Longitudinal in vivo microcomputed tomography of mouse lungs: No evidence for radiotoxicity.

Before microcomputed tomography (micro-CT) can be exploited to its full potential for longitudinal monitoring of transgenic and experimental mouse models of lung diseases, radiotoxic side effects such as inflammation or fibrosis must be considered. We evaluated dose and potential radiotoxicity to the lungs for long-term respiratory-gated high-resolution micro-CT protocols. Free-breathing C57Bl/6 mice underwent four different retrospectively respiratory gated micro-CT imaging schedules of repeated scans during 5 or 12 wk, followed by ex vivo micro-CT and detailed histological and biochemical assessment of lung damage. Radiation exposure, dose, and absorbed dose were determined by ionization chamber, thermoluminescent dosimeter measurements and Monte Carlo calculations. Despite the relatively large radiation dose delivered per micro-CT acquisition, mice did not show any signs of radiation-induced lung damage or fibrosis when scanned weekly during 5 and up to 12 wk. Doubling the scanning frequency and once tripling the radiation dose as to mimic the instant repetition of a failed scan also stayed without detectable toxicity after 5 wk of scanning. Histological analyses confirmed the absence of radiotoxic damage to the lungs, thereby demonstrating that long-term monitoring of mouse lungs using high-resolution micro-CT is safe. This opens perspectives for longitudinal monitoring of (transgenic) mouse models of lung diseases and therapeutic response on an individual basis with high spatial and temporal resolution, without concerns for radiation toxicity that could potentially influence the readout of micro-CT-derived lung biomarkers. This work further supports the introduction of micro-CT for routine use in the preclinical pulmonary research field where postmortem histological approaches are still the gold standard.

Contrast-to-noise ratio optimization for a prototype phase-contrast computed tomography scanner.

In the field of biomedical X-ray imaging, novel techniques, such as phase-contrast and dark-field imaging, have the potential to enhance the contrast and provide complementary structural information about a specimen. In this paper, a first prototype of a preclinical X-ray phase-contrast CT scanner based on a Talbot-Lau interferometer is characterized. We present a study of the contrast-to-noise ratios for attenuation and phase-contrast images acquired with the prototype scanner. The shown results are based on a series of projection images and tomographic data sets of a plastic phantom in phase and attenuation-contrast recorded with varying acquisition settings. Subsequently, the signal and noise distribution of different regions in the phantom were determined. We present a novel method for estimation of contrast-to-noise ratios for projection images based on the cylindrical geometry of the phantom. Analytical functions, representing the expected signal in phase and attenuation-contrast for a circular object, are fitted to individual line profiles of the projection data. The free parameter of the fit function is used to estimate the contrast and the goodness of the fit is determined to assess the noise in the respective signal. The results depict the dependence of the contrast-to-noise ratios on the applied source voltages, the number of steps of the phase stepping routine, and the exposure times for an individual step. Moreover, the influence of the number of projection angles on the image quality of CT slices is investigated. Finally, the implications for future imaging purposes with the scanner are discussed.

Experimental results from a preclinical X-ray phase-contrast CT scanner.

To explore the future clinical potential of improved soft-tissue visibility with grating-based X-ray phase contrast (PC), we have developed a first preclinical computed tomography (CT) scanner featuring a rotating gantry. The main challenge in the transition from previous bench-top systems to a preclinical scanner are phase artifacts that are caused by minimal changes in the grating alignment during gantry rotation. In this paper, we present the first experimental results from the system together with an adaptive phase recovery method that corrects for these phase artifacts. Using this method, we show that the scanner can recover quantitatively accurate Hounsfield units in attenuation and phase. Moreover, we present a first tomography scan of biological tissue with complementary information in attenuation and phase contrast. The present study hence demonstrates the feasibility of grating-based phase contrast with a rotating gantry for the first time and paves the way for future in vivo studies on small animal disease models (in the mid-term future) and human diagnostics applications (in the long-term future).

Limits on the spatial resolution of monolithic scintillators read out by APD arrays.

Cramér-Rao theory can be used to derive the lower bound on the spatial resolution achievable with position-sensitive scintillation detectors as a function of the detector geometry and the pertinent physical properties of the scintillator, the photosensor and the readout electronics. Knowledge of the Cramér-Rao lower bound (CRLB) can for example be used to optimize the detector design and to test the performance of the method used to derive position information from the detector signals. Here, this approach is demonstrated for monolithic scintillator detectors for positron emission tomography. Two detector geometries are investigated: a 20 × 10 × 10 mm(3) and a 20 × 10 × 20 mm(3) monolithic LYSO:Ce(3+) crystal read out by one or two Hamamatsu S8550SPL avalanche photodiode (APD) arrays, respectively. The results indicate that in these detectors the CRLB is primarily determined by the APD excess noise factor and the number of scintillation photons detected. Furthermore, it is shown that the use of a k-nearest neighbor (k-NN) algorithm for position estimation allows the experimentally obtained spatial resolution to closely approach the CRLB. The approach outlined in this work can in principle be applied to any scintillation detector in which position information is encoded in the distribution of the scintillation light over multiple photosensor elements.

Development of a prototype gantry system for preclinical x-ray phase-contrast computed tomography.

