the predetermined amount and spatial distribution of radiation in step a, optionally wherein the use further comprising repeating step a , step b and step c at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter.

In one embodiment of the use, said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, optionally further comprising mapping three-dimensional spatial distribution of optically stimulated luminescence. In one embodiment of the use, said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of emitted luminescence for a plurality of positions.

In one embodiment of the use, said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non- orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and intensity of emitted luminescence are spatially resolved in a plane comprising said light sheet.

In one embodiment of the use, said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.

In one embodiment of the use, a step of CT scanning the phantom and/or dosimeter may optionally be performed ahead of steps a-c, in order to verify the radiodensity and define the specific dose distribution.

Within the present disclosure is also provided a method for estimating and/or determining three-dimensional dose distribution of an ionising radiation in a dosimeter, such as in a phantom.

In one embodiment of the present disclosure, the method comprises at least the steps: a. Providing a dosimeter, such as a phantom according to the present disclosure, such as a phantom comprising a plurality of LiF:Cu crystallites embedded in a hydrogel matrix, optionally wherein said dosimeter has previously been calibrated, such as by means of irradiations with one or more known doses; b. Irradiating said dosimeter using a medically relevant source of radiation, such as ionising radiation, such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter; c. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter, such as by irradiating the dosimeter with light of a specified excitation wavelength, optionally, wherein said readout comprises mapping three-dimensional spatial distribution of optically stimulated luminescence; and d. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step c, to the predetermined amount and spatial distribution of radiation in step b, optionally further comprising optionally repeating step b , step c and step d at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter.

In one embodiment of the method, said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, such as a wavelength of 445 nm.

In one embodiment of the method, said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of emitted luminescence for a plurality of positions.

In one embodiment of the method, said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non- orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and intensity of emitted luminescence are spatially resolved in a plane comprising said light sheet.

In one embodiment of the method, said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.

Definitions

Unless explicitly stated otherwise, all parameters and symbols used herein have the same meaning as normally used within the technical field of dosimetry. Furthermore, all values for parameters presented herein are to be understood as referring to normal conditions of temperature and pressure (NTP). For completeness, normal temperature as referred to herein is 293.15 K (20 °C) and 1 atmosphere (atm) of pressure (101.325 kPa)

As used herein, the term 'phantom' is to be understood a mechanical model, such as a mechanical model of a human or animal body part, such as an anthropomorphic model, which phantom enables measuring a dose of irradiation which the phantom may be subjected to. That is to say a phantom most often comprises a type of dosimeter. More particularly, the phantom may comprise a dosimeter that undergoes a change properties and/or emits light of a certain wavelength subject to optical stimulation, which change in properties and/or emitted light may be indicative of the dose of irradiation. Said phantom may be non-biological, such as not comprising living or dead tissue. Phantom may be employed interchangeably with "three-dimensional dosimeter" or simply “dosimeter” within the present disclosure.

As used herein, the term “matrix” is to be understood a material in which something is enclosed or embedded. The matrix of the phantom may be understood to be solid, homogeneous, monolithic and/or polymeric, such as exemplary hydrogels which are common and known in the art.

As used herein, the term "hydrogel," and/or "hydrophilic gel" refers to a continuous phase of a hydrophilic polymer that is capable of swelling upon contact with water and other hydrophilic swelling agents, whereby the swelling agent is absorbed into the polymer structure without any dissolution of the polymer. In the dry state, the polymer may be provided in the form of powders, granules, microparticles, fibres or films. In the wet, when the polymer swelling reaches equilibrium, a gel, typically referred to as a hydrogel, is formed. The term is used generally herein to refer only to the hydrated state. Useful hydrogels for the purpose of the present invention generally take up water in an amount corresponding to at least 10% by weight based on the hydrogel's weight in an anhydrous state. Hydrogels capable of absorbing a quantity of water in excess of 95% of their overall weight are in the art defined as "superabsorbent" polymers (SAP). Hydrogels are hydrophilic polymers characterised by their hydrophilicity (i.e. , ability of absorbing large amounts of fluids such as water). The hydrogels within the present invention are typically transparent, in the hydrated state. Hydrogels are generally distinguishable from hydrocolloids, which typically comprise a hydrophobic matrix that contains dispersed hydrophilic particles.

As used herein, the term 'particles' may be understood solid structures which have relatively small volume and dimensions with respect to the volume and dimensions of the matrix material. The particles may comprise or consist of crystalline material. The particles may have dimensions, such as dimensions in each and all 3 geometrical directions, within the order of nanometres to micrometres, such as within 20-2000 nanometre, such as within 50-200 nanometre and is preferably 100 nanometre or less in all 3 geometrical directions.

As used herein, the term 'embedded (in said matrix)' may be understood to enclose closely, such as to make the embedded structure(s) an integral part of the embedding structure, such as the matrix and the embedded particles forming an integral structure. By 'enclose closely' may be understood that there is little or substantially no, such as no, air (or other gas-filled) gap between the embedding (matrix) and embedded (particles) material, such as any gap is equal to or smaller than 1 times, such as 0.5 times, such as 0.25 times, such as 0.1 times, such as 0.01 times, the smallest wavelength of the optically stimulating wavelength and the wavelength of the photons emitted as optically stimulated luminescence.

