Ionization Cluster Size Distributions Research Articles

Local weighting of nanometric track structure properties in macroscopic voxel geometries for particle beam treatment planning

The research project BioQuaRT within the European Metrology Research Programme aimed at correlating ion track structure characteristics with the biological effects of radiation and developed measurement and simulation techniques for determining ion track structure on different length scales from about 2 nm to about 10 μm. Within this framework, we investigated methods to translate track-structure quantities derived on a nanometre scale to macroscopic dimensions. Here we make use of parameterizations that link the energy of the projectile to the ionization pattern of the track using nanodosimetric ionization cluster size distributions. They were defined with data generated by simulations of ion tracks in liquid water using the Geant4 Monte Carlo toolkit with the Geant4-DNA processes. For the clinical situation with a mixed radiation field, where particles of various energies hit a cell from several directions, we have to find macroscopic relevant mean values. They can be determined by appropriate local weighting functions for the identified parameterization. We show that a stopping power weighted mean value of the mentioned track structure properties can describe the overall track structure in a cell exposed to a mixed radiation field. The parameterization, together with the presented stopping power weighting approach, show how nanometric track structure properties could be integrated into treatment planning systems without the need to perform time consuming simulations on the nanometer level for each individual patient.

Influence of the geometrical detail in the description of DNA and the scoring method of ionization clustering on nanodosimetric parameters of track structure: a Monte Carlo study using Geant4-DNA

The aim of this study was to evaluate the influence of the geometrical detail of the DNA on nanodosimetric parameters of track structure induced by protons and alpha particles of different energies (LET values ranging from 1 to ) as calculated by Geant4-DNA Monte Carlo simulations.The first geometry considered consisted of a well-structured placement of a realistic description of the DNA double helix wrapped around cylindrical histones (GeomHist) forming a 18 kbp-long chromatin fiber. In the second geometry considered, the DNA was modeled as a total of 1800 ten bp-long homogeneous cylinders (2.3 nm diameter and 3.4 nm height) placed in random positions and orientations (GeomCyl). As for GeomHist, GeomCyl contained a DNA material equivalent to 18 kbp. Geant4-DNA track structure simulations were performed and ionizations were counted in the scoring volumes. For GeomCyl, clusters were defined as the number of ionizations (ν) scored in each 10 bp-long cylinder. For GeomHist, clusters of ionizations scored in the sugar-phosphate groups of the double-helix were revealed by the DBSCAN clustering algorithm according to a proximity criteria among ionizations separated by less than 10 bp. The topology of the ionization clusters formed using GeomHist and GeomCyl geometries were compared in terms of biologically relevant nanodosimetric quantities.The discontinuous modeling of the DNA for GeomCyl led to smaller cluster sizes than for GeomHist. The continuous modeling of the DNA molecule for GeomHist allowed the merging of ionization points by the DBSCAN algorithm giving rise to larger clusters, which were not detectable within the GeomCyl geometry. Mean cluster size (m1) was found to be of the order of 10% higher for GeomHist compared to GeomCyl for LET . For higher LETs, the difference increased with LET similarly for protons and alpha particles. Both geometries showed the same relationship between m1 and the cumulative relative frequency of clusters with (f3) within statistical variations, independently of particle type.In order to obtain ionization cluster size distributions relevant for biological DNA lesions, the complex DNA geometry and a scoring method without fixed boundaries should be preferred to the simple cylindrical geometry with a fixed scoring volume.

Secondary ionisations in a wall-less ion-counting nanodosimeter: quantitative analysis and the effect on the comparison of measured and simulated track structure parameters in nanometric volumes

