Cerenkov luminescence imaging: a study of its quantitative capabilities

Introduction and motivations Functional imaging is a method used by physicians to detect a certain type of physiological activity related to the physical distribution of the radioisotope used. The imaging method should allow to image and to localize the activity distribution (imaging), but it should also allow to quantify the same distribution (quantification). In functional imaging techniques such as positron emission tomography (PET) these requirements are fulfilled by combining PET with computed tomography (CT) and by calibrating the response of the PET imaging system with a reference standard. Cerenkov luminescence imaging (CLI) is a novel functional imaging technique that has been introduced to study beta-emitting radiotracers and radiopharmaceuticals through the Cerenkov radiation they produce in biological tissue. Up to date, several studies have demonstrated the imaging capabilities of CLI in different applications field, but a complete quantitative reconstruction of the activity distribution has not been demonstrated yet and very few bibliographical references are available on the topic. In order to achieve this goal, one should be able to calibrate the detector response in terms of radiance at the tissue surface (that is the measured quantity) and to relate this quantity to the activity distribution deep in tissue through the distribution of the produced Cerenkov radiation. This reconstruction is difficult for several reasons: the lack of a tissue-equivalent material able to mimic the tissue interactions with optical light, the heterogeneity of the optical properties of different tissues and the limited amount of available data, and the dependence of the Cerenkov radiation production on factors like the properties and geometry of the material and the isotope used. A Monte Carlo simulation can be a powerful tool to shed some light on such a complex scenario, which would not only be useful to help in the reconstruction, but would also be a valid means to use in experiment planning and in studying potential applications for CLI. Work done The main goals of this thesis were the development of a Monte Carlo code to model all the physical processes involved in a CLI experiment (the radioactive decay, the Cerenkov radiation production and transport as well as the detector response) and the test of the predictive capabilities of the code. To this aim, the simulation output was compared with experimental results obtained with different systems. The imaging system representing the gold standard for CLI (the IVIS imaging system) was used first for measurements in tissue to compare the simulated and measured light distribution at the tissue surface, and a custom imaging system featuring a charge coupled device was built to compare quantitatively the simulation output and the measured signal. In addition, a feasibility study with digital silicon photomultipliers was performed to evaluate the capabilities of this technology as an alternative to charge coupled devices. Results and Conclusions The comparison of the simulation results with the acquisitions performed in tissue with the IVIS imaging system demonstrated that the Monte Carlo is able to predict the spatial distribution of the Cerenkov light at the tissue surface within a 25% precision. Very modest results were obtained in terms of the transmitted spectrum, with differences as high as 40% between the predicted and measured spectral components, because this aspect depends on the spectral response of the detector which could not be fully modeled. So far, the custom CCD-based imaging system was the only imaging system that allowed an absolute quantitative comparison of the experimental and simulated results, and provided an acceptable and constant discrepancy between measurements and simulations in water. In fact, the Monte Carlo code was able to predict the electron count rate produced in the CCD in a known geometry with different isotopes and different activity levels, but the simulated results typically underestimated the real results by a factor 0.8. However, this factor was a constant offset among different measurements, thus it is reasonable to assume that it is due to a fixed contribution that was not considered in the simulation and that could presumably be corrected. The experimental results with this system also suggest that for quantitative CLI measurements a conventional CCD is preferable over an EMCCD because the measured signal is less influenced by noise factors that depend on the acquisition settings. The experimental results obtained with the digital silicon photomultipliers suggest that this technology might be an appealing alternative to CCDs for quantitative CLI, because the detected signal showed a dynamic response to the source activity and depth in tissue, but more work is needed to understand and to quantify the experimental factors (e.g. afterpulse) to correct when recovering quantitatively the measured signal

Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study.

BackgroundA feasibility study was done to assess the capability of digital silicon photomultipliers to measure the Cherenkov luminescence emitted by a β source. Cherenkov luminescence imaging (CLI) is possible with a charge coupled device (CCD) based technology, but a stand-alone technique for quantitative activity measurements based on Cherenkov luminescence has not yet been developed. Silicon photomultipliers (SiPMs) are photon counting devices with a fast impulse response and can potentially be used to quantify β-emitting radiotracer distributions by CLI.MethodsIn this study, a Philips digital photon counting (PDPC) silicon photomultiplier detector was evaluated for measuring Cherenkov luminescence. The PDPC detector is a matrix of avalanche photodiodes, which were read one at a time in a dark count map (DCM) measurement mode (much like a CCD). This reduces the device active area but allows the information from a single avalanche photodiode to be preserved, which is not possible with analog SiPMs. An algorithm to reject the noisiest photodiodes and to correct the measured count rate for the dark current was developed.ResultsThe results show that, in DCM mode and at (10-13) °C, the PDPC has a dynamic response to different levels of Cherenkov luminescence emitted by a β source and transmitted through an opaque medium. This suggests the potential for this approach to provide quantitative activity measurements. Interestingly, the potential use of the PDPC in DCM mode for direct imaging of Cherenkov luminescence, as a opposed to a scalar measurement device, was also apparent.ConclusionsWe showed that a PDPC tile in DCM mode is able to detect and image a β source through its Cherenkov radiation emission. The detector's dynamic response to different levels of radiation suggests its potential quantitative capabilities, and the DCM mode allows imaging with a better spatial resolution than the conventional event-triggered mode. Finally, the same acquisition procedure and data processing could be employed also for other low light levels applications, such as bioluminescence