As used herein, the term 'Optically Stimulated Luminescence' (OSL) has the same technical meaning as is common in the art, more particularly the term refers broadly speaking to the emission of photons from an OSL material upon exposure to stimulating radiation. It may furthermore be understood that the OSL material may be irradiated with ionising radiation to populate OSL trap states. Thus, OSL material is radiation excitable by ionizing radiation, (such as electrons in the particles may be brought into trapped states via transfer of energy from the ionising radiation) and capable of emitting optically stimulated luminescence (such as may be brought to luminesce via stimulation with electromagnetic radiation, such as incident electromagnetic radiation, such as in the form of light of a specific OSL materialdependent wavelength, may trigger recombination of electrons from the trap states releasing energy as stimulated radiative luminescence, which will also have an OSL material dependent emission wavelength). Optically stimulated luminescence (OSL) employs dielectric crystalline materials with long-lived defect states (such as point defects in the crystal lattice, which are usually intentionally introduced by doping) in their band gaps, which can be populated by ionising radiation. In OSL dosimetry, the population of these trap states (corresponding to metastable, localised energy levels within the forbidden band, which are related to the defect states) may be read out by irradiating the sample with a moderately intense light source of appropriate wavelength to promote the trapped electrons to the conduction band and detecting the luminescence at shorter wavelength from, e.g. inter-band (electron-hole) recombination. The whole process is typically, but not always, recorded by a photomultiplier tube (PMT) inside an OSL reader, which is equipped with light sources of wavelengths specified according to the OSL material, such as OSL particles, used. As a result, one can measure the time-dependent luminescent signal (and optionally the so-called OSL decay-curve), and from this evaluate the absorbed dose. Practical use of the OSL method may be facilitated by efficient light sources in the form of LEDs and/or lasers.

In order to perform an OSL excitation and readout, at least three steps are required, the first being irradiation of the OSL material (in the ground state) with ionising radiation to populate the OSL trap-states. The second step is irradiation of the excited OSL material with electromagnetic radiation in the form of light of a first material-specific wavelength, referred to herein as the excitation wavelength or optimally stimulating wavelength. This irradiation stimulates the luminescence from the OSL material (as exemplified in Figure 1). The final step is the measurement and/or detection of the emitted light which will have a second material-dependent wavelength, referred to herein as the optically stimulated luminescence wavelength, or simply OSL wavelength.

Materials which enable OSL may be interchangeably referred to as OSL materials, materials exhibiting OSL properties, OSL active materials and/or optically stimulable luminescent materials. The particles of the present invention are understood to comprise, such as consist of, an OSL material. LiF:Cu as used herein is one example of an OSL active material and refers to Cu-doped lithium fluoride.

As used herein, the term 'a size of the phantom along each and all of the three geometrical dimensions' may be understood that for at least one choice of Cartesian coordinate system, the largest length of the phantom along each of the three axes is at least a given size. In an embodiment, the phantom at least fills a volume corresponding to a solid cube with a side length corresponding to the given size. An advantage of having a size of at least 10 x 10 x 10 mm³ may be that this matches a length scale, which is relevant for humans, and which may be resolved in three-dimensions, e.g. for voxels being 1 x 1 x 1 mm³. An advantage of having a larger size may be that it enables matching length scales or larger structures or regions within a human.

Examples

Example 1 - molding of LiF:Cu@hydrogel (5 cm x 5 cm x 5 cm cube)

Synthesis of LiF:Cu nanoparticles was performed following the procedure set out in C. L. Nielsen et al., (2022) (Supporting information, Synthesis and Characterization) which is incorporated by reference, using the specified precursors in a concentration of 0.5 M. After successful synthesis of LiF:Cu nanocrystallites, these were twice washed using deionised water.

In the experimental procedure, LiF:Cu nanoparticles, totaling approximately 5 grams, were suspended in 20 mL of deionised H2O. Simultaneously, a heating bath of sufficient size to accommodate the beaker used for the hydrogel preparation was filled with a liquid medium and placed on a heating plate set at 50-65 °C. Suitable liquid media for the heating batch includes at least water, glycerol and mineral oil such as paraffin oil.

For the hydrogel preparation, 8.4 grams of gelatin from porcine skin (Sigma-Aldrich, Cat. No. G1890, CAS 9000-70-8) were weighed and mixed with 76 mL of deionised H2O and 48 mL of bidistilled glycerol (99.5%) (VWR Chemicals, Cat. No. 24388.320) (density of glycerol being 1.25 g/cm³). The mixture was placed in a 250 mL flat- bottomed beaker, covered with parafilm to prevent water evaporation, and a magnet was added. The beaker was then positioned in the heating bath on the heater, with a magnetic stirrer set at 200 rpm. The gelatine dissolved in the water-glycerol mixture over approximately 30 minutes, at a set bath temperature of 65°C. Upon achieving a clear solution without visible gelatine grains, the temperature was reduced to 35 °C before addition of the LiF:Cu nanoparticles. While the gelatine melted and dissolved into the water-glycerol solution, an ultrasound bath (Branson Ultrasonic Cleaners, Model no. 2510) was heated to 35 °C. A suitable glass container, with a diameter larger than 5*^2 cm was placed into the ultrasound bath.

The LiF:Cu nanoparticle dispersion was added to the hydrogel solution, and after stirring for approximately 5 minutes at 35 °C, the LiF:Cu@hydrogel solution was poured into a 5 x 5 x 5 cm³ quartz cuvette, maximising its fill. The cuvette was immediately placed in the ultrasound bath (at 35 °C) within the glass container, the ultrasound bath being filled with deionised H2O almost to the cuvette's edge. The ‘degas option’ of the ultrasound bath was activated, and the sample degassed for approximately 15 minutes.