The object of investigation in nanodosimetry is the physical characteristics of the microscopic structure of ionising particle tracks, i.e. the sequence of the interaction types and interaction sites of a primary particle and all its secondaries, which reflects the stochastic nature of the radiation interaction. In view of the upcoming radiation therapy with protons and carbon ions, the ionisation structure of the ion track is of particular interest. Owing to limitations in current detector technology, the only way to determine the ionisation cluster size distribution in a DNA segment is to simulate the particle track structure in condensed matter. This is done using dedicated computer programs based on Monte Carlo procedures simulating the interaction of the primary ions with the target. Hence, there is a need to benchmark these computer codes using suitable experimental data. Ionisation cluster size distributions produced in the nanodosimeter’s sensitive volume by monoenergetic protons and alpha particles (with energies between 0.1 MeV and 20 MeV) were measured at the PTB ion accelerator facilities. C3H8 and N2 were alternately used as the working gas. The measured data were compared with the simulation results obtained with the PTB Monte-Carlo code PTra [B. Grosswendt, Radiat. Environ. Biophys. 41, 103 (2002); M.U. Bug, E. Gargioni, H. Nettelbeck, W.Y. Baek, G. Hilgers, A.B. Rosenfeld, H. Rabus, Phys. Rev. E 88, 043308 (2013)]. Measured and simulated characteristics of the particle track structure are generally in good agreement for protons over the entire energy range investigated. For alpha particles with energies higher than the Bragg peak energy, a good agreement can also be seen, whereas for energies lower than the Bragg peak energy differences of as much as 25% occur. Significant deviations are only observed for large ionisation cluster sizes. These deviations can be explained by a background consisting of secondary ions. These ions are produced in the region downstream of the extraction aperture by electrons with a kinetic energy of about 2.5 keV, which are themselves released by ions of the “primary” ionisation cluster hitting an electrode in the ion transport system. Including this background of secondary ions in the simulated cluster size distributions leads to a significantly better agreement between measured and simulated data, especially for large ionisation clusters.

Energy dependent track structure parametrisations for protons and carbon ions based on nanometric simulations

The BioQuaRT project within the European Metrology Research Programme aims at correlating ion track structure characteristics with the biological effects of radiation and develops measurement and simulation techniques for determining ion track structure on different length scales from about 2 nm to about 10 μm. Within this framework, we investigate methods to translate track-structure quantities derived on a nanometre scale to macroscopic dimensions. Input data sets were generated by simulations of ion tracks of protons and carbon ions in liquid water using the Geant 4 Monte Carlo toolkit with the Geant4-DNA processes. Based on the energy transfer points — recorded with nanometre resolution — we investigated parametrisations of overall properties of ion track structure. Three different track structure parametrisations have been developed using the distances to the 10 next neighbouring ionisations, the radial energy distribution and ionisation cluster size distributions. These parametrisations of nanometric track structure build a basis for deriving biologically relevant mean values which are essential in the clinical situation where each voxel is exposed to a mixed radiation field.

Investigating ionisation cluster size distribution due to sub-1 keV electrons in view of Heisenberg's Uncertainty

As the wavelengths of low energy electrons become comparable with the length scale of the mean ionisation step size, each event particle should be treated with care as the condition outlined in Heisenberg's uncertainty principle (HUP) should also be satisfied. Within this quantum-classical regime, spatial delocalisations of individual ionisation event sites that are generated outside the target region are calculated, and particular attention is given to the validity of using classical transport methods in simulations of nanodosimetric parameters such as mean cluster size, first and second moments, variance and cumulative frequency of ionisation cluster-size probability distributions. This paper presents the comparison between conventionally calculated nanodosimetric quantities and the ones where interacting particles are treated semi-classically with spatial uncertainties satisfied by HUP. The simulated primary charged particles are electrons of energies between 100 eV and 1 keV in DNA equivalent target aqueous water volumes using GEANT4-DNA.

Nanodosimetry of electrons: analysis by experiment and modelling

Nanodosimetry experiments for high-energy electrons from a (131)I radioactive source interacting with gaseous nitrogen with sizes on a scale equivalent to the mass per area of a segment of DNA and nucleosome are described. The discrete ionisation cluster-size distributions were measured in experiments carried out with the Jet Counter. The experimental results were compared with those obtained by Monte Carlo modelling. The descriptors of radiation damages have been derived from the data obtained from ionisation cluster-size distributions.

Experimental investigation of ionisation track structure of carbon ions at HIL Warsaw.

In view of the upcoming radiation therapy with carbon ions, the ionisation structure of the carbon ion track at the nanometre scale is of particular interest. Two different nanodosimeters capable of measuring track structure of ionising particles in a gas target equivalent to a nanometric site in condensed matter were involved in the presented experimental investigation, namely the NCBJ Jet Counter and the PTB Ion Counter. At the accelerator facility of the HIL in Warsaw, simulated nanometric volumes were irradiated with carbon ions of 45 and 76 MeV of kinetic energy, corresponding to a range in the tissue of ∼85 µm and ∼190 µm, respectively. The filling gas of both nanodosimeters' ionisation volume was molecular nitrogen N2, and the ionisation cluster size distributions, i.e. the statistical distribution of the number of ionizations produced by one single primary carbon ion in the filling gas, were measured for the two primary particle energies.

Characterisation of a track structure imaging detector.

