Purpose: The range precision in carbon ion therapy is extremely sensitive to tissue density variations. Ahigh energy carbon beam, after crossing a high-gradient edge parallel to the beam direction, suffers from range mixing leading to the detection of multiple Bragg peaks (BPs) varying intensity and water equivalent thickness (WET). The purpose of this work was to introduce a model that determines the position of a high-gradient edge based on information acquired from carbon transmission imaging. Methods: A model was derived to determine the lateral distance between the irradiation beam propagation axis and the edge position. To validate it, carbon beams were simulated and propagated through two parametric phantoms: (1) a bone cube in a water tank and (2) a semi-cylindrical bone insert in a water tank. The method was tested in a lung tumor case where range mixing led to more than two BPs being detected, requiring an iterative BP decomposition to determine the fraction of carbon ions crossing the materials surrounding the edge of interest. Results: The theoretical model predicted the edge position relative to the beam position with an error <= 1 mm for all studied cases with a maximum dose delivered of 24 mu Gy. Conclusions: The method presented here is a proof of principle. It does not take into account clinical uncertainties. However, this approach provided promising results suggesting that future extension to assess the impact of clinical uncertainties should be performed.

Proton radiography combined with X-ray computed tomography (CT) has been proposed to obtain a patient-specific calibration curve and reduce range uncertainties in cancer treatment with charged particles. The main aim of this study was to identify the optimal charged particle for the generation of the radiographies and to determine the optimal number of projections necessary to obtain minimal range errors. Three charged particles were considered to generate the radiographies: proton (p-rad), helium ions ({\alpha}-rad) and carbon ions (c-rad). The problem formulation was viewed as a least square optimization, argmin_x (||Ax -b||_2^2 ), where the projection matrix A represents the cumulative path crossed by each particle in each material, b is the charged particle list-mode radiography expressed as the crossed water equivalent thickness (WET) and x is the relative stopping power (RSP) map to be optimized. The charged particle radiographies were simulated using the Geant4 Monte Carlo (MC) toolkit and an anthropomorphic adult head phantom. A was determined by calculating the particles trajectory through the X-ray CT employing a convex hull detection combined with a cubic spline path. For all particle types, the impact of using multiple projections was assessed (from 1 to 6 projections). In this study, tissue segmentation methods were also investigated in terms of achievable accuracy. The best results (mean RSP error below 0.7% and range errors below 1 mm) were obtained for a-rad when 3 projections were used. The dose delivered to the phantom by a single {\alpha}-rad was 8 \muGy, lower than the dose of X-ray radiography.

PURPOSE Research in carbon imaging has been growing over the past years, as a way to increase treatment accuracy and patient positioning in carbon therapy. The purpose of this tool is to allow a fast and flexible way to generate CDRR data without the need to use Monte Carlo (MC) simulations. It can also be used to predict future clinically measured data. METHODS A python interface has been developed, which uses information from CT or 4DCT and thetreatment calibration curve to compute the Water Equivalent Path Length (WEPL) of carbon ions. A GPU based ray tracing algorithm computes the WEPL of each individual carbon traveling through the CT voxels. A multiple peak detection method to estimate high contrast margin positioning has been implemented (described elsewhere). MC simulations have been used to simulate carbons depth dose curves in order to simulate the response of a range detector. RESULTS The tool allows the upload of CT or 4DCT images. The user has the possibility to selectphase/slice of interested as well as position, angle…). The WEPL is represented as a range detector which can be used to assess range dilution and multiple peak detection effects. The tool also provides knowledge of the minimum energy that should be considered for imaging purposes. The multiple peak detection method has been used in a lung tumor case, showing an accuracy of 1mm in determine the exact interface position. CONCLUSION The tool offers an easy and fast way to simulate carbon imaging data. It can be used for educational and for clinical purposes, allowing the user to test beam energies and angles before real acquisition. An analysis add-on is being developed, where the used will have the opportunity to select different reconstruction methods and detector types (range or energy). Fundacao para a Ciencia e a Tecnologia (FCT), PhD Grant number SFRH/BD/85749/2012.

