Development of proton computed tomography detectors for applications in hadron therapy
Abstract
Radiation therapy with protons and heavier ions is an attractive form of cancer treatment that could enhance local control and survival of cancers that are currently difficult to cure and lead to less side effects due to sparing of normal tissues. However, particle therapy faces a significant technical challenge because one cannot accurately predict the particle range in the patient using data provided by existing imaging technologies. Proton computed tomography (pCT) is an emerging imaging modality capable of improving the accuracy of range prediction. In this paper, we describe the successive pCT scanners designed and built by our group with the goal to support particle therapy treatment planning and image guidance by reconstructing an accurate 3D map of the stopping power relative to water in patient tissues. The pCT scanners we have built to date consist of silicon telescopes, which track the proton before and after the object to be reconstructed, and an energy or range detector, which measures the residual energy and/or range of the protons used to evaluate the water equivalent path length (WEPL) of each proton in the object. An overview of a decade-long evolution of the conceptual design of pCT scanners and their calibration is given. Results of scanner performance tests are presented, which demonstrate that the latest pCT scanner approaches readiness for clinical applications in hadron therapy.
... The scope of our study was to further investigate, both experimentally and using MC simulations, the potential of gadolinium-based NPs as contrast agent in proton imaging (pRad and pCT). This imaging modality is not yet clinically available, but with increasing number of proton therapy facilities, prototype scanners for human patients (Bashkirov et al 2016, Esposito et al 2018 and small animals (Meyer et al 2020, Schneider et al 2022 are currently being developed at several research institutes worldwide. To provide a context for the results obtained in this study for proton imaging, comparative measurements were performed with an x-ray CBCT scanner of a commercial small animal x-ray irradiation platform. ...
Orthotopic tumor models in pre-clinical translational research are becoming increasingly popular, raising the demands on accurate tumor localization prior to irradiation. This task remains challenging both in x-ray and proton computed tomography (xCT and pCT, respectively), due to the limited contrast of tumor tissue compared to the surrounding tissue. We investigate the feasibility of gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for both imaging modalities. We performed proton radiographies at the experimental room of the Trento Proton Therapy Center using a MiniPIX-Timepix detector and dispersions of gadolinium oxide nanoparticles in sunflower oil with mass fractions up to 8wt%. To determine the minimum nanoparticle concentration required for the detectability of small structures, pCT images of a cylindrical water phantom with cavities of varying gadolinium oxide concentration were simulated using a dedicated FLUKA Monte Carlo framework. These findings are complemented by simulating pCT at dose levels from 80 mGy to 320 mGy of artificially modified murine xCT data, mimicking different levels of gadolinium oxide accumulation inside a fictitious tumor volume. To compare the results obtained for proton imaging to x-ray imaging, cone-beam CT images of a cylindrical PMMA phantom with cavities of dispersions of oil and gadolinium oxide nanoparticles with mass fractions up to 8wt% were acquired at a commercial pre-clinical irradiation setup. For proton radiography, considerable contrast enhancement was found for a mass fraction of 4wt%. Slightly lower values were found for the simulated pCT images at imaging doses below 200 mGy. In contrast, full detectability of small gadolinium oxide loaded structures in xCT at comparable imaging dose is already achieved for 0.5wt%. Achieving such concentrations required for pCT imaging inside a tumor volume in in-vivo experiments may be challenging, yet it might be feasible using different targeting and/or injection strategies.
... P ROTON computed tomography (pCT) is a relatively new imaging modality that has been developed from early beginnings [1], [2], [3], [4] towards a recent preclinical realization of a pCT scanner [5], [6], [7]; a comprehensive review of pCT development can be found in [8]. The main motivation of pCT has been to improve the accuracy of proton therapy dose planning due to more accurate maps of relative stopping power (RSP) with respect to water, which determines how protons lose energy in human tissues in reference to water as a medium. ...