The spatial distribution of radiation-induced ionisations in sub-cellular structures plays an important role in the initial formation of radiation damage to biological tissues. Using the nanodosimetry approach, physical characteristics of the track structure can be measured and correlated to DNA damage. In this work, a novel nanodosimeter is presented, which detects positive ions produced by radiation interacting with a gas-sensitive volume in order to obtain a high resolution image of the radiation track structure. The characterisation of the detector prototype was performed and different configurations of the device were tested by varying the detector cathode material and the working gas. Preliminary results show that the ionisation cluster size distribution can be obtained with this approach. Further work is planned to improve the detector efficiency in order to register the complete three-dimensional track structure of ionising radiation.

Nanodosimetric track structure in homogeneous extended beams.

Physical aspects of particle track structure are important in determining the induction of clustered damage in relevant subcellular structures like the DNA and higher-order genomic structures. The direct measurement of track-structure properties of ionising radiation is feasible today by counting the number of ionisations produced inside a small gas volume. In particular, the so-called track-nanodosimeter, installed at the TANDEM-ALPI accelerator complex of LNL, measures ionisation cluster-size distributions in a simulated subcellular structure of dimensions 20 nm, corresponding approximately to the diameter of the chromatin fibre. The target volume is irradiated by pencil beams of primary particles passing at specified impact parameter. To directly relate these measured track-structure data to radiobiological measurements performed in broad homogeneous particle beams, these data can be integrated over the impact parameter. This procedure was successfully applied to 240 MeV carbon ions and compared with Monte Carlo simulations for extended fields.

A novel approach to study radiation track structure with nanometer-equivalent resolution

Clustered DNA damages are considered the critical lesions in the pathways leading from the initial energy deposition by radiation to radiobiological damage. The spatial distribution of the initial DNA damage is mainly determined by radiation track-structure at the nanometer level. In this work, a novel experimental approach to image the three-dimensional structure of micrometric radiation track segments is presented. The approach utilizes the detection of single ions created in low-pressure gas. Ions produced by radiation drift towards a GEM-like 2D hole-pattern detector. When entering individual holes, ions can induce ion-impact ionization of the working-gas starting a confined electron avalanche that generates the output signal. By registering positive ions rather than electrons, diffusion is reduced and a spatial resolution of the track image of the order of water-equivalent nanometers can be achieved. Measurements and simulations to characterize the performance of a few detector designs were performed. Different cathode materials were tested and ionization cluster size distributions of 241Am alpha particles were measured. The electric field configuration in the detector was calculated to optimize the ion focusing into the detector holes. The preliminary results obtained show the directions for further development of the detector.

Nanodosimetry of 125I Auger electrons

Purpose: The nanodosimetric description of the radiation action of Auger electrons on nitrogen targets of nanometric size is presented.Materials and methods: Experimental microdosimetry at nanometer scale for Auger electrons has been accomplished with the set-up called Jet Counter. This consists of a pulse-operated valve which injects an expanding nitrogen jet into an interaction chamber where a gaseous sensitive volume of cylindrical shape is created. The ionization cluster size distributions (ICSD) created by Auger electrons emitted by 125I while crossing a nanometer-sized volume have been measured.Results: The ICSD for the sensitive volumes corresponding to 3 and 12 nm in diameter (in unit density 1 g/cm3) irradiated by electrons emitted by a 125I source were collected and compared with the corresponding Monte Carlo (MC) simulation. The preliminary results of the experiments with Auger electrons of 125I interacting with a nitrogen jet having nanometric size comparable to a deoxyribonucleic acid (DNA) and nucleosome, showing the discrete spectrum of ICSD with extended cluster size, are described.Conclusions: The presented paper describes for the first time the nanodosimetric experiments with Auger electrons emitted by 125I. A set of the new descriptors of the radiation quality describing the radiation effect at nanometer level is proposed. The ICSD were determined for the first time for an Auger emitter of 125I.

Nanodosimetry of 125I – Auger electrons – Experiment and modeling

The experiment with 125 I-Auger electrons, interacting with gaseous nitrogen with size equivalent to segment of DNA in mass per unit area scale, are described. The discrete ionization cluster-size distributions have been obtained. The shapes of which are definitely determined by the size of the interaction volumes. The volume sizes studied in the present work are comparable with a segment of DNA and of nucleosome. The experiments have been carried out with the set up, called Jet Counter, and are the first cluster-size distributions as yet measured for an Auger-electron emitter like 125 I. The experimental results have been compared with those obtained by Monte Carlo simulation. The results for 125 I have been compared with calculated cluster size distribution for 131 I. ► The results of nanodosimetric experiments using Auger electrons of 125 I are presented. ► The cluster distribution of radiation is the primary source of radiation damage. ► The new descriptors of electron interaction at the DNA level are defined.

