Macrophages are essential players in the process of fracture healing, acting by remodeling of the extracellular matrix and enabling vascularization. Whilst activated macrophages of M1-like phenotype ...are present in the initial pro-inflammatory phase of hours to days of fracture healing, an anti-inflammatory M2-like macrophage phenotype is supposed to be crucial for the induction of downstream cascades of healing, especially the initiation of vascularization. In a mouse-osteotomy model, we provide a comprehensive characterization of vessel (CD31
, Emcn
) and macrophage phenotypes (F4/80, CD206, CD80, Mac-2) during the process of fracture healing. To this end, we phenotype the phases of vascular regeneration-the expansion phase (d1-d7 after injury) and the remodeling phase of the endothelial network, until tissue integrity is restored (d14-d21 after injury). Vessels which appear during the bone formation process resemble type H endothelium (CD31
Emcn
), and are closely connected to osteoprogenitors (Runx2
, Osx
) and F4/80
macrophages. M1-like macrophages are present in the initial phase of vascularization until day 3 post osteotomy, but they are rare during later regeneration phases. M2-like macrophages localize mainly extramedullary, and CD206
macrophages are found to express Mac-2
during the expansion phase. VEGFA expression is initiated by CD80
cells, including F4/80
macrophages, until day 3, while subsequently osteoblasts and chondrocytes are main contributors to VEGFA production at the fracture site. Using Longitudinal Intravital Microendoscopy of the Bone (LIMB) we observe changes in the motility and organization of CX3CR1
cells, which infiltrate the injury site after an osteotomy. A transient accumulation, resulting in spatial polarization of both, endothelial cells and macrophages, in regions distal to the fracture site, is evident. Immunofluorescence histology followed by histocytometric analysis reveals that F4/80
CX3CR1
myeloid cells precede vascularization.
To ensure the optimal outcome of proton therapy, in vivo range verification is highly desired. Prompt γ-ray imaging (PGI) is a possible approach for in vivo range monitoring. For PGI, dedicated ...detection systems, e.g. Compton cameras, are currently under investigation. The presented paper deals with substantial requirements regarding hardware and software that a Compton camera used in clinical routine has to meet. By means of GEANT4 simulations, we investigate the load on the detectors and the percentage of background expected in a realistic irradiation and we simulate γ-ray detections subsequently used as input data for the reconstruction. By reconstructing events from simulated sources of well-defined geometry, we show that large-area detectors are favourable. We investigate reconstruction results in dependence of the number of events. Finally, an end-to-end test for a realistic patient scenario is presented: starting with a treatment plan, the γ-ray emissions are calculated, the detector response is modelled, and the image reconstruction is performed. By this, the complexity of the system is shown, and requirements and limitations regarding precision and costs are determined.
Range verification and dose monitoring in proton therapy is considered as highly desirable. Different methods have been developed worldwide, like particle therapy positron emission tomography ...(PT-PET) and prompt gamma imaging (PGI). In general, these methods allow for a verification of the proton range. However, quantification of the dose from these measurements remains challenging. For the first time, we present an approach for estimating the dose from prompt γ-ray emission profiles. It combines a filtering procedure based on Gaussian-powerlaw convolution with an evolutionary algorithm. By means of convolving depth dose profiles with an appropriate filter kernel, prompt γ-ray depth profiles are obtained. In order to reverse this step, the evolutionary algorithm is applied. The feasibility of this approach is demonstrated for a spread-out Bragg-peak in a water target.
Proton and ion beam therapies become increasingly relevant in radiation therapy. To fully exploit the potential of this irradiation technique and to achieve maximum target volume conformality, the ...verification of particle ranges is highly desirable. Many research activities focus on the measurement of the spatial distributions of prompt gamma rays emitted during irradiation. A passively collimating knife-edge slit camera is a promising option to perform such measurements. In former publications, the feasibility of accurate detection of proton range shifts in homogeneous targets could be shown with such a camera. We present slit camera measurements of prompt gamma depth profiles in inhomogeneous targets. From real treatment plans and their underlying CTs, representative beam paths are selected and assembled as one-dimensional inhomogeneous targets built from tissue equivalent materials. These phantoms have been irradiated with monoenergetic proton pencil beams. The accuracy of range deviation estimation as well as the detectability of range shifts is investigated in different scenarios. In most cases, range deviations can be detected within less than 2 mm. In close vicinity to low-density regions, range detection is challenging. In particular, a minimum beam penetration depth of 7 mm beyond a cavity is required for reliable detection of a cavity filling with the present setup. Dedicated data post-processing methods may be capable of overcoming this limitation.
In-beam SPECT during therapeutic proton beam irradiation is a novel method for three dimensional in-vivo dose verification. For this purpose a Compton camera design is evaluated with respect to the ...special requirements and conditions that arise from this application. Different concepts are studied by means of simulation concerning the angular resolution and efficiency. It was found that a cadmium zinc telluride system can perform sufficiently well. For further evaluation the construction of a semiconductor scintillator hybrid system is under way.