Previous work showed that total variation superiorization (TVS) improves reconstructed image quality in proton computed tomography (pCT). The structure of the TVS algorithm has evolved since then and this work investigated if this new algorithmic structure provides additional benefits to pCT image quality. Structural and parametric changes introduced to the original TVS algorithm included: (1) inclusion or exclusion of TV reduction requirement, (2) a variable number, N, of TV perturbation steps per feasibility-seeking iteration, and (3) introduction of a perturbation kernel . The structural change of excluding the TV reduction requirement check tended to have a beneficial effect for and allows full parallelization of the TVS algorithm. Repeated perturbations per feasibility-seeking iterations reduced total variation (TV) and material dependent standard deviations for . The perturbation kernel , equivalent to in the original TVS algorithm, reduced TV and standard deviations as was increased beyond , but negatively impacted reconstructed relative stopping power (RSP) values for . The reductions in TV and standard deviations allowed feasibility-seeking with a larger relaxation parameter than previously used, without the corresponding increases in standard deviations experienced with the original TVS algorithm. This work demonstrates that the modifications related to the evolution of the original TVS algorithm provide benefits in terms of both pCT image quality and computational efficiency for appropriately chosen parameter values.
... This advancement has the potential to enhance the precision of proton therapy and optimize the corresponding dose calculation process. Furthermore, precise PCT imaging can enhance the accuracy of preclinical small animal irradiation experiments, facilitating the exploration of the underlying biological mechanisms of proton beams, which remain unclear. 2 The current proton imaging systems can be broadly classified into two types 4 : proton-tracking systems [6][7][8][9][10][11][12] and proton-integrating systems. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] A proton-tracking system typically incorporates two position-sensitive detectors and a residual energy detector, enabling the acquisition of position and residual energy information for individual protons. ...
Background
The accuracy of proton therapy and preclinical proton irradiation experiments is susceptible to proton range uncertainties, which partly stem from the inaccurate conversion between CT numbers and relative stopping power (RSP). Proton computed tomography (PCT) can reduce these uncertainties by directly acquiring RSP maps.
Purpose
This study aims to develop a novel PCT imaging system based on scintillator‐based proton range detection for accurate RSP reconstruction.
Methods
The proposed PCT system consists of a pencil‐beam brass collimator with a 1 mm aperture, an object stage capable of translation and 360° rotation, a plastic scintillator for dose‐to‐light conversion, and a complementary metal oxide semiconductor (CMOS) camera for light distribution acquisition. A calibration procedure based on Monte Carlo (MC) simulation was implemented to convert the obtained light ranges into water equivalent ranges. The water equivalent path lengths (WEPLs) of the imaged object were determined by calculating the differences in proton ranges obtained with and without the object in the beam path. To validate the WEPL calculation, measurements of WEPLs for eight tissue‐equivalent inserts were conducted. PCT imaging was performed on a custom‐designed phantom and a mouse, utilizing both 60 and 360 projections. The filtered back projection (FBP) algorithm was employed to reconstruct the RSP from WEPLs. Image quality was assessed based on the reconstructed RSP maps and compared to reference and simulation‐based reconstructions.
Results
The differences between the calibrated and reference ranges of 110–150 MeV proton beams were within 0.18 mm. The WEPLs of eight tissue‐equivalent inserts were measured with accuracies better than 1%. Phantom experiments exhibited good agreement with reference and simulation‐based reconstructions, demonstrating average RSP errors of 1.26%, 1.38%, and 0.38% for images reconstructed with 60 projections, 60 projections after penalized weighted least‐squares algorithm denoising, and 360 projections, respectively. Mouse experiments provided clear observations of mouse contours and major tissue types. MC simulation estimated an imaging dose of 3.44 cGy for decent RSP reconstruction.
Conclusions
The proposed PCT imaging system enables RSP map acquisition with high accuracy and has the potential to improve dose calculation accuracy in proton therapy and preclinical proton irradiation experiments.
... Protons at initial energy and proton at its stopping location will not have same energy because protons are affected by fluctuation and energy loss. This known as energy straggling [6]. ...
This review focuses on modern scintillators, the heart of ionizing radiation detection with applications in medical diagnostics, homeland security, research, and other areas. The conventional method to improve their characteristics, such as light output and timing properties, consists of improving in material composition and doping, etc., which are intrinsic to the material. On the contrary, we review recent advancements in cutting-edge approaches to shape scintillator characteristics via photonic and metamaterial engineering, which are extrinsic and introduce controlled inhomogeneity in the scintillator’s surface or volume. The methods to be discussed include improved light out-coupling using photonic crystal (PhC) coating, dielectric architecture modification producing the Purcell effect, and meta-materials engineering based on energy sharing. These approaches help to break traditional bulk scintillators’ limitations, e.g., to deal with poor light extraction efficiency from the material due to a typically large refractive index mismatch or improve timing performance compared to bulk materials. In the Outlook section, modern physical phenomena are discussed and suggested as the basis for the next generations of scintillation-based detectors and technology, followed by a brief discussion on cost-effective fabrication techniques that could be scalable.
