Whole-body Small Animal Imaging Research Articles

NEMA NU 1-2018 performance characterization and Monte Carlo model validation of the Cubresa Spark SiPM-based preclinical SPECT scanner

BackgroundThe Cubresa Spark is a novel benchtop silicon-photomultiplier (SiPM)-based preclinical SPECT system. SiPMs in SPECT significantly improve resolution and reduce detector size compared to preclinical cameras with photomultiplier tubes requiring highly magnifying collimators. The NEMA NU 1 Standard for Performance Measurements of Gamma Cameras provides methods that can be readily applied or extended to characterize preclinical cameras with minor modifications. The primary objective of this study is to characterize the Spark according to the NEMA NU 1-2018 standard to gain insight into its nuclear medicine imaging capabilities. The secondary objective is to validate a GATE Monte Carlo simulation model of the Spark for use in preclinical SPECT studies.MethodsNEMA NU 1-2018 guidelines were applied to characterize the Spark’s intrinsic, system, and tomographic performance with single- and multi-pinhole collimators. Phantoms were fabricated according to NEMA specifications with deviations involving high-resolution modifications. GATE was utilized to model the detector head with the single-pinhole collimator, and NEMA measurements were employed to tune and validate the model. Single-pinhole and multi-pinhole SPECT data were reconstructed with the Software for Tomographic Image Reconstruction and HiSPECT, respectively.ResultsThe limiting intrinsic resolution was measured as 0.85 mm owing to a high-resolution SiPM array combined with a 3 mm-thick scintillation crystal. The average limiting tomographic resolution was 1.37 mm and 1.19 mm for the single- and multi-pinhole collimators, respectively, which have magnification factors near unity at the center of rotation. The maximum observed count rate was 15,400 cps, and planar sensitivities of 34 cps/MBq and 150 cps/MBq were measured at the center of rotation for the single- and multi-pinhole collimators, respectively. All simulated tests agreed well with measurement, where the most considerable deviations were below 7%.ConclusionsNEMA NU 1-2018 standards determined that a SiPM detector mitigates the need for highly magnifying pinhole collimators while preserving detailed information in projection images. Measured and simulated NEMA results were highly comparable with differences on the order of a few percent, confirming simulation accuracy and validating the GATE model. Of the collimators initially provided with the Spark, the multi-pinhole collimator offers high resolution and sensitivity for organ-specific imaging of small animals, and the single-pinhole collimator enables high-resolution whole-body imaging of small animals.

Whole-Body Photoacoustic Imaging Techniques for Preclinical Small Animal Studies.

Photoacoustic imaging is a hybrid imaging technique that has received considerable attention in biomedical studies. In contrast to pure optical imaging techniques, photoacoustic imaging enables the visualization of optical absorption properties at deeper imaging depths. In preclinical small animal studies, photoacoustic imaging is widely used to visualize biodistribution at the molecular level. Monitoring the whole-body distribution of chromophores in small animals is a key method used in preclinical research, including drug-delivery monitoring, treatment assessment, contrast-enhanced tumor imaging, and gastrointestinal tracking. In this review, photoacoustic systems for the whole-body imaging of small animals are explored and summarized. The configurations of the systems vary with the scanning methods and geometries of the ultrasound transducers. The future direction of research is also discussed with regard to achieving a deeper imaging depth and faster imaging speed, which are the main factors that an imaging system should realize to broaden its application in biomedical studies.

Stack-Layer Dual-Element Ultrasonic Transducer for Broadband Functional Photoacoustic Tomography.

Current Photoacoustic tomography (PAT) approaches are based on a single-element transducer that exhibits compromised performance in clinical imaging applications. For example, vascular, tumors are likely to have complicated shapes and optical absorptions, covering relatively wide spectra in acoustic signals. The wide ultrasonic spectra make it difficult to set the detection bandwidth optimally in advance. In this work, we propose a stack-layer dual-element ultrasonic transducer for PAT. The central frequencies of the two piezoelectric elements are 3.06 MHz (99.3% bandwidth at –6 dB) and 11.07 MHz (85.2% bandwidth at –6 dB), respectively. This transducer bridges the sensitivity capability of ultrasound and the high contrast of optical methods in functional photoacoustic tomography. The dual-element transducer enabled multiscale analysis of the vascular network in rat brains. Using a multi-wavelength imaging scheme, the blood oxygen saturation was also detected. The preliminary results showed the great potential of broad-bandwidth functional PAT on vascular network visualization. The method can also be extended to whole-body imaging of small animals, breast cancer detection, and finger joint imaging.