Subsequently, the quartz cuvette comprising the still liquid hydrogel was taken off the heat and allowed to solidify upon cooling to room temperature. To seal the cuvette and prevent any solvent loss due to evaporation, a lid was then placed on top and sealed with parafilm along the edges. The sealed cuvette was stored for subsequent analysis.

Example 2 - Dosimeter Proof-of-Concept - homogeneous irradiation and readout of LiF:Cu@hydrogel (5 cm x 5 cm x 5 cm) cube

To test the dosimetric properties of the hydrogel dosimeter, it was irradiated with two homogeneous photon fields (6 MV, 50 gray (Gy) each) from each side. Each of these fields deposit a dose to the dosimeter, the magnitude of which decays exponentially as the photons pass through the volume and are gradually attenuated. The combination of two opposing fields minimises the effect of the exponential decay, since the two irradiations from opposite sides added together will give an approximatively constant dose throughout. Right behind the two faces, where the photon fields hit, there will be an effect of the photon build-up region, which will not be compensated for by the opposing field. The expected dose distribution is therefore constant across most of the cube with “soft corners” on each of the sides.

Homogenous irradiations were carried out using two opposing 6 MV, 10 cm x 10 cm, jaw-defined, flattened photon beams, each of 5000 MU (monitor units), using a Varian Truebeam linear accelerator at Aarhus University Hospital, Aarhus, Denmark. The beams were delivered with a machine-set dose rate of 600 MU/rnin, and the machine output was within the tolerance of clinical patient treatments. In the treatment room, the dosimeter was placed on a solid water block on the treatment couch and aligned using the in-room lasers (patient alignment system, green lasers in Figure 2A); the sides of the cube were parallel with laser sheets, and the dosimeter centre of mass coincided with the irradiation isocenter. Positioning was done by visual inspection.

The alignment lasers were turned off during and following photon irradiation. The two opposing irradiation fields were given without moving the cube, by instead positioning the gantry at +90° and -90°.

After irradiation, the cube was placed in a dark box and transported to the read-out system (details can be found in section 2.1 : Optical Readout System of M. L. Jensen et al., (2023), the entire contents of which are incorporated by reference). The cube was then read out by scanning the laser sheet from back to front, stimulating a layer of 1 mm thickness at a time. An image of the stimulating laser sheet passing through the center of the cube is seen in Figure 2B. The cube was read out in voxels of volume 0.8x0.8x1.0 mm³ along the X, Y, and Z direction, respectively. A series of projections can be seen in Figures 3 A-D.

While the dosimeter shows an approximately constant signal along the X- and Y- directions fitting nicely with the expected dose distribution, the signal along the depth of the dosimeter (as seen from the perspective of the camera) decays when stemming from deeper within the volume. This is due to a relatively high absorption of the UV signal by gelatine, as well as impurities stemming from the specific glycerol used in the hydrogel, as well as contributions from light scattering originating from a remaining small mismatch between the refractive index of the matrix and the nanocrystals. New iterations of the hydrogel with a lower gelatine content as well as using glycerol of a higher purity grade was expected to enhance the transparency especially in the UV. Initial transmission results showed that the UV transmission could be increased by a factor of two with such improved formulations (see Figure 4). The transmission data was acquired on a Perkin Elmer Lambda 1050 spectrophotometer used in Total Transmission mode with an integrating sphere. The spectra were measured using resolution-optimized integration times for each wavelength and in steps of 2 nm. An empty 1 cm quartz cuvette was measured as a reference. Fresnel reflections in the surfaces was taken into account to estimate the transmission through the gel.

In order to test the reproducibility of the readout, the sample was irradiated in exactly the same manner as described above and read out this time scanning the laser sheet from the front-end to the back, opposite the first readout above. While there was an optical artefact due to the presence of an air bubble at the top of the dosimeter reflecting some of the stimulating laser light and thereby obstructing the X- and Y- directions, the depth profile is interesting to compare to the one obtained in the first readout, where the exponential decay was stipulated to arise from absorption of the UV signal. In the second readout (front-to-back), the exponential attenuation curve fits almost perfectly with the one observed in the back-to-front readout of the first run (Figures 5 A+B). Note that the curves have been normalised to their signal in the layer closest to the camera to highlight their similar behavior, since varying light exposure after irradiation or the optical artefact from the air bubble in the second readout may have caused their slightly different signal levels (see absolute signals in the plot to the right). Nevertheless, the two irradiations and read-outs illustrate the reusability of the dosimeter.

In order to validate and calibrate the effect of attenuation, a second experiment applied the same uniform irradiation to a second dosimeter comprising an identical composition but for the glycerol part of the hydrogel which was of +99.5% purity (spectroscopical grade) as previously described. The result of this experiment is shown in Figures 6 A- C.

Example 3 - Dosimeter Proof-of-Concept - spatially modulated irradiation and readout of LiF:Cu@hydrogel (5 cm x 5 cm x 5 cm) cube

In order to demonstrate the applicability of the new dosimeter in a clinical workflow, a dosimeter was taken through the procedure normally used when treating patients.