A comparison of X-ray and proton beam low energy secondary electron track structures using the low energy models of Geant4

Purpose: Lethal cell damage by ionising radiation is generally initiated by the formation of complex strand breaks, resulting from ionisation clusters in the DNA molecule. A better understanding of the effect of the distribution of ionisation clusters within the cell and particularly in regard to DNA segments could be beneficial to radiation therapy treatment planning. Low energy X-rays generate an abundance of low energy electrons similar to that associated with MeV protons. The study and comparison of the track structure of photon and proton beams could permit the substitution of photon microbeams for single cell ion irradiations at proton facilities used to predict the relative biological effectiveness (RBE) of charged particle fields. Materials and methods: The track structure of X-ray photons is compared with proton pencil beams in voxels of approximate DNA strand size (2 × 2 × 5 nm). The Very Low Energy extension models of the Monte Carlo simulation toolkit GEometry ANd Tracking 4 (Geant4) is used. Simulations were performed in a water phantom for an X-ray and proton beam of energies 100 keV and 20 MeV, respectively. Results: The track structure of the photon and proton beams are evaluated using the ionisation cluster size distribution as well as the radial dose deposition of the beam. Conclusions: A comparative analysis of the ionisation cluster distribution and radial dose deposition obtained is presented, which suggest that low energy X-rays could produce similar ionisation cluster distributions to MeV protons on the DNA scale of size at depths greater than ∼10 μm and at distances greater than ∼1 μm from the beam centre. Here the ionisation cluster size for each beam is less than ∼100. The radial dose deposition is also approximately equal at large depths and at distances greater than 10 μm from the beam centre.

Simulation of ionisation clusters formed in nanometric volumes of the deoxyribose-substitute tetrahydrofuran

Purpose: To investigate the implications of using interaction cross sections of liquid water for the target volume when studying radiation action at the DNA level by particle track structure simulations.Materials and methods: Absolute interaction cross sections for low energy electrons between 20 eV and 1 keV were measured for tetrahydrofuran (THF), which is a substitute for deoxyribose. From these data a complete interaction cross section data set was derived and integrated in our PTB Track structure Monte Carlo code ‘PTra’. Simulations of electron track structure in THF and water were performed and ionisation cluster size distributions in nanometric target volumes were determined. From these a nanodosimetric estimate for the probability to produce a double strand break was derived.Results: The probability distribution of ionisation cluster sizes was found to be shifted towards smaller values for a THF-filled target as compared to a water-filled one. For all electron energies investigated, the nanodosimetric estimates for double-strand break probability in the THF-filled target have lower values than for a target of liquid water.Conclusion: The preliminary results indicate that simulations based on cross sections of water would overestimate the initial direct radiation damage to the DNA.

Nanodosimetry: Bridging the gap to radiation biophysics

Nanodosimetry strives to link phenomenological dosimetric concepts like radiation quality and relative biological effectiveness to measurable physical quantities related to the track structure of ionising radiation. The ultimate goal of nanodosimetry is therefore to determine novel dosimetric quantities that include the initial biological or biophysical action of ionising radiation. As a step towards this, experimental and numerical techniques have been developed to characterise particle track structure based on the formation of ionisation clusters within a target volume comparable in mass per unit area to a DNA segment. Several attempts have been made to connect the nanodosimetric parameters derived from these ionisation cluster size distributions to biological radiation effects. This work gives an overview of the basic aspects of nanodosimetry, including a discussion of two nanodosimetry-based approaches used to derive estimators of biological effectiveness of ionising radiation. It also includes preliminary results from an ongoing Monte Carlo study into the limitations of using the physical properties of liquid water to approximate those of DNA in nanodosimetric modelling. The findings suggest an overestimation of radiobiological effectiveness may occur when the cross section data for liquid water are used as a substitute for those of DNA.

Track nanodosimetry of 20-MeV protons at 20 nm

Track nanodosimetry is the theoretical and experimental research which studies the stochastic aspects of ionisation yield produced by ionising particles in nanometric target volumes, positioned at different distances from the primary particle track. The STARTRACK experimental set-up, mounted on the +50° beam line at the Tandem-Alpi particle accelerator of Legnaro National Laboratories, has been conceived to give an experimental basis to nanodosimetric calculations. STARTRACK is a detection system able to measure the ionisation cluster-size distributions in a 20 nm propane site, by counting the electrons set in motion by different ion tracks, with the resolution of one electron. The 'sensitive volume' SV can be moved at different distances from the primary particle track (different impact parameter). Distributions of 20-MeV protons have been measured and compared with Monte Carlo calculations.