Signal-to-noise ratio analysis and improvement for fluorescence tomography imaging.

CCD-based fluorescence tomography is widely used for small animal whole-body imaging. In this report, systematic signal-to-noise ratio (SNR) analyses of a fluorescence tomography imaging (FTI) system were performed, resulting in an easy-to-follow strategy to optimize hardware configurations and operational conditions for acquiring high-quality imaging data and for improving the overall system performance. Phantom experiments were conducted to demonstrate the performance improvement by these optimizations. The improved performance was further verified by imaging a tumor-bearing mouse in vivo. This report provides general and practical guidelines for setting up a high-performance electron multiplying charge coupled device based FTI system to achieve an optimized SNR, which can be useful for future FTI technology development.

Small-animal, whole-body imaging with metamaterial-inspired RF coil.

Particular applications in preclinical magnetic resonance imaging require the entire body of an animal to be imaged with sufficient quality. This is usually performed by combining regions scanned with small coils with high sensitivity or long scans using large coils with low sensitivity. Here, a metamaterial-inspired design employing a parallel array of wires operating on the principle of eigenmode hybridization was used to produce a small-animal imaging coil. The coil field distribution responsible for the coil field of view and sensitivity was simulated in an electromagnetic simulation package and the coil geometrical parameters were optimized for whole-body imaging. A prototype coil was then manufactured and assembled using brass telescopic tubes with copper plates as distributed capacitance. Its field distribution was measured experimentally using the B1+ mapping technique and was found to be in close correspondence with the simulated results. The coil field distribution was found to be suitable for large field of view small-animal imaging and the coil image quality was compared with a commercially available coil by whole-body scanning of living mice. Signal-to-noise measurements in living mice showed higher values than those of a commercially available coil with large receptive fields, and rivalled the performance of small receptive field and high-sensitivity coils. The coil was deemed to be suitable for some whole-body, small-animal preclinical applications.

Multiview Hilbert transformation in full-ring transducer array-based photoacoustic computed tomography.

Based on the photoacoustic (PA) effect, PA tomography directly measures specific optical absorption, i.e., absorbed optical energy per unit volume. We recently developed a full-ring ultrasonic transducer array-based photoacoustic computed tomography (PACT) system for small-animal whole-body imaging. The system has a full-view detection angle and high in-plane resolution (∼100 μm). However, due to the bandpass frequency response of the piezoelectric transducer elements and the limited elevational detection coverage of the full-ring transducer array, the reconstructed images present bipolar (i.e., both positive and negative) pixel values, which cause ambiguities in image interpretation for physicians and biologists. We propose a multiview Hilbert transformation method to recover the unipolar initial pressure for full-ring PACT. The effectiveness of the proposed algorithm was first validated by numerical simulations and then demonstrated with ex vivo mouse brain structural imaging and in vivo mouse whole-body imaging.

Single-impulse Panoramic Photoacoustic Computed Tomography of Small-animal Whole-body Dynamics at High Spatiotemporal Resolution.

Imaging of small animals has played an indispensable role in preclinical research by providing high dimensional physiological, pathological, and phenotypic insights with clinical relevance. Yet pure optical imaging suffers from either shallow penetration (up to ~1–2 mm) or a poor depth-to-resolution ratio (~1/3), and non-optical techniques for whole-body imaging of small animals lack either spatiotemporal resolution or functional contrast. Here, we demonstrate that standalone single-impulse photoacoustic computed tomography (SIP-PACT) mitigates these limitations by combining high spatiotemporal resolution (125-µm in-plane resolution, 50 µs / frame data acquisition and 50-Hz frame rate), deep penetration (48-mm cross-sectional width in vivo), anatomical, dynamical and functional contrasts, and full-view fidelity. By using SIP-PACT, we imaged in vivo whole-body dynamics of small animals in real time and obtained clear sub-organ anatomical and functional details. We tracked unlabeled circulating melanoma cells and imaged the vasculature and functional connectivity of whole rat brains. SIP-PACT holds great potential for both pre-clinical imaging and clinical translation.