First, the dosimeter was CT scanned (Brilliance CT BigBore, Philips Medical Systems) with 0.5 mm slice thickness and imported to the Eclipse treatment planning system (TPS - v. 16.1 - Varian Medical System). The irradiation isocenter was chosen to coincide with the centre of mass of the gel, and treatment was planned with three orthogonal 1.5 cm x 1.5 cm, jaw-defined, flattened beams, delivering 5000 MU each with a beam quality of 6 MV. The calculation resolution was set to 0.1 cm, and the maximum dose was 131.8 Gy. Treatment was delivered with a machine-set dose rate of 600 MU/min, and the machine output was within clinical acceptance for patient treatments. The dosimeter was aligned in the treatment room by fusing a cone-beam CT, acquired by the accelerator's onboard imaging system, with the planning CT. The couch was corrected with four degrees of freedom (translational and rotational) according to the shift obtained from registering the cone-beam to planning CT. After that, the treatment was delivered.

The CT scan is shown in Figure 7. The measured CT signal (in terms of so-called Hounsfield units - HU) shows the high tissue equivalence of the dosimeter material. Typically, soft tissue has between -300 HU and +200 HU (M. Bazalova et al (2008)), while the average for the dosimeter material is 150 HU.

Second, a clinically relevant dose distribution was planned on the dosimeter. Specifically, the dose distribution was three photon fields from three perpendicular directions, each beam having a nominal size of 15 x 15 mm². Such a dose distribution mimics a specific high-resolution (stereotactic) treatment plan administered to certain tumor sites, such as tumors in the head or neck regions. The applied maximum dose was 115 Gy in order to ensure a higher OSL signal, however still low enough that standard clinical dose-delivery techniques can readily be applied. The beam quality was 6 MV.

Third, the planned dose was given to the dosimeter using a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, USA). Alignment of the dosimeter in the accelerator was carried out using the clinical standard of using cone-beam CT.

Fourth, the dosimeter was read out using the same method as above in Example 2. The resulting measured dose distribution is shown in Figure 8. Note that the data have been scaled as a function of distance from the detection (camera) side to account for the light attenuation through the dosimeter as determined from the homogeneous irradiations in Example 2. Fifth, the measurements were evaluated and compared to the planned dose. The raw data clearly demonstrate the high resolution of the dosimeter in both space and dose, and Figures 8 A+B show a high similarity between the prescribed and measured dose. In future clinical use, the similarity could be quantified, e.g. using a so-called gamma analysis, which is a preferred clinical measure for agreement between plans and measurements and known to those of average skill in the art, such as from D. A. Low et al., (1998) the contents of which is incorporated by reference.

References

C. L. Nielsen et al., A Novel Nanocomposite Material for Optically Stimulated Luminescence Dosimetry, Nano Lett. 2022, 22, 4, 1566-1572. https://doi.org/10.1021/acs.nanolett.1c04384

M. L. Jensen et al., High-resolution three-dimensional dosimetry in clinically relevant volumes utilizing optically stimulated luminescence. Med Phys. 2023, 1-10. https://aapm.onlinelibrary.wiley.com/doi/10.1002/mp.16796

C. L. Nielsen et al., Optimizing the transparency of nano-UF:Cu/silicone nanocomposites for 3D optically stimulated luminescence dosimetry. J. Phys.: Conf. Ser. 2023, 2630 012023 https://iopscience.iop.Org/article/10.1088/1742-6596/2630/1/012023

D. A. Low et al., A technique for the quantitative evaluation of dose distributions. Med. Phys. 1998, 25, 656-661. https://aapm.onlinelibrary.wiley.eom/doi/abs/10.1118/1.598248

B. Fleming et al., Advanced environmentally resistant lithium fluoride mirror coatings for the next generation of broadband space observatories," Appl. Opt. 2017, 56, 9941- 9950. https://doi.Org/10.1364/AO.56.009941

E. G. Yukihara et al., Optically stimulated luminescence (OSL) dosimetry in medicine,

Phys. Med. Biol. 2008, 53, R351-R379. https://iopscience. iop.org/article/10.1088/0031-9155/53/20/R01 M. Bazalova et al., Dual-energy CT-based material extraction fortissue segmentation in Monte Carlo dose calculations, Phys. Med. Biol. 2008, 53, 2439 https://iopscience. iop.org/article/10.1088/0031-9155/53/9/015

Items

1 . A phantom for dosimetry comprising a composition comprising a plurality of nanoparticle crystallites, each crystallite having a size of less than 100 nm x 100 nm x 100 nm, wherein said crystallites are characterised by exhibiting optically stimulated luminescence properties, and wherein said crystallites are embedded in a hydrogel matrix.

2. The phantom according to item 1 , wherein said phantom is for three- dimensional dosimetry.

3. The phantom according to any one of the preceding items, wherein the nanoparticle crystallites comprise lithium fluoride crystallites (LiF).

4. The phantom according to item 3, wherein the lithium fluoride crystallites comprise lithium fluoride crystallites doped with a dopant atom X (LiF:X), wherein X is a combination of sodium (Na), magnesium (Mg), phosphorous (P), titanium (Ti), copper (Cu), zink (Zn), silver (Ag), cerium (Ce), europium (Eu), and/or ytterbium (Yb).

5. The phantom according to any one of the preceding items, wherein the nanoparticle crystallites comprise Cu-doped lithium fluoride crystallites (LiF:Cu).

6. The phantom according to any of the preceding items, wherein the nanoparticle crystallites are characterised by a first refractive index (n_Crystai), the hydrogel matrix is characterised by a second refractive index (nhydrogei), and wherein the difference between n_Crystai and nhydrogei (A„) is no more than 2.0%, preferably by no more than 1.0%, more preferably by no more than 0.5%.