FOOT: a new experiment to measure nuclear fragmentation at intermediate energies

Summary: Charged particle therapy exploits proton or 12C beams to treat deep-seated solid tumors. Due to the advantageous characteristics of charged particles energy deposition in matter, the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However, the beam nuclear interactions with the patient tissues induces fragmentation both of projectile and target nuclei and needs to be carefully taken into account. In proton treatments, target fragmentation produces low energy, short range fragments along all the beam range, which deposit a non negligible dose in the entry channel. In 12C treatments the main concern is represented by long range fragments due to beam fragmentation that release their dose in the healthy tissues beyond the tumor. The FOOT experiment (FragmentatiOn Of Target) of INFN is designed to study these processes, in order to improve the nuclear fragmentation description in next generation Treatment Planning Systems and the treatment plans quality. Target (16O and 12C nuclei) fragmentation induced by –proton beams at therapeutic energies will be studied via an inverse kinematic approach, where 16O and 12C therapeutic beams impinge on graphite and hydrocarbon targets to provide the nuclear fragmentation cross section on hydrogen. Projectile fragmentation of 16O and 12C beams will be explored as well. The FOOT detector includes a magnetic spectrometer for the fragments momentum measurement, a plastic scintillator for ΔE and time of flight measurements and a crystal calorimeter to measure the fragments kinetic energy. These measurements will be combined in order to make an accurate fragment charge and isotopic identification. Keywords: Hadrontherapy, Nuclear fragmentation cross sections, Tracking detectors, Scintillating detector

Una nuova tecnica di imaging mediante radiazione Cherenkov

E' in fase di sviluppo una nuova tecnica di imaging che sfrutta l'emissione di radiazione Cherenkov durante il decadimento di radionuclidi beta emettenti utilizzati in ambito clinico. Lo scopo della tesi è di studiare l'applicabilità della tecnica. Questo avviene analizzando in primo luogo dal punto di vista teorico la generazione e il trasporto della radiazione Cherenkov nei tessuti biologici. Le conclusioni di questa analisi permettono di determinare in che modo il fenomeno può essere modellizzato mediante simulazioni Monte Carlo implementate in GEANT4. Le simulazioni sviluppate sono validate dal confronto con i risultati attesi dalla teoria e attraverso la riproduzione di esperimenti reali presenti in letteratura. I risultati delle simulazioni mostrano che la nuova tecnica ha effettivamente numerose potenzialità

Cerenkov luminescence imaging: physics principles and potential applications in biomedical sciences

Cerenkov luminescence imaging (CLI) is a novel imaging modality to study charged particles with optical methods by detecting the Cerenkov luminescence produced in tissue. This paper first describes the physical processes that govern the production and transport in tissue of Cerenkov luminescence. The detectors used for CLI and their most relevant specifications to optimize the acquisition of the Cerenkov signal are then presented, and CLI is compared with the other optical imaging modalities sharing the same data acquisition and processing methods. Finally, the scientific work related to CLI and the applications for which CLI has been proposed are reviewed. The paper ends with some considerations about further perspectives for this novel imaging modality

Performance evaluation of the LightPath imaging system for intra-operative Cerenkov luminescence imaging

The performances of an intra-operative optical imaging system for Cerenkov luminescence imaging of resected tumor specimens were evaluated with phantom studies. The spatial resolution, the linearity of the measured signal with the activity concentration and the minimum detectable activity concentration were considered. A high linearity was observed over a broad range of activity concentration (R2⩾0.99 down to ∼40 kBq/ml of18F-FDG). For18F-FDG activity distributions 2 mm deep in biological tissue, the measured detection limit was 8 kBq/ml and a spatial resolution of 2.5 mm was obtained. The detection limit of the imaging system is comparable with clinical activity concentrations in tumor specimens, and the spatial resolution is compatible with clinical requirements

Development of a simulation environment for Cerenkov luminescence imaging

In vivo Cerenkov luminescence imaging (CLI) is a demanding application requiring advanced pre-clinical small animal optical imaging devices. Here we propose a Monte Carlo based simulation workflow aimed to improve the development of an efficient Cerenkov optical imager for small animals. Our work makes use of a modular approach by considering open source, freely available or custom built software to solve the forward light propagation problem from source to detector in the following steps: i) simulation of the efficiency of Cerenkov light production of beta-emitting radionuclide in tissue using GEANT4 ii) optical transport of the simulated emitted photons through a precise mouse CT-segmented model using Molecular Optical Simulation Environment (MOSE), iii) free space transport of light from the mouse surface to a CCD sensor and simulation of the system response. Results showed the effects of the choice of lens and sensor based on system characteristics. An internal 90-Y source was simulated considering a mouse phantom and the Cerenkov light detection by a CCD. We conclude that the modular approach presented in this work combines the strengths of the different simulation codes used and thus provides a complete work frame for optical simulations. © 2013 IEEE

Additional file 2 of Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study

Comparison of measurements at same temperature. Distribution of the differences in the count rates measured in two independent acquisitions performed at the same temperature (12.5¹0.4 °C), for all dies. Labels and legend follow Fig. 9, and plot positions refer to die positions in the die (Fig. 2-center). (PNG 44 kb