A PET/SPECT/X-ray prototype for whole body mouse imaging

Introduction In this work we present a hybrid, prototype SPECT/PET/CT system, suitable for whole-body small animal imaging. The integrated SPECT/PET/CT system has three components and is mounted on a computer-controlled rotating gantry. Purpose The main goal of this work is to provide a robust infrastructure for animal studies on national and regional level. Materials and methods The SPECT component is based on two H8500 Position-Sensitive-Photomultiplier-Tubes, a 1 × 1 × 5mm 3 NaI(Tl) pixelated scintillator and a general purpose hexagonal collimator. The PET components are based on the same PSPMTs coupled to 2 × 2 × 5 mm 3 BGO pixelated scintillators. The X-Ray detector is a high speed, low noise and high sensitivity flat panel detector, model C10900D-40 from Hamamatsu. It is based on the CMOS technology and it is suitable for real-time static and CT imaging with high dynamic range. The X-ray tube, SourceBlock™ by Source-Ray Inc, integrates an X-ray tube and a high voltage generator into one physical package. The SB-80-500 model has a 33 μm minimal focal spot, a variable voltage 35–80 kVp and 20–500 μA current. Results The SPECT system has been evaluated with phantoms and small animals and has a 1.5 mm spatial resolution for 99m Tc, while it can provide fast images for dynamic mice studies. Two additional collimators allow imaging of higher energy isotopes. The spatial resolution of the PET system is equal to 2.5 mm, while further optimization is possible by using proper reconstruction algorithms and corrections. The X-ray system provides high resolution (10 μm) anatomical images of mice, which are fused with the functional images of PET/SPECT. Conclusions The presented system provides unique infrastructure to support preclinical research on national and regional level.

FIM$^{2c\;}$: Multicolor, Multipurpose Imaging System to Manipulate and Analyze Animal Behavior.

In vivo whole-body imaging of small animals plays an important role for biomedical studies. In particular, animals like the fruit fly Drosophila melanogaster or the nematode Caenorhabditis elegans are popular model organisms for preclinical research since they offer sophisticated genetic tool-kits. Recording these translucent animals with high contrast in a large arena is however not trivial. Furthermore, fluorescent proteins are widely used to mark cells in vivo and report their functions. This paper introduces a novel optical imaging technique called FIM2c enabling simultaneous detection of the animals posture and movement as well as fluorescent markers like green fluorescent protein (GFP). FIM2c utilizes frustrated total internal reflection of two distinct wavelengths and captures both, reflected and emitted light. The resultant two-color high-contrast images are superb compared to other imaging systems for larvae or worms. This multipurpose method enables a large variety of different experimental approaches. For example, FIM2c can be used to image GFP positive cells/tissues/animals and supports the integration of fluorescent tracers into multitarget tracking paradigms. Moreover, optogenetic tools can be applied in large-scale behavioral analysis to manipulate and study neuronal functions. To demonstrate the benefit of our system, we use FIM2c to resolve colliding larvae in a high-throughput approach, which was impossible given the existing tools. Finally, we present a comprehensive database including images and locomotion features of more than 1300 resolved collisions available for the community. In conclusion, FIM2c is a versatile tool for advanced imaging and locomotion analysis for a variety of different model organisms.

Correction of MRI-induced geometric distortions in whole-body small animal PET-MRI.