This paper presents the results of ceramic synthesis in the field of a powerful flux of high-energy electrons on powder mixtures. The synthesis is carried out via the direct exposure of the radiation flux to a mixture with high speed (up to 10 g/s) and efficiency without the use of any methods or means for stimulation. These synthesis qualities provide the opportunity to optimize compositions and conditions in a short time while maintaining the purity of the ceramics. The possibility of synthesizing ceramics from powders of metal oxides and fluorides (MgF2, BaF2, WO3, Ga2O3, Al2O3, Y2O3, ZrO2, MgO) and complex compounds from their stoichiometric mixtures (Y3Al3O12, Y3AlxGa(5−x) O12, MgAl2O4, ZnAl2O4, MgWO4, ZnWO4, BaxMg(2−x) F4), including activators, is demonstrated. The ceramics synthesized in the field of high-energy electron flux have a structure and luminescence properties similar to those obtained by other methods, such as thermal methods. The results of studying the processes of energy transfer of the electron beam mixture, quantitative assessments of the distribution of absorbed energy, and the dissipation of this energy are presented. The optimal conditions for beam treatment of the mixture during synthesis are determined. It is shown that the efficiency of radiation synthesis of ceramics depends on the particle dispersion of the initial powders. Powders with particle sizes of 1–10 µm, uniform for the synthesis of ceramics of complex compositions, are optimal. A hypothesis is put forward that ionization processes, resulting in the radiolysis of particles and the exchange of elements in the ion–electron plasma, dominate in the formation of new structural phases during radiation synthesis.
Purpose:
To assess the feasibility of a proton radiography (pRG) system based on a single thin pixelated detector for water-equivalent path length (WEPL) and relative stopping power (RSP) measurements.
Methods:
A model of a pRG system consisting of a single pixelated detector measuring energy deposition and proton fluence was investigated in a Geant4-based Monte Carlo study. At the position directly after an object traversed by a broad proton beam, spatial 2D distributions are calculated of the energy deposition in, and the number of protons entering the detector. Their ratio relates to the 2D distribution of the average stopping power of protons in the detector. The system response is calibrated against the residual range in water of the protons to provide the 2D distribution of the WEPL of the object. The WEPL distribution is converted into the distribution of the RSP of the object. Simulations have been done, where the system has been tested on 13 samples of homogeneous materials of which the RSPs have been calculated and compared with RSPs determined from simulations of residual-range-in-water, which we refer to as reference RSPs.
Results:
For both human-tissue- and non-human-tissue-equivalent materials, the RSPs derived with the detector agree with the reference values within 1%.
Conclusion:
The study shows that a pRG system based on one thin pixelated detection screen has the potential to provide RSP predictions with an accuracy of 1%.
By using a melt-quenching technique in an air atmosphere, barium-gadolinium-fluoroborate scintillating glasses with different concentrations of BaO and CeF3 were fabricated. The purpose of developing glasses is to be applied as proton or x-ray energy detectors for medical purposes. Physical and scintillating properties of the fabricated glasses were tested and analyzed, including glass density and spectroscopic properties such as transmittance, photoluminescence, x-ray absorption near edge structure, and x-ray-induced luminescence. Moreover, the glasses were impinged by a 70 MeV proton beam at the Proton Center of King Chulalongkorn Memorial Hospital to observe their proton-induced light emission. The absorption edge of the transmittance revealed that the glasses showed a redshift at high concentrations of BaO and CeF3. The glasses had a broad emission band centering around 400 nm due to the 5d–4f transition of Ce3+ induced by x-ray. The higher light yield was observed at a higher cerium compound glass. Our glass can clearly measure the depth-dose profile of the impinging proton beam by varying different water thicknesses. Moreover, the depth-dose profile results are in good agreement with that of the energy deposition of proton beams in glass calculated via GATE simulation.