Theoretical stopping power values were inter-compared for the Bichsel, Janni, ICRU and Schneider relative stopping power ( RSP) estimation models, for a variety of tissues and tissue substitute materials taken from the literature. The RSPs of eleven plastic tissue substitutes were measured using Bragg peak shift measurements in water in order to establish a gold standard of RSP values specific to our centre's proton beam characteristics. The theoretical tissue substitute RSP values were computed based on literature compositions to assess the four different computation approaches. The Bichsel/Janni/ICRU approaches led to mean errors in the RSP of -0.1/+0.7/-0.8%, respectively. Errors when using the Schneider approach, with I-values from the Bichsel, Janni and ICRU sources, followed the same pattern but were generally larger. Following this, the mean elemental ionisation energies were optimized until the differences between theoretical RSP values matched measurements. Failing to use optimized I-values when applying the Schneider technique to 72 human tissues could introduce errors in the RSP of up to -1.7/+ 1.1/-0.4% when using Bichsel/Janni/ICRU I-values, respectively. As such, it may be necessary to introduce an additional step in the current stoichiometric calibration procedure in which tissue insert RSPs are measured in a proton beam. Elemental I-values can then optimized to match these measurements, reducing the uncertainty when calculating human tissue RSPs.

PurposeTo compare different algorithms to optimize the scanning path in charged particle therapy with quasidiscrete scanning. We implemented a Hybrid Genetic Algorithm with Heuristics (HyGA) and combined it with clustering techniques. The performance was compared to Simulated Annealing (SA) and to commercially available treatment planning system (TPS).MethodsPerformance and clinical implications were assessed using data from 10 patients treated at CNAO (Centro Nazionale di Adroterapia Oncologica). Clinical treatments are performed relying on beam deflection, avoiding irradiation for transitions between adjacent spots larger than 2 cm. A clustering method was implemented with HyGA (HyGA_Cl), which assumes beam deflection during transition between clusters. Clinical performance was determined as the total number of particles delivered during spot transitions and the number of particles wasted due to beam deflection. Results were compared to scan paths obtained with CNAO TPS.ResultsSA and HyGA produced on average shorter paths compared to the currently available TPS. This did not result in a reduction of transit particles, due to the concomitant effect of beam deflection out of the extraction line. HyGA_Cl achieved 2% average reduction in transit particles when compared to CNAO TPS. As a drawback, wasted particles increased, due to more frequent use of beam deflection. Both the SA and HyGA algorithms reduced the number of wasted particles.ConclusionSA and HyGA proved to be the most cost-effective methods in reducing wasted particles, with benefits in terms of shorter scan paths. A decrease in transit particles delivered with beam deflection can be achieved using HyGA_Cl.

To develop an accurate phenomenological model of the cubic spline path estimate of the proton path, accounting for the initial proton energy and water equivalent thickness (WET) traversed. Monte Carlo (MC) simulations were used to calculate the path of protons crossing various WET (10–30 cm) of different material (LN300, water and CB2-50% CaCO3) for a range of initial energies (180–330 MeV). For each MC trajectory, cubic spline trajectories (CST) were constructed based on the entrance and exit information of the protons and compared with the MC using the root mean square (RMS) metric. The CST path is dependent on the direction vector magnitudes (|P0,1|). First, |P0,1| is set to the proton path length (with factor Λ0,1Norm ?> = 1.0). Then, two optimal factor Λ0,1 ?> are introduced in |P0,1|. The factors are varied to minimize the RMS difference with MC paths for every configuration. A set of Λ0,1opt ?> factors, function of WET/water equivalent path length (WEPL), that minimizes the RMS are presented. MTF analysis is then performed on proton radiographs of a line-pair phantom reconstructed using the CST trajectories. Λ0,1opt ?> was fitted to the WET/WEPL ratio using a quadratic function (Y = A + BX2 where A = 1.01,0.99, B = 0.43,−  0.46 respectively for Λ0opt ?>, Λ1opt ?>). The RMS deviation calculated along the path, between the CST and the MC, increases with the WET. The increase is larger when using Λ0,1Norm ?> than Λ0,1opt ?> (difference of 5.0% with WET/WEPL = 0.66). For 230/330 MeV protons, the MTF10% was found to increase by 40/16% respectively for a thin phantom (15 cm) when using the Λ0,1opt ?> model compared to the Λ0,1Norm ?> model. Calculation times for Λ0,1opt ?> are scaled down compared to MLP and RMS deviation are similar within standard deviation. Based on the results of this study, using CST with the Λ0,1opt ?> factors reduces the RMS deviation and increases the spatial resolution when reconstructing proton trajectories.