The fusion of positron emission tomography (PET) and magnetic resonance imaging (MRI) data can be a challenging task in whole-body PET-MRI. The quality of the registration between these two modalities in large field-of-views (FOV) is often degraded by geometric distortions of the MRI data. The distortions at the edges of large FOVs mainly originate from MRI gradient nonlinearities. This work describes a method to measure and correct for these kind of geometric distortions in small animal MRI scanners to improve the registration accuracy of PET and MRI data. The authors have developed a geometric phantom which allows the measurement of geometric distortions in all spatial axes via control points. These control points are detected semiautomatically in both PET and MRI data with a subpixel accuracy. The spatial transformation between PET and MRI data is determined with these control points via 3D thin-plate splines (3D TPS). The transformation derived from the 3D TPS is finally applied to real MRI mouse data, which were acquired with the same scan parameters used in the phantom data acquisitions. Additionally, the influence of the phantom material on the homogeneity of the magnetic field is determined via field mapping. The spatial shift according to the magnetic field homogeneity caused by the phantom material was determined to a mean of 0.1 mm. The results of the correction show that distortion with a maximum error of 4 mm could be reduced to less than 1 mm with the proposed correction method. Furthermore, the control point-based registration of PET and MRI data showed improved congruence after correction. The developed phantom has been shown to have no considerable negative effect on the homogeneity of the magnetic field. The proposed method yields an appropriate correction of the measured MRI distortion and is able to improve the PET and MRI registration. Furthermore, the method is applicable to whole-body small animal imaging routines including different standard MRI sequences.

Towards Whole-Body Fluorescence Imaging in Humans

Dynamic near-infrared fluorescence (DNIF) whole-body imaging of small animals has become a popular tool in experimental biomedical research. In humans, however, the field of view has been limited to body parts, such as rheumatoid hands, diabetic feet or sentinel lymph nodes. Here we present a new whole-body DNIF-system suitable for adult subjects. We explored whether this system (i) allows dynamic whole-body fluorescence imaging and (ii) can detect modulations in skin perfusion. The non-specific fluorescent probe indocyanine green (ICG) was injected intravenously into two subjects, and fluorescence images were obtained at 5 Hz. The in- and out-flow kinetics of ICG have been shown to correlate with tissue perfusion. To validate the system, skin perfusion was modulated by warming and cooling distinct areas on the chest and the abdomen. Movies of fluorescence images show a bolus passage first in the face, then in the chest, abdomen and finally in the periphery (∼10, 15, 20 and 30 seconds, respectively). When skin perfusion is augmented by warming, bolus arrives about 5 seconds earlier than when the skin is cooled and perfusion decreased. Calculating bolus arrival times and spatial fitting of basis time courses extracted from different regions of interest allowed a mapping of local differences in subcutaneous skin perfusion. This experiment is the first to demonstrate the feasibility of whole-body dynamic fluorescence imaging in humans. Since the whole-body approach demonstrates sensitivity to circumscribed alterations in skinperfusion, it may be used to target autonomous changes in polyneuropathy and to screen for peripheral vascular diseases.

Small-animal whole-body photoacoustic tomography: a review.

With the wide use of small animals for biomedical studies, in vivo small-animal whole-body imaging plays an increasingly important role. Photoacoustic tomography (PAT) is an emerging whole-body imaging modality that shows great potential for preclinical research. As a hybrid technique, PAT is based on the acoustic detection of optical absorption from either endogenous tissue chromophores, such as oxyhemoglobin and deoxyhemoglobin, or exogenous contrast agents. Because ultrasound scatters much less than light in tissue, PAT generates high-resolution images in both the optical ballistic and diffusive regimes. Using near-infrared light, which has relatively low blood absorption, PAT can image through the whole body of small animals with acoustically defined spatial resolution. Anatomical and vascular structures are imaged with endogenous hemoglobin contrast, while functional and molecular images are enabled by the wide choice of exogenous optical contrasts. This paper reviews the rapidly growing field of small-animal whole-body PAT and highlights studies done in the past decade.

Whole-body ring-shaped confocal photoacoustic computed tomography of small animals in vivo

We report a novel small-animal whole-body imaging system called ring-shaped confocal photoacoustic computed tomography (RC-PACT). RC-PACT is based on a confocal design of free-space ring-shaped light illumination and 512-element full-ring ultrasonic array signal detection. The free-space light illumination maximizes the light delivery efficiency, and the full-ring signal detection ensures a full two-dimensional view aperture for accurate image reconstruction. Using cylindrically focused array elements, RC-PACT can image a thin cross section with 0.10 to 0.25 mm in-plane resolutions and 1.6 s/frame acquisition time. By translating the mouse along the elevational direction, RC-PACT provides a series of cross-sectional images of the brain, liver, kidneys, and bladder.

Biomedical photoacoustic imaging.

Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2-3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.