In this work, Ce3+-doped gadolinium aluminum fluoroborate glass scintillators, 25Gd2O3-(65-x)B2O3–10AlF3-xCeF3, where, x = 0, 0.05, 0.1, 0.2, and, 0.3 mol%, were prepared and studied systematically for developing a proton calorimeter used in proton-computed tomography. Various properties of the prepared glass scintillators were evaluated through density, X-ray absorption near edge spectroscopy, transmittance, photoluminescence, decay time, X-ray-induced luminescence, and proton-induced luminescence measurements. The highest density of the fabricated glass scintillators reached 4.31 g/cm3. The X-ray-induced luminescence showed a broad emission band centered at approximately 400 nm, and the decay time was less than 30 ns. The glass scintillators were irradiated by a proton beam with a beam energy of 100–115 MeV. It was found that the glass scintillators emitted light at almost the same wavelength as that of the X-ray-induced luminescence. Moreover, the energy deposition inside the fabricated glass scintillators was simulated using GATE simulation and compared with the results obtained for proton-induced luminescence. The energy deposition obtained from the simulation showed the same trend as that for the fraction of light emitted from the proton irradiation measurement. Therefore, these fabricated glass scintillators can be used as calorimeter in medical physics and other applications related to proton or X-ray irradiation.
Purpose:
Protoncomputed tomography (pCT) will enable accurate prediction of proton and ion range in a patient while providing the benefit of lower radiation exposure than in x-ray CT. The accuracy of the range prediction is essential for treatment planning in proton or ion therapy and depends upon the detector used to evaluate the water-equivalent path length (WEPL) of a proton passing through the object. A novel approach is presented for an inexpensive WEPL detector for pCT and proton radiography.
Methods:
A novel multistage detector with an aperture of 10 × 37.5 cm was designed to optimize the accuracy of the WEPL measurements while simplifying detector construction and the performance requirements of its components. The design of the five-stage detector was optimized through simulations based on the geant4detector simulation toolkit, and the fabricated prototype was calibrated in water-equivalent millimeters with 200 MeV protons in the research beam line of the clinical proton synchrotron at Loma Linda University Medical Center. A special polystyrene step phantom was designed and built to speed up and simplify the calibration procedure. The calibrated five-stage detector was tested in the 200 MeV proton beam as part of the pCT head scanner, using a water phantom and polystyrene slabs to verify the WEPL reconstruction accuracy.
Results:
The beam-test results demonstrated excellent performance of the new detector, in good agreement with the simulation results. The WEPL measurement accuracy is about 3.0 mm per proton in the 0–260 mm WEPL range required for a pCT head scan with a 200 MeV proton beam.
Conclusions:
The new multistage design approach to WEPL measurements for protonCT and radiography has been prototyped and tested. The test results show that the design is competitive with much more expensive calorimeter and range-counter designs.
Proton computed tomography (pCT) is an imaging modality that is based on tracking individual protons as they traverse the object to be imaged. Proton-by-proton tracking is necessary due to the effects of multiple Coulomb scattering (MCS), a process that deviates the proton path from a striaght line. If optimal spatial resolution is to be achieved, the path of each proton must be predicted with a maximum likelihood formalism that models MCS. Further, image reconstruction methods are required that are able to handle these non-linear paths. This had led to the exploration of algebraic reconstruction techniques (ART) in pCT. However, because iterative algebraic methods are computationally expensive, parallel compatible versions of the ART class, executed simultaneously over multiple processing units are required if pCT is to be realistic for a clinical environment. In this study we investigate the image quality achieveable with block-iterative and string-averaging projection algorithms in application to simulated pCT data. From the results we make a recommendation as to which algorithms should be used in future studies with pCT image reconstruction.
A unique CMOS chip has been designed to serve as the front-end of the tracking detector data acquisition system of a pre-clinical prototype scanner for proton computed tomography (pCT). The scanner is to be capable of measuring one to two million proton tracks per second, so the chip must be able to digitize the data and send it out rapidly while keeping the front-end amplifiers active at all times. One chip handles 64 consecutive channels, including logic for control, calibration, triggering, buffering, and zero suppression. It outputs a formatted cluster list for each trigger, and a set of field programmable gate arrays merges those lists from many chips to build the events to be sent to the data acquisition computer. The chip design has been fabricated, and subsequent tests have demonstrated that it meets all of its performance requirements, including excellent low-noise performance.