7. The phantom according to any one of the preceding items, wherein A„ is no more than 2%, preferably no more than 1.0%, more preferably no more than 0.5% in the region from 300 nm to 500 nm, more preferably from 325 nm to 445 nm.

8. The phantom according to any one of the preceding items, wherein said hydrogel matrix is based on natural or synthetic polymers.

9. The phantom according to any one of the preceding items, wherein said hydrogel matrix is based on at least one polymer selected from the group consisting of gelatine, collagen, starch, alginate, agarose, agar, hyaluronic acid, chitosan, heparin, pectin and fibrin.

10. The phantom according to any one of the preceding items, wherein said hydrogel matrix is based on at least one polymer selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium polyacrylate, and mixtures thereof.

11 . The phantom according to any one of the preceding items, wherein said hydrogel matrix is based on gelatine.

12. The phantom according to any one of the preceding items, wherein said hydrogel comprises an alcohol.

13. The phantom according to any one of the preceding items, wherein said alcohol is selected from the group consisting of glycerol, ethylene glycol, propylene glycol, ethanol and isopropyl alcohol.

14. The phantom according to any one of the preceding items, wherein said alcohol is glycerol or ethylene glycol, preferably glycerol.

15. The phantom according to any one of the preceding items, wherein glycerol makes up 30 to 50% by weight of the hydrogel composition.

16. The phantom according to any one of the preceding items, wherein the hydrogel matrix is transparent. 17. The phantom according to any one of the preceding items, wherein the hydrogel matrix has a light transmission above 30% per centimetre, preferably above 50% per centimetre, at the optically stimulated luminescence wavelength, as measured using LIV-VIS spectroscopy.

18. The phantom according to any one of the preceding items, wherein the hydrogel matrix has a light transmission above 30% per centimetre, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at 325 nm, as measured using LIV-VIS spectroscopy.

19. The phantom according to any one of the preceding items, wherein the hydrogel matrix is essentially colourless.

20. The phantom according to any one of the preceding items, wherein said hydrogel is obtained by the admixing of gelatine, glycerol and water.

21. The phantom according to any one of the preceding items, wherein said hydrogel is obtained by the admixing of (based on total hydrogel weight) gelatine (4-6 wt.%), glycerol (30-40 wt.%) and water (50-60 wt.%).

22. The phantom according to any one of the preceding items, wherein said hydrogel is obtained by the admixing of (based on total hydrogel weight) gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%).

23. The phantom according to any one of the preceding items, wherein said admixing of gelatine, glycerol and water is carried out at 40-80 °C, preferably at 50-65 °C.

24. The phantom according to any one of the preceding items, wherein the nanoparticle crystallites have a cubic and/or cube shape.

25. The phantom according to any one of the preceding items, wherein the Cu- doped lithium fluoride crystallites have a Cu-doping of 0.01 to 2.0 mol%, preferably 0.05 mol% 26. The phantom according to any one of the preceding items, wherein the nanoparticle crystallites are present in the hydrogel in an amount corresponding to from 0.1 wt.% to 10.0 wt.%.

27. The phantom according to any one of the preceding items, wherein substantially all exposed facets/faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}.

28. The phantom according to any one of the preceding items, wherein all exposed facets/faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}.

29. The phantom according to any one of the preceding items, wherein an attenuation coefficient of the phantom is equal to or less than 10 cm^-1 at a wavelength, where optical stimulation of the particles can be carried out at said wavelength and/or at a wavelength where stimulated luminescence takes place.

30. The phantom according to any one of the preceding items, wherein the wavelength where optical stimulation takes place is 450 ± 50 nm, and/or wherein said stimulated luminescence wavelength is 325 ± 25 nm

31. The phantom according to any one of the preceding items, wherein the density of LiF:Cu crystallites in said hydrogel is within 10'⁶ to 10'³ g/mm³.

32. The composition according to any one of the preceding items, wherein the composition is characterised by a Young’s Modulus of 2 MPa or less, such as 1 MPa or less.

33. The phantom according to any one of the preceding items, wherein said hydrogel does not comprise silicone.

34. The phantom according to any one of the preceding items, further comprising an external casing in the form of a closable container. 35. The phantom according to any one of the preceding items, wherein the container is reversibly- or irreversibly sealable.

36. The phantom according to any one of the preceding items, wherein the container is irreversibly sealable.

37. The phantom according to any one of the preceding items, wherein the container is water and/or moisture impermeable.

38. The phantom according to any one of the preceding items, wherein the container is gas- and/or liquid impermeable.

39. The phantom according to any one of the preceding items, wherein the container is characterised by a refractive index (n_CUbe) which is 1.45±0.1 at the OSL wavelength.

40. The phantom according to any one of the preceding items, wherein the container is made essentially of quartz having a refractive index of 1.4816 at the OSL wavelength.

41. Use of the phantom according to any one of the preceding items as a dosimeter in dosimetry.

42. The use according to item 39, wherein the dosimetry is two-dimensional (2D) dosimetry or three-dimensional (3D) dosimetry.

43. The use according to any one of items 41 to 42, wherein the dosimetry is three- dimensional (3D) dosimetry.

44. The use according to any one of items 41 to 43, wherein the dosimeter is an external dosimeter.

45. The use according to any one of items 41 to 44, wherein the dosimeter is a reversible and/or re-usable dosimeter. 46. The use according to any one of items 41 to 45, wherein the dosimetry is based on irradiation with ionising radiation, such as photons, electrons and/or protons.