The only method for in vivo dose delivery verification in proton beam radiotherapy in clinical use today is positron emission tomography (PET) of the positron emitters produced in the patient during ...irradiation. PET imaging while the beam is on (so called beam-on PET) is an attractive option, providing the largest number of counts, the least biological washout and the fastest feedback. In this implementation, all nuclides, independent of their half-life, will contribute. As a first step towards assessing the relevance of short-lived nuclides (half-life shorter than that of 10C, T1/2 = 19 s) for in vivo dose delivery verification using beam-on PET, we measured their production in the stopping of 55 MeV protons in water, carbon, phosphorus and calcium The most copiously produced short-lived nuclides and their production rates relative to the relevant long-lived nuclides are: 12N (T1/2 = 11 ms) on carbon (9% of 11C), 29P (T1/2 = 4.1 s) on phosphorus (20% of 30P) and 38mK (T1/2 = 0.92 s) on calcium (113% of 38gK). No short-lived nuclides are produced on oxygen. The number of decays integrated from the start of an irradiation as a function of time during the irradiation of PMMA and 4 tissue materials has been determined. For (carbon-rich) adipose tissue, 12N dominates up to 70 s. On bone tissue, 12N dominates over 15O during the first 8-15 s (depending on carbon-to-oxygen ratio). The short-lived nuclides created on phosphorus and calcium provide 2.5 times more beam-on PET counts than the long-lived ones produced on these elements during a 70 s irradiation. From the estimated number of 12N PET counts, we conclude that, for any tissue, 12N PET imaging potentially provides equal to superior proton range information compared to prompt gamma imaging with an optimized knife-edge slit camera. The practical implementation of 12N PET imaging is discussed.
The additive manufacturing (AM) technology Fused Filament Fabrication (FFF) and topology optimization (TO) for the manufacturing of robot grippers shows high potential regarding material efficiency ...and weight reduction, leading to CO2-emission reduction. For conventional series production, steel or aluminium gripper elements are machined by milling, drilling, and turning. In determining the ecological efficiency of a circular economy concept with topologically optimized additive manufactured gripper, a CO2 assessment is presented considering the cycles of raw material, production, usage, and reuse or recycling of the gripper. The CO2-emissions of both a conventionally designed and a lightweight gripper with application of TO and FFF is compared within this assessment.
Proton therapy is an advantageous treatment modality compared to conventional radiotherapy. In contrast to photons, charged particles have a finite range and can thus spare organs at risk. ...Additionally, the increased ionization density in the so-called Bragg peak close to the particle range can be utilized for maximum dose deposition in the tumour volume. Unfortunately, the accuracy of the therapy can be affected by range uncertainties, which have to be covered by additional safety margins around the treatment volume. A real-time range and dose verification is therefore highly desired and would be key to exploit the major advantages of proton therapy. Prompt gamma rays, produced in nuclear reactions between projectile and target nuclei, can be used to measure the proton's range. The prompt gamma-ray timing (PGT) method aims at obtaining this information by determining the gamma-ray emission time along the proton path using a conventional time-of-flight detector setup. First tests at a clinical accelerator have shown the feasibility to observe range shifts of about 5 mm at clinically relevant doses. However, PGT spectra are smeared out by the bunch time spread. Additionally, accelerator related proton bunch drifts against the radio frequency have been detected, preventing a potential range verification. At OncoRay, first experiments using a proton bunch monitor (PBM) at a clinical pencil beam have been conducted. Elastic proton scattering at a hydrogen-containing foil could be utilized to create a coincident proton-proton signal in two identical PBMs. The selection of coincident events helped to suppress uncorrelated background. The PBM setup was used as time reference for a PGT detector to correct for potential bunch drifts. Furthermore, the corrected PGT data were used to image an inhomogeneous phantom. In a further systematic measurement campaign, the bunch time spread and the proton transmission rate were measured for several beam energies between 69 and 225 MeV as well as for variable momentum limiting slit openings. We conclude that the usage of a PBM increases the robustness of the PGT method in clinical conditions and that the obtained data will help to create reliable range verification procedures in clinical routine.
Range verification of particle beams in real time is considered a key for tapping the full potential of radio-oncological particle therapies. The novel technique of prompt gamma-ray timing (PGT), ...recently proposed and explored in first proof-of-principle experiments, promises range assessment at reasonable expense but challenges detectors, electronics, and data acquisition. Energy-selected time distributions have to be measured at very high throughput rates to obtain the statistics necessary for range verification with single pencil beam spots. Clinically applicable systems should provide a time resolution of about 200 ps, to be obtained with large (about 2" diameter) scintillators, detector loads in the few-Mcps range, and data acquisition rates around 1 Mcps, if possible with compact and inexpensive systems. Such requirements can be met best with CeBr 3 scintillators read out with conventional photomultiplier tubes, coupled to commercial but customized electronics featuring high-resolution pulse digitization and fast digital signal processing. The paper deduces design parameters from the constraints given by typical treatment conditions, and presents first results obtained with prototype detectors and electronics developed in accordance with the derived specifications.
In-beam PET is a clinically proven method for monitoring ion beam cancer treatment. The objective is predominantly the verification of the range of the primary particles. Due to different processes ...leading to dose and activity, evaluation is done by comparing measured data to simulated. Up to now, the comparison is performed by well-trained observers (clinicians, physicists). This process is very time consuming and low in reproducibility. However, an automatic method is desirable. A one-dimensional algorithm for range comparison has been enhanced and extended to three dimensions. System-inherent uncertainties are handled by means of a statistical approach. To test the method, a set of data was prepared. Distributions of β+-activity calculated from treatment plans were compared to measurements performed in the framework of the German Heavy Ion Tumor Therapy Project at GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany. Artificial range deviations in the simulations served as test objects for the algorithm. Range modifications of different depth (4, 6 and 10 mm water equivalent path length) can be detected. Even though the sensitivity and specificity of a visual evaluation are higher, the method is feasible as the basis for the selection of patients from the data pool for retrospective evaluation of treatment and treatment plans and correlation with follow-up data. Furthermore, it can be used for the development of an assistance tool for a clinical application.
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