"Acute tubular necrosis (ATN)-like" changes in type I acute antibody- mediated rejection (AAMR) have been proposed since 2005, but the presence of "ATN-like" injury in AAMR has not well been established. The aim of this study was to confirm the presence of acute tubular injury in type I AAMR, using the specific proximal tubular injury marker, kidney injury molecule-1 (KIM-1).
The study included 3 groups of cases, namely, a negative control group (normal nontransplantation renal parenchyma as group 1, n = 11), a positive control group (transplant ATN with negative C4d staining as group 2, n = 12), and study cases (type 1 AAMR as group 3, n = 19). Biopsy specimens from all groups were stained immunohistochemically for KIM-1 (monoclonal antibody) and KIM-1 staining intensity in proximal tubules was graded from 0.5 to 3+. Clinical indices were also correlated and analyzed.
Group 1 demonstrated significantly lower serum creatinine levels (1.02 ± 0.10 mg/dL) when compared with both group 2 and group 3. Both groups 2 and 3 showed similar serum creatinine levels (4.02 ± 0.59 mg/dL in group 2 and 3.24 ± 0.34 mg/dL in group 3). The negative control group demonstrated negative proximal tubule staining for KIM-1, whereas both groups 2 and 3 showed positive KIM-1 staining in proximal tubules (intensity ranging from 1+ to 3+ in group 2 and from 0.5 to 3+ in group 3).
Our results, using KIM-1 immunohistochemistry, demonstrated that acute tubular injury is an important component of type I AAMR.
Silicon detectors normally have an inactive region along the perimeter of the sensor. In this paper we describe a “scribe, cleave, and passivate” (SCP) technique for the fabrication of slim edges in a post processing with finished detectors. The scribing was done by laser-scribing and etching. After scribing and cleaving steps, the sidewalls are passivated with a dielectric. We present results for n- and p-type sensors with different sidewall passivations. The leakage current depends strongly on the type of sidewall passivation. An alumina passivation leads to very low leakage currents for p-type sensors because of a negative interface charge. For n-type sensors, a hydrogenated silicon nitride shows the lowest leakage currents. Furthermore, we applied the technique to large area n-type single-sided strip detectors (cleaving length up to 3.5 cm).
We describe a Proton Range Radiography system with an imaging area of 10×10cm2, deploying a pair of Gas Electron Multiplier position-sensitive detectors and a scintillator stack to measure the residual proton range after crossing a target. The detector has been tested in the laboratory and in beam exposures at the Paul Scherrer Institute; images recorded with several phantoms of variable thickness and composition confirm the sub-millimetre accuracy and few percent energy resolution of the instrument. A new device with identical design and larger acceptance, 30×30cm2, is in construction.
We describe a new head scanner developed for Proton Computed Tomography (pCT) in support of proton therapy treatment planning, aiming at reconstructing an accurate map of the stopping power (S.P.) in a phantom and, in the future, in patients. The system consists of two silicon telescopes which track the proton before and after the phantom/patient, and an energy detector which measures the residual energy or range of the proton to reconstruct the Water Equivalent Path Length (WEPL) in the phantom. Based on the experience of the existing prototype and extensive Geant4 simulations and CT reconstructions, the new pCT scanner will support clinically useful proton fluxes.
This paper presents the test results of a single element of a Cesium Iodide CsI(TI) crystal calorimeter matrix using proton beam energies of 35 MeV, 100 MeV and 200 MeV. The detector element was designed to comply with the demands of high energy resolution of a few percent and with a dynamic range of two orders of magnitude under a counting rate of 10 kHz per channel. The energy range investigated in the current work was an order of magnitude less than the design capability. The readout was provided by a 28 × 28 mm2 Hamamatsu S3584-08 photodiode coupled with the crystal through a silicone optical interface. A charge-sensitive preamplifier with low noise at high photodiode capacitance was chosen. We also report on the data acquired during crystal calibration with cosmic rays, and give a description of our data acquisition (DAQ) system.