Fabrication of customized implants based on patient bone defect characteristics is required for successful clinical application of bone tissue engineering. Recently a new surgical procedure, tibial tuberosity advancement (TTA), has been used to treat cranial cruciate ligament (CrCL) deficient stifle joints in dogs, which involves an osteotomy and the use of substitutes to restore the bone. However, limitations in the use of non-biodegradable implants have been reported. To overcome these limitations, this study presents the development of a bioceramic customized cage to treat a large domestic dog assigned for TTA treatment. A cage was designed using a suitable topology optimization methodology in order to maximize its permeability whilst maintaining the structural integrity, and was manufactured using low temperature 3D printing and implanted in a dog. The cage material and structure was adequately characterized prior to implantation and the in vivo response was carefully monitored regarding the biological response and patient limb function. The manufacturing process resulted in a cage composed of brushite, monetite and tricalcium phosphate, and a highly permeable porous morphology. An overall porosity of 59.2% was achieved by the combination of a microporosity of approximately 40% and a designed interconnected macropore network with pore sizes of 845 μm. The mechanical properties were in the range of the trabecular bone although limitations in the cage's reliability and capacity to absorb energy were identified. The dog's limb function was completely restored without patient lameness or any adverse complications and also the local biocompatibility and osteoconductivity were improved. Based on these observations it was possible to conclude that the successful design, fabrication and application of a customized cage for a dog CrCL treatment using a modified TTA technique is a promising method for the future fabrication of patient-specific bone implants, although clinical trials are required.

PURPOSE:To characterize the modulation transfer function (MTF) of proton/carbon radiography using Monte Carlo simulations. To assess the spatial resolution of proton/carbon radiographic imaging.METHODS:A phantom was specifically modeled with inserts composed of two materials with three different densities of bone and lung. The basic geometry of the phantom consists of cube-shaped inserts placed in water. The thickness of the water, the thickness of the cubes, the depth of the cubes in the water, and the particle beam energy have all been varied and studied. There were two phantom thicknesses considered 20 and 28 cm. This represents an average patient thickness and a thicker sized patient. Radiographs were produced for proton beams at 230 and 330 MeV and for a carbon ion beam at 400 MeV per nucleon. The contrast-to-noise ratio (CNR) was evaluated at the interface of two materials on the radiographs, i.e., lung-water and bone-water. The variation in CNR at interface between lung-water and bone-water were study, where a sigmoidal fit was performed between the lower and the higher CNR values. The full width half-maximum (FWHM) value was then obtained from the sigmoidal fit. Ultimately, spatial resolution was defined by the 10% point of the modulation-transfer-function (MTF10%), in units of line-pairs per mm (lp/mm).RESULTS:For the 20 cm thick phantom, the FWHM values varied between 0.5 and 0.7 mm at the lung-water and bone-water interfaces, for the proton beam energies of 230 and 330 MeV and the 400 MeV/n carbon beam. For the 28 cm thick phantom, the FWHM values varied between 0.5 and 1.2 mm at the lung-water and bone-water interface for the same inserts and beam energies. For the 20 cm phantom the MTF10% for lung-water interface is 2.3, 2.4, and 2.8 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. For the same 20 cm thick phantom but for the bone-water interface the MTF10% yielded 1.9, 2.3, and 2.7 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. In the case of the thicker 28 cm phantom, the authors observed that at the lung-water interface the MTF10% is 1.6, 1.9, and 2.6 lp/mm, respectively, for 230, 330, and 400 MeV/n beams. While for the bone-water interface the MTF10% was 1.4, 1.9, and 2.9 lp/mm, respectively, for 230, 330, and 400 MeV/n beams.CONCLUSIONS:Carbon radiography (400 MeV/n) yielded best spatial resolution, with MTF10% = 2.7 and 2.8 lp/mm, respectively, at the lung-water and bone-water interfaces. The spatial resolution of the 330 MeV proton beam was better than the 230 MeV proton, because higher incident proton energy suffer smaller deflections within the patient and thus yields better proton radiographic images. The authors also observed that submillimeter resolution can be obtained with both proton and carbon beams.

