In-vivo Imaging Of Small Animals Research Articles

Multimodality imaging beyond CLEM: Showcases of combined in-vivo preclinical imaging and ex-vivo microscopy to detect murine mural vascular lesions.

In imaging, penetration depth comes at the expense of lateral resolution, which restricts the scope of 3D in-vivo imaging of small animals at micrometer resolution. Bioimaging will need to expand beyond correlative light and electron microscopy (CLEM) approaches to combine insights about in-vivo dynamics in a physiologically relevant 3D environment with ex-vivo information at micrometer resolution (or beyond) within the spatial, structural and biochemical contexts. Our report demonstrates the immense potential for biomedical discovery and diagnosis made available by bridging preclinical in-vivo imaging with ex-vivo biological microscopy to zoom in from the whole organism to individual structures and by adding localized spectroscopic information to structural and functional information. We showcase the use of two novel imaging pipelines to zoom into mural lesions (occlusions/hyperplasia and micro-calcifications) in murine vasculature in a truly correlative manner, that is using exactly the same animal for all integrated imaging modalities. This correlated multimodality imaging (CMI) approach includes well-established technologies such as Positron Emission Tomography (microPET), Autoradiography, Magnetic Resonance Imaging (microMRI) and Computed Tomography (microCT), and imaging approaches that are more novel in the biomedical setting, such as X-Ray Fluorescence Spectroscopy (microXRF) and High Resolution Episcopic Microscopy (HREM). Although the current pipelines are focused on mural lesions, they would also be beneficial in preclinical and clinical investigations of vascular diseases in general.

Single-Sided Magnetic Particle Imaging Device with Field-Free-Line Geometry for in-vivo Imaging Applications.

Magnetic Particle Imaging (MPI) has shown great promise to surpass existing in vivo imaging modalities in some clinical applications. However, one of the challenges to MPI being translated into clinical practice has been the ability to scale up the selection field coils to surround a human body while being able to generate and drive a sufficiently strong magnetic field gradient. These requirements impose safety concerns as well as prohibitively high-power consumption in devices with large cylindrical volume. Therefore, we consider an alternative approach such as a single-sided topology, in which all the hardware is located on one side of the imaging volume accommodating larger subjects. Moreover, different from the previously implemented field-free point single-sided scanners, we realized a field-free line geometry providing, in principle, factor of ten higher signal and benefiting from a more robust back-projection image reconstruction technique. In this work, we present and characterize a first prototype of a single-sided MPI device with field-free-line geometry suited for in-vivo imaging of small animals as well as regions of interest in humans.

Monte Carlo simulation of the bremsstrahlung X-rays emitted from H-3 and C-14 for the in-vivo imaging of small animals

For the imaging using low energy pure beta-emitting radionuclides, autoradiography is used by slicing the subjects because the range of beta particles is short and thought to be impossible to detect beta particles from outside the subjects. Contrary to this scientific consensus, we recently found that the distributions of C-14 could be measured by detecting the bremsstrahlung X-rays emitted from the solution of C-14 and may also be applicable to lower energy pure beta-emitting radionuclide, H-3. Although the detection of bremsstrahlung X-rays emitted from H-3 and C-14 may be a possible method for in-vivo imaging of small animals, the absorption of the bremsstrahlung X-rays in the subjects are significant because the energy of bremsstrahlung X-rays is relatively low. In addition, the generations of bremsstrahlung X-rays are lower for low energy beta particles. They may make the in-vivo imaging of these beta radionuclides difficult. To clarify these points for the in-vivo imaging of bremsstrahlung X-rays emitted from H-3 and C-14, we used Monte Carlo simulation to calculate the numbers of counts and the energy spectra of the bremsstrahlung X-rays emitted from H-3 and C-14 in water. The simulation results showed that the fraction of detected bremsstrahlung X-rays by a 4 cm × 4 cm detector in all emitted beta particles was 3.5 × 10−6 at 0.1 mm from the source. Thus, with a 10 M Bq of H-3, we will detect ~35 cps at 0.1 mm from the source so in-vivo imaging at surface area will be possible. For C-14, the fraction of detected bremsstrahlung X-rays by the detector without and with collimator were 7.0 × 10−5 and 1.1 × 10−6 at 10 mm from the source, respectively. Thus, with a 10 M Bq of C-14, we will detect ~700 cps and ~11 cps at 10 mm from the source without and with collimator, respectively. The count rate without collimator is easy to form an image in a short time using a low energy X-ray detector. With collimator, in-vivo imaging of distribution of C-14 will be possible. We conclude that in-vivo imaging of small animals by detecting the bremsstrahlung X-rays emitted from H-3 and C-14 is possible and promising for a new molecular imaging technology.