PURPOSE: To explore the potential of grating-based x-ray phase-contrast imaging for clinical applications, a first compact gantry system was developed. It is designed such that it can be implemented into an in-vivo small-animal phase-contrast computed tomography (PC-CT) scanner. The purpose of the present study is to assess the accuracy and quantitativeness of the described gantry in both absorption and phase-contrast. METHODS: A phantom, containing six chemically well-defined liquids, was constructed. A tomography scan with cone-beam reconstruction of this phantom was performed yielding the spatial distribution of the linear attenuation coefficient µ and decrement δ of the complex refractive index. Theoretical values of µ and δ were calculated for each liquid from tabulated data and compared with the experimentally measured values. Additionally, a color-fused image representation is proposed to display the complementary absorption and phase-contrast information in a single image. RESULTS: Experimental and calculated data of the phantom agree well confirming the quantitativeness and accuracy of the reconstructed spatial distributions of µ and δ. The proposed color-fused image representation, which combines the complementary absorption and phase information, considerably helps in distinguishing the individual substances. CONCLUSIONS: The concept of grating-based phase-contrast computed tomography (CT) can be implemented into a compact, cone-beam geometry gantry setup. The authors believe that this work represents an important milestone in translating phase-contrast x-ray imaging from previous proof-of-principle experiments to first preclinical biomedical imaging applications on small-animal models.

Model of the point spread function of monolithic scintillator PET detectors for perpendicular incidence.

PURPOSE: Previously, we demonstrated the potential of positron emission tomography detectors consisting of monolithic scintillation crystals read out by arrays of solid-state light sensors. We reported detector spatial resolutions of 1.1-1.3 mm full width at half maximum (FWHM) with no degradation for angles of incidence up to 30 degrees, energy resolutions of approximately 11% FWHM, and timing resolutions of approximately 2 ns FWHM, using monolithic LYSO:Ce3+ crystals coupled to avalanche photodiode (APD) arrays. Here we develop, validate, and demonstrate a simple model of the detector point spread function (PSF) of such monolithic scintillator detectors. METHODS: A PSF model was developed that essentially consists of two convolved components, one accounting for the spatial distribution of the energy deposited by annihilation photons within the crystal, and the other for the influences of statistical signal fluctuations and electronic noise. The model was validated through comparison with spatial resolution measurements on a detector consisting of an LYSO:Ce3+ crystal read out by two APD arrays. RESULTS: The model is shown to describe the measured detector spatial response well at the noise levels found in the experiments. In addition, it is demonstrated how the model can be used to correct the measured spatial response for the influence of the finite diameter of the annihilation photon beam used in the experiments, thus obtaining an estimate of the intrinsic detector PSF. CONCLUSIONS: Despite its simplicity, the proposed model is an accurate tool for analyzing the detector PSF of monolithic scintillator detectors and can be used to estimate the intrinsic detector PSF from the measured one.

Optical simulation of monolithic scintillator detectors using GATE/GEANT4.

Much research is being conducted on position-sensitive scintillation detectors for medical imaging, particularly for emission tomography. Monte Carlo simulations play an essential role in many of these research activities. As the scintillation process, the transport of scintillation photons through the crystal(s), and the conversion of these photons into electronic signals each have a major influence on the detector performance; all of these processes may need to be incorporated in the model to obtain accurate results. In this work the optical and scintillation models of the GEANT4 simulation toolkit are validated by comparing simulations and measurements on monolithic scintillator detectors for high-resolution positron emission tomography (PET). We have furthermore made the GEANT4 optical models available within the user-friendly GATE simulation platform (as of version 3.0). It is shown how the necessary optical input parameters can be determined with sufficient accuracy. The results show that the optical physics models of GATE/GEANT4 enable accurate prediction of the spatial and energy resolution of monolithic scintillator PET detectors.

Monolithic scintillator PET detectors with intrinsic depth-of-interaction correction.

We developed positron emission tomography (PET) detectors based on monolithic scintillation crystals and position-sensitive light sensors. Intrinsic depth-of-interaction (DOI) correction is achieved by deriving the entry points of annihilation photons on the front surface of the crystal from the light sensor signals. Here we characterize the next generation of these detectors, consisting of a 20 mm thick rectangular or trapezoidal LYSO:Ce crystal read out on the front and the back (double-sided readout, DSR) by Hamamatsu S8550SPL avalanche photodiode (APD) arrays optimized for DSR. The full width at half maximum (FWHM) of the detector point-spread function (PSF) obtained with a rectangular crystal at normal incidence equals approximately 1.05 mm at the detector centre, after correction for the approximately 0.9 mm diameter test beam of annihilation photons. Resolution losses of several tenths of a mm occur near the crystal edges. Furthermore, trapezoidal crystals perform almost equally well as rectangular ones, while improving system sensitivity. Due to the highly accurate DOI correction of all detectors, the spatial resolution remains essentially constant for angles of incidence of up to at least 30 degrees . Energy resolutions of approximately 11% FWHM are measured, with a fraction of events of up to 75% in the full-energy peak. The coincidence timing resolution is estimated to be 2.8 ns FWHM. The good spatial, energy and timing resolutions, together with the excellent DOI correction and high detection efficiency of our detectors, are expected to facilitate high and uniform PET system resolution.