Check of the scaling procedure of track structures of ionizing radiation in nanometric volumes

Abstract In nanodosimetry, the track structure of ionizing radiation is characterized by the probability distribution of the number of ionizations produced by an ionizing particle in a target volume. By Monte-Carlo simulations of the track structure, this so called ionization cluster size distribution can be determined for nanometric cylindrical water targets used as substitute for the radiation sensitive biological target, namely a DNA-segment of about 20 base pairs length. Measurements of ionization cluster size distributions are carried out in an ion-counting nanodosimeter filled with an appropriate working gas at low pressure. A scaling procedure was proposed by Grosswendt (2006) to derive an operating pressure depending on the working gas for which the measured ionization cluster size distribution becomes equivalent to the ionization cluster size distribution within a nanometric target of liquid water. This scaling procedure was previously tested by means of Monte-Carlo simulations and is now tested experimentally. Ionization cluster size distributions produced by mono-energetic proton and alpha particle beams in the energy range between 0.1 MeV and 20 MeV were measured at the accelerator facilities of the PTB. The working gases used in this experiment were C 3 H 8 and N 2 . According to the NIST databases for stopping power and mean ionization energy ( NIST, 2009 ), equivalent cluster size distributions for protons and alpha particles should be obtained for pressures of 0.25 mbar C 3 H 8 and 1.2 mbar N 2 . Measurements reveal the best agreement with pressures of 0.425 mbar C 3 H 8 and 1.2 mbar N 2 for protons and 0.46 mbar C 3 H 8 and 1.2 mbar N 2 for alpha particles.

A nanodosimetric model of radiation-induced clustered DNA damage yields

We present a nanodosimetric model for predicting the yield of double strand breaks (DSBs) and non-DSB clustered damages induced in irradiated DNA. The model uses experimental ionization cluster size distributions measured in a gas model by an ion counting nanodosimeter or, alternatively, distributions simulated by a Monte Carlo track structure code developed to simulate the nanodosimeter. The model is based on a straightforward combinatorial approach translating ionizations, as measured or simulated in a sensitive gas volume, to lesions in a DNA segment of one–two helical turns considered equivalent to the sensitive volume of the nanodosimeter. The two model parameters, corresponding to the probability that a single ion detected by the nanodosimeter corresponds to a single strand break or a single lesion (strand break or base damage) in the equivalent DNA segment, were tuned by fitting the model-predicted yields to previously measured double-strand break and double-strand lesion yields in plasmid DNA irradiated with protons and helium nuclei. Model predictions were also compared to both yield data simulated by the PARTRAC code for protons of a wide range of different energies and experimental DSB and non-DSB clustered DNA damage yield data from the literature. The applicability and limitations of this model in predicting the LET dependence of clustered DNA damage yields are discussed.

New descriptors of radiation quality based on nanodosimetry, a first approach

After a short overview on the latest developments in nanodosimetry, measured frequency distributions of ionisation cluster size caused by 4.6 MeV alpha-particles or low-energy electrons in 'nanometric' volumes of nitrogen are compared with cluster-size distributions for liquid water cylinders that are equal in size to segments of DNA of 10 base-pairs length. Such frequency distributions are, to a greater part, governed by the same basic physical interaction data as those to be expected, if charged particles interact with DNA segments. Quantities derived from ionisation cluster-size distributions should, therefore, behave as a function of radiation quality similarly to the yields of single or double strand breaks in the DNA. To test this assumption, extensive Monte Carlo simulations were performed for electrons in the energy range between 12.5 eV and 100 keV for protons at energies between 0.7 MeV and 250 MeV and for alpha-particles in the energy range between 2 MeV and 100 MeV. The results are then compared with the yields of single- or double-strand breaks in the DNA, taken from the literature.

Influence of ionization cross-section data on the Monte Carlo calculation of nanodosimetric quantities

In this work, we discuss the effect of cross-section data in the determination of nanodosimetric quantities, such as ionization cluster-size distributions and mean cluster sizes. In particular, two different theoretical approaches to determine secondary electron distributions after proton interactions in nitrogen and propane were tested by means of a Monte Carlo code. The results show that differences of 10–15% in the cross-section data lead to differences of up to 10–20% in the calculated mean cluster sizes, especially at low energies, suggesting the need for new, reliable and consistent experimental cross-section data.