47. The use according to any one of items 41 to 46, wherein the dosimetry is based on irradiation with photons.

48. The use according to any one of items 41 to 47, wherein the dosimetry is based on irradiation with protons.

49. The use according to any one of items 41 to 48, wherein the use comprises at least the steps: a. irradiation of the dosimeter using a medically relevant source of radiation such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter, optionally wherein said medically relevant source of radiation is ionising radiation; b. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter; c. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step b, to the predetermined amount and spatial distribution of radiation in step a.

50. The use according to any one of items 41 to 49, further comprising optionally repeating step a , step b and step c at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter.

51. The use according to any one of items 41 to 50, wherein said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, optionally further comprising mapping three-dimensional spatial distribution of detected optically stimulated luminescence of the OSL wavelength. 52. The use according to any one of items 41 to 51 , wherein said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of OSL emission for a plurality of positions.

53. The use according to any one of items 41 to 52, wherein said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non-orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and intensity of OSL emission are spatially resolved in a plane comprising said light sheet.

54. The use according to item 53, wherein said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.

55. A method for estimating and/or determining three-dimensional dose distribution of an ionising radiation in a dosimeter, such as in a phantom, said method comprising the steps: a. Providing a dosimeter, such as the phantom of any one of items 1 to 40; b. Irradiating said dosimeter using a medically relevant source of radiation, such as ionising radiation, such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter; c. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter, such as by irradiating the dosimeter with light of a specified excitation wavelength, optionally, wherein said readout comprises mapping three-dimensional spatial distribution of optically stimulated luminescence; d. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step c, to the predetermined amount and spatial distribution of radiation in step b.

56. The method according to item 55, further comprising optionally repeating step b, step c and step d at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter. The method according to any one of items 55 to 56, wherein said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, such as a material-specific excitation wavelength, such as wherein the wavelength is 445 nm. The method according to any one of items 55 to 57, wherein said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of emitted luminescence for a plurality of positions. The method according to any one of items 55 to 58, wherein said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non-orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and emitted intensity of luminescence are spatially resolved in a plane comprising said light sheet. The method according to item 59, wherein said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.

Items 2

1 . A phantom for three-dimensional dosimetry comprising a composition comprising a plurality of nanoparticle crystallites, each crystallite having a size of less than 100 nm x 100 nm x 100 nm, wherein said crystallites are characterised by exhibiting optically stimulated luminescence properties, and wherein said crystallites are embedded in a hydrogel matrix.

2. The phantom according to the preceding item, wherein the nanoparticle crystallites comprise Cu-doped lithium fluoride crystallites (LiF:Cu).

3. The phantom according to any of the preceding items, wherein the nanoparticle crystallites are characterised by a first refractive index (n_Crystai), the hydrogel matrix is characterised by a second refractive index (nhydrogei), and wherein the difference between n_Crystai and nhydrogei (A„) is no more than 2.0%, preferably by no more than 1.0%, more preferably by no more than 0.5%.

4. The phantom according to item 3, wherein A„ is no more than 2%, preferably no more than 1.0%, more preferably no more than 0.5% in the region from 300 nm to 500 nm, more preferably from 325 nm to 445 nm.

5. The phantom according to any one of the preceding items, wherein said hydrogel matrix is comprises gelatine.

6. The phantom according to any one of the preceding items, wherein said hydrogel comprises an alcohol, wherein said alcohol is glycerol or ethylene glycol, preferably glycerol.

7. The phantom according to any one of the preceding items, wherein the hydrogel matrix has a light transmission above 30% per centimetre, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at 325 nm, as measured using LIV-VIS spectroscopy. 8. The phantom according to any one of items 2 to 7, wherein the Cu-doped lithium fluoride crystallites are characterised by a Cu-doping of 0.01 to 2.0 mol%, preferably 0.05 mol%

9. The phantom according to any one of the preceding items, wherein the nanoparticle crystallites are present in the hydrogel matrix in an amount corresponding to from 0.1 wt.% to 10.0 wt.%.

10. The phantom according to any one of the preceding items, wherein said hydrogel does not comprise silicone.

11. The phantom according to any one of the preceding items, further comprising an external casing in the form of a closable container, wherein the container is water and/or moisture impermeable.

12. The phantom according to item 11 , wherein the container is characterised by a refractive index (n_CUbe) which is 1.45 ± 0.1 at the OSL wavelength.

13. Use of the phantom according to any one of the preceding items in dosimetry based on irradiation with ionising radiation, such as photons, electrons and/or protons.

14. The use according to item 13, wherein the use comprises at least the steps: a. irradiation of the phantom using a medically relevant source of radiation such as to deposit a predetermined amount and spatial distribution of radiation in the phantom, optionally wherein said medically relevant source of radiation is ionising radiation; b. read-out of the phantom by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the phantom; and c. Comparing the actual amount and spatial distribution of radiation deposited in the phantom in step b, to the predetermined amount and spatial distribution of radiation in step a. A method for estimating and/or determining three-dimensional dose distribution of an ionising radiation in a phantom, said method comprising the steps: a. Providing a phantom of any one of items 1 to 12; b. Irradiating said phantom using a medically relevant source of radiation, such as ionising radiation, such as to deposit a predetermined amount and three-dimensional dose distribution of radiation in the phantom; c. read-out of the phantom by optically stimulated luminescence (OSL) to estimate and/or determine the actual amount and three-dimensional dose distribution of radiation deposited in the phantom, such as by irradiating the phantom with light of a specified excitation wavelength, optionally, wherein said read-out comprises mapping three-dimensional spatial distribution of optically stimulated luminescence; and d. Comparing the actual amount and three-dimensional dose distribution of radiation deposited in the phantom in step c, to the predetermined amount and three-dimensional dose distribution of radiation in step b.