Time-resolved early-photon scheme for high-resolution fluorescence molecular tomography with perturbation Monte Carlo modeling: Experimental validations using a multichannel TCSPC system

In near-infrared fluorescence molecular tomography (FMT), high turbidity of biological tissue exerts severe adversity to image reconstruction. In contrast to highly diffusive photons, early-photons preserve a significant amount of spatial information, and thereby considerably improve image quality by reducing ill-posedness in inversion processes. However, light propagation of early-photons is hard to be accurately modeled by the mathematically simple diffusion equation (DE), and the rich information in the time-resolved (TR) measurements has not been effectively utilized in reconstruction with the traditional single-gate (SG) data type. In order to take an advantage of the early-photons in time-domain FMT for in-vivo imaging of small animals, we have proposed an early-photon FMT based on a perturbation Monte-Carlo (pMC) modeling and an overlap-delaying TR data type. In this method, the fluorescence Jacobians are generated by the pMC-based forward calculations with calibration by measured instrumental response function for each source-detector pair, and the measured time-of-flight distributions of excitation and emission light are averaged over time-gates for enhancing the noise robustness. The proposed early-photon FMT based on TR-pMC has been verified by phantom experiments, demonstrating improved image qualities, such as the spatial resolution, gray-scale resolution, quantitativeness, and peak signal-to-noise ratio when compared with the early-photon FMT based on TR-DE and SG-pMC.

Adaptive-mesh-based algorithm for fluorescence molecular tomography using an analytical solution

Fluorescence molecular tomography (FMT) has become an important method for in-vivo imaging of small animals. It has been widely used for tumor genesis, cancer detection, metastasis, drug discovery, and gene therapy. In this study, an algorithm for FMT is proposed to obtain accurate and fast reconstruction by combining an adaptive mesh refinement technique and an analytical solution of diffusion equation. Numerical studies have been performed on a parallel plate FMT system with matching fluid. The reconstructions obtained show that the algorithm is efficient in computation time, and they also maintain image quality.

A compact gamma camera for biological imaging

A compact detector, sized particularly for imaging a mouse, is described. The active area of the detector is approximately 46 mm /spl times/ 96 mm. Two flat-panel Hamamatsu H8500 position-sensitive photomultiplier tubes (PSPMTs) are coupled to a pixellated NaI(Tl) scintillator which views the animal through a copper-beryllium (CuBe) parallel-hole collimator specially designed for /sup 125/I. Although the PSPMTs have insensitive areas at their edges and there is a physical gap, corrections for scintillation light collection at the junction between the two tubes results in a uniform response across the entire rectangular area of the detector. The system described has been developed to optimize both sensitivity and resolution for in-vivo imaging of small animals injected with iodinated compounds. We demonstrate an in-vivo application of this detector, particularly to SPECT, by imaging mice injected with approximately 10-15 /spl mu/Ci of /sup 125/I.

Radio-imaging in small animals.

As the resolution of radio-imaging systems improves, the prospect of in-vivo imaging of small animals becomes more attractive. Purpose-built positron emission tomography (PET) scanners capable of imaging individual tissues within the rat brain are now in routine experimental use and in-vivo tracer and saturation-kinetic studies are now possible. The study of small animals in this way does have intrinsic problems and constraints associated with it. For example, the animal must be completely immobilized, stable ligand within the radiolabelled preparation may be limiting and anatomical definition may be poor. In spite of this, consistent, semi-quantitative data can be produced and in-vivo radio-imaging can provide a genuine and unique complement to more conventional techniques. Animal numbers can be significantly reduced and the quality of data improved due to reduced inter-animal variation, and longitudinal studies, to monitor disease progression, are feasible. As the resolution of imaging systems improves still further, such studies could be extended to mouse, in addition to rat, models of disease.