This study investigate the use of ion radiography as a tool for patient set-up and tumor tracking capabilities for image guided particle therapy (IGPT) using Monte Carlo simulations. One pediatric, two lung and one liver cancer patients were considered in this study. For each patient, 230 and 330 MeV proton, and 500 MeV/nucleon carbon ion pencil beams were simulated through their computed tomography (CT) data set using GEANT4.9.0. Energy, position and direction cosines of each particle were recorded in front and behind the patient. Ion radiographs were subsequently reconstructed using a dedicated in-house software. The image quality was assessed by evaluating the contrast-to-noise ratio of the tumor and its surrounding tissue. In the lung and liver cases, each CT phase of the breathing cycle was treated individually and dynamic sequences were later produced to appreciate tumor motion. Reconstructed radiographs show high spatial resolution. This allows for excellent imaging capabilities in pediatric patients, comparable to X-ray imaging at a fraction of the imaging dose. There is clear visualization of the tumor edges in the lung due to the great contrast-to-noise ratio between the tumor and its surrounding tissues; tumor motion is observed and comparable to 4D CT data thus allowing for on-line tumor tracking during ion radiotherapy. Conversely, tumor edge detection is difficult in liver, and fiducial markers are required to attempt indirect tumor tracking for IGPT. Ion radiographs with high spatial resolution can be generated using the PR-creator software resulting in pediatric patient set-up capabilities at a fraction of the current imaging dose, as well as the capacity to track moving targets in order to achieve IGPT.

The development of artificial bone substitutes that mimic the properties of bone and simultaneously promote the desired tissue regeneration is a current issue in bone tissue engineering research. An approach to create scaffolds with such characteristics is based on the combination of novel design and additive manufacturing processes. The objective of this work is to characterize the microstructural and the mechanical properties of scaffolds developed by coupling both topology optimization and a low temperature 3D printing process. The scaffold design was obtained using a topology optimization approach to maximize the permeability with constraints on the mechanical properties. This procedure was studied to be suitable for the fabrication of a cage prototype for tibial tuberosity advancement application, which is one of the most recent and promising techniques to treat cruciate ligament rupture in dogs. The microstructural and mechanical properties of the scaffolds manufactured by reacting α/β-tricalcium phosphate with diluted phosphoric acid were then assessed experimentally and the scaffolds strength reliability was determined. The results demonstrate that the low temperature 3D printing process is a reliable option to create synthetic scaffolds with tailored properties, and when coupled with topology optimization design it can be a powerful tool for the fabrication of patient-specific bone implants.

Bone tissue is a natural structural material that is able to adapt its form to the function. Thus, a mathematical description of the functional adaptation of bone is essential not only to understand the bone adaptive behaviour but also to build models that are able to support the design of new bone implants and bone scaffolds for tissue engineering and to help in disease diagnostic. This paper describes the research efforts, performed at the Institute of Mechanical Engineering (IDMEC-IST), in order to achieve mathematical and computational models to describe the bone behaviour and its response to the mechanical environment. A computational bone remodelling model is briefly described as well as its application to bone tissue engineering and implant design. It shows the role that computational tools can play in the development of new medical devices and to support pre-clinical evaluation.