Claims

1 . A phantom for dosimetry comprising a composition comprising a plurality of at least one type of nanoparticle crystallites embedded in a hydrogel matrix, each of the at least one type of crystallites having a size of less than 100 nm x 100 nm x 100 nm, the composition characterized in that the at least one type of crystallites are characterised by exhibiting optically stimulated luminescence (OSL) properties, further wherein said at least one type of crystallites comprise or consist of Cu-doped lithium fluoride crystallites (LiF:Cu).

2. The phantom according to claim 1 , wherein said phantom is for three- dimensional dosimetry.

3. The phantom according to any one of the preceding claims, wherein the nanoparticle crystallites consist of Cu-doped lithium fluoride crystallites (LiF:Cu).

4. The phantom according to any of the preceding claims, wherein the nanoparticle crystallites are characterised by a first refractive index (n_Crystai), the hydrogel matrix is characterised by a second refractive index (nhydrogei), and wherein the difference between n_Crystai and nhydrogei (A„) is no more than 2.0%, preferably by no more than 1.0%, more preferably by no more than 0.5%, optionally wherein the difference is a normalized difference.

5. The phantom according to any one of the preceding claims, wherein A„ is no more than 2%, preferably no more than 1.0%, more preferably no more than 0.5% in the region from 300 nm to 500 nm, more preferably from 325 nm to 445 nm, optionally wherein the difference is a normalized difference.

6. The phantom according to any one of the preceding claims, wherein said hydrogel matrix is based on natural or synthetic polymers.

7. The phantom according to any one of the preceding claims, wherein said hydrogel matrix is based on at least one polymer selected from the group consisting of gelatine, collagen, starch, alginate, agarose, agar, hyaluronic acid, chitosan, heparin, pectin and fibrin.

8. The phantom according to any one of the preceding claims, wherein said hydrogel matrix is based on at least one polymer selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium polyacrylate, and mixtures thereof.

9. The phantom according to any one of the preceding claims, wherein said hydrogel matrix is based on gelatine.

10. The phantom according to any one of the preceding claims, wherein said hydrogel comprises an alcohol.

11 . The phantom according to any one of the preceding claims, wherein said alcohol is selected from the group consisting of glycerol, ethylene glycol, propylene glycol, ethanol and isopropyl alcohol.

12. The phantom according to any one of the preceding claims, wherein said alcohol is glycerol or ethylene glycol, preferably glycerol.

13. The phantom according to any one of the preceding claims, wherein glycerol makes up 30 to 50% by weight of the hydrogel composition.

14. The phantom according to any one of the preceding claims, wherein the hydrogel matrix is transparent.

15. The phantom according to any one of the preceding claims, wherein the hydrogel matrix has a light transmission above 30% per centimetre, preferably above 50% per centimetre, at the optically stimulated luminescence wavelength, as measured using LIV-VIS spectroscopy.

16. The phantom according to any one of the preceding claims, wherein the hydrogel matrix has a light transmission above 30% per centimetre, such as above 40% per centimetre, such as above 50% per centimetre, such as above 60% per centimetre, such as above 65% per centimetre at 325 nm, as measured using LIV-VIS spectroscopy.

17. The phantom according to any one of the preceding claims, wherein the hydrogel matrix is essentially colourless.

18. The phantom according to any one of the preceding claims, wherein said hydrogel is obtained by the admixing of gelatine, glycerol and water.

19. The phantom according to any one of the preceding claims, wherein said hydrogel is obtained by the admixing of (based on total hydrogel weight) gelatine (4-6 wt.%), glycerol (30-40 wt.%) and water (50-60 wt.%).

20. The phantom according to any one of the preceding claims, wherein said hydrogel is obtained by the admixing of (based on total hydrogel weight) gelatine (5±1 wt.%), glycerol (36±2 wt.%) and water (58±2 wt.%).

21. The phantom according to any one of the preceding claims, wherein said admixing of gelatine, glycerol and water is carried out at 40-80 °C, preferably at 50-65 °C.

22. The phantom according to any one of the preceding claims, wherein the nanoparticle crystallites have a cubic and/or cube shape.

23. The phantom according to any one of the preceding claims, wherein the Cu- doped lithium fluoride crystallites have a Cu-doping of 0.01 to 2.0 mol%, preferably 0.05 mol%

24. The phantom according to any one of the preceding claims, wherein the nanoparticle crystallites are present in the hydrogel in an amount corresponding to from 0.1 wt.% to 10.0 wt.%.

25. The phantom according to any one of the preceding claims, wherein substantially all exposed facets/faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}.

26. The phantom according to any one of the preceding claims, wherein all exposed facets/faces of the Cu-doped lithium fluoride crystallites correspond to Bravais crystal lattice planes characterised by the Miller indices {100}.

27. The phantom according to any one of the preceding claims, wherein an attenuation coefficient of the phantom is equal to or less than 10 cm^-1 at a wavelength, where optical stimulation of the particles can be carried out at said wavelength and/or at a wavelength where stimulated luminescence takes place.

28. The phantom according to any one of the preceding claims, wherein the wavelength where optical stimulation takes place is 450 ± 50 nm, and/or wherein said stimulated luminescence wavelength is 325 ± 25 nm

29. The phantom according to any one of the preceding claims, wherein the density of LiF:Cu crystallites in said hydrogel is within 10'⁶ to 10'³ g/mm³.

30. The composition according to any one of the preceding claims, wherein the composition is characterised by a Young’s Modulus of 2 MPa or less, such as 1 MPa or less.

31. The phantom according to any one of the preceding claims, wherein said hydrogel does not comprise silicone.

32. The phantom according to any one of the preceding claims, further comprising an external casing in the form of a closable container.

33. The phantom according to any one of the preceding claims, wherein the container is reversibly- or irreversibly sealable.

34. The phantom according to any one of the preceding claims, wherein the container is irreversibly sealable.

35. The phantom according to any one of the preceding claims, wherein the container is water and/or moisture impermeable.

36. The phantom according to any one of the preceding claims, wherein the container is gas- and/or liquid impermeable.

37. The phantom according to any one of the preceding claims, wherein the container is characterised by a refractive index (n_CUbe) which is 1.45±0.1 at the OSL wavelength.

38. The phantom according to any one of the preceding claims, wherein the container is made essentially of quartz having a refractive index of 1.4816 at the OSL wavelength.

39. Use of the phantom according to any one of the preceding claims as a dosimeter in dosimetry.

40. The use according to claim 39, wherein the dosimetry is two-dimensional (2D) dosimetry or three-dimensional (3D) dosimetry.

41. The use according to any one of claims 39 to 40, wherein the dosimetry is three-dimensional (3D) dosimetry.

42. The use according to any one of claims 39 to 41, wherein the dosimeter is an external dosimeter.

43. The use according to any one of claims 39 to 42, wherein the dosimeter is a reversible and/or re-usable dosimeter.

44. The use according to any one of claims 39 to 43, wherein the dosimetry is based on irradiation with ionising radiation, such as photons, electrons and/or protons.

45. The use according to any one of claims 39 to 44, wherein the dosimetry is based on irradiation with photons.

46. The use according to any one of claims 39 to 45, wherein the dosimetry is based on irradiation with protons.

47. The use according to any one of claims 39 to 46, wherein the use comprises at least the steps: a. irradiation of the dosimeter using a medically relevant source of radiation such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter, optionally wherein said medically relevant source of radiation is ionising radiation; b. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter; c. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step b, to the predetermined amount and spatial distribution of radiation in step a.

48. The use according to any one of claims 39 to 47, further comprising optionally repeating step a , step b and step c at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter.

49. The use according to any one of claims 39 to 48, wherein said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, optionally further comprising mapping three-dimensional spatial distribution of detected optically stimulated luminescence of the OSL wavelength.

50. The use according to any one of claims 39 to 49, wherein said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of OSL emission for a plurality of positions.

51 . The use according to any one of claims 39 to 50, wherein said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non-orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and intensity of OSL emission are spatially resolved in a plane comprising said light sheet.

52. The use according to claim 51, wherein said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.

53. A method for estimating and/or determining three-dimensional dose distribution of an ionising radiation in a dosimeter, such as in a phantom, said method comprising the steps: a. Providing a dosimeter, such as the phantom of any one of claims 1 to 38, optionally wherein said dosimeter has previously been calibrated, such as by means of irradiations with one or more known doses; b. Irradiating said dosimeter using a medically relevant source of radiation, such as ionising radiation, such as to deposit a predetermined amount and spatial distribution of radiation in the dosimeter; c. read-out of the dosimeter by optically stimulated luminescence (OSL) to determine the actual amount and spatial distribution of radiation deposited in the dosimeter, such as by irradiating the dosimeter with light of a specified excitation wavelength, optionally, wherein said readout comprises mapping three-dimensional spatial distribution of optically stimulated luminescence; d. Comparing the actual amount and spatial distribution of radiation deposited in the dosimeter in step c, to the predetermined amount and spatial distribution of radiation in step b.

54. The method according to claim 53, further comprising optionally repeating step b, step c and step d at least once in an iterative cycle such as to minimise the disagreement between predetermined and actual deposited amount and spatial distribution of radiation in the dosimeter.

55. The method according to any one of claims 53 to 54, wherein said read-out of the dosimeter comprises irradiating the dosimeter with a beam of light of a specified excitation wavelength, such as a material-specific excitation wavelength, such as wherein the wavelength is 445 nm.

56. The method according to any one of claims 53 to 55, wherein said mapping comprises registering corresponding values of coordinates of said light irradiation and intensity of emitted luminescence for a plurality of positions.

57. The method according to any one of claims 53 to 56, wherein said irradiating with a beam of light comprises irradiating the dosimeter at a plurality of positions along an optical axis with the beam of light forming a sheet of light, wherein a surface normal of said sheet of light is non-orthogonal, such as parallel with the optical axis, and wherein said corresponding values of coordinates of said light irradiation and emitted intensity of luminescence are spatially resolved in a plane comprising said light sheet.

58. The method according to claim 57, wherein said optical axis is defined as a vector between the centre of the dosimeter and the centre of an optical detector such as a photomultiplier tube or a CCD detector or camera.