Development of fully 3D image reconstruction techniques for pinhole SPECT imaging

The purpose of this study was to develop fully 3D image reconstruction techniques for pinhole SPECT imaging with our Micro-SPECT system. Our studies involve in the derivation of projection operators, analysis of the sampling characteristics of pinhole SPECT imaging in Radon space, development of effective geometric calibration method for system misalignment, and 3D image reconstruction development and implementation with quantitative degrading compensation for pinhole SPECT with both circular and helical scan. The performances of pinhole SPECT imaging were evaluated using computer simulations and experiments with the Ultra-Micro Hot-Spot phantom, Ultra-Micro Defrise phantom and small-animal imaging. The results from the computer simulations and phantom imaging experiments indicate that the statistically-based iterative algorithms with quantitative compensation provide overall image quality improvement, and the system resolution is significantly recovered for quantitative imaging. The helical pinhole SPECT improves the axial field-of-view (FOV) as compared with the standard pinhole SPECT with circular-orbit scan. The mouse bone imaging experiment shows that the helical pinhole SPECT imaging also provides decent high-resolution whole-body small animal imaging. In conclusion, we have successfully developed a set of valid fully 3D image reconstruction techniques for single-pinhole SPECT imaging. These techniques can be easily extended to multi-pinhole SPECT imaging.

In vivo small animal imaging: Current status and future prospects

The use of small animal models in basic and preclinical sciences constitutes an integral part of testing new pharmaceutical agents prior to commercial translation to clinical practice. Whole-body small animal imaging is a particularly elegant and cost-effective experimental platform for the timely validation and commercialization of novel agents from the bench to the bedside. Biomedical imaging is now listed along with genomics, proteomics, and metabolomics as an integral part of biological and medical sciences. Miniaturized versions of clinical diagnostic modalities, including but not limited to microcomputed tomography, micromagnetic resonance tomography, microsingle-photon-emission tomography, micropositron-emission tomography, optical imaging, digital angiography, and ultrasound, have all greatly improved our investigative abilities to longitudinally study various experimental models of human disease in mice and rodents. After an exhaustive literature search, the authors present a concise and critical review of in vivo small animal imaging, focusing on currently available modalities as well as emerging imaging technologies on one side and molecularly targeted contrast agents on the other. Aforementioned scientific topics are analyzed in the context of cancer angiogenesis and innovative antiangiogenic strategies under-the-way to the clinic. Proposed hybrid approaches for diagnosis and targeted site-specific therapy are highlighted to offer an intriguing glimpse of the future.

Adaptive improved element free Galerkin method for quasi- or multi-spectral bioluminescence tomography

Bioluminescence tomography (BLT) has become a powerful tool for whole-body small animal imaging. In this contribution, an adaptive improved element free Galerkin method (IEFGM) is presented to perform a quantitative reconstruction of the internal light source using quasi- or multi-spectral information, which not only can avoid the time-consuming mesh generation but also can reduce the ill-posedness of BLT effectively. In the algorithm, the reconstruction can be largely enhanced by an adaptive technology based on a posteriori error estimation. Finally, the numerical and physical phantom experiment results show that the bioluminescent source can be recovered accurately.

Multispectral optoacoustic tomography (MSOT) scanner for whole-body small animal imaging

A major difficulty arising from whole-body optoacoustic imaging is the long acquisition times associated with recording signals from multiple spatial projections. The acquired signals are also generally weak and the signal-to-noise-ratio is low, problems often solved by signal averaging, which complicates acquisition and increases acquisition times to an extent that makes many in vivo applications challenging or even impossible. Herein we present a fast acquisition multispectral optoacoustic tomography (MSOT) scanner for whole-body visualization of molecular markers in small animals. Multi-wavelength illumination offers the possibility to resolve exogenously administered fluorescent probes, biomarkers, and other intrinsic and exogenous chromophores. The system performance is determined in phantom experiments involving molecular probes and validated by imaging of small animals of various scales.

Feasibility of in vivo imaging of fluorescent proteins using lifetime contrast

We show that fluorescence lifetime is a powerful contrast mechanism that can enhance the whole-body imaging of fluorescent proteins (FPs), in the presence of background tissue autofluorescence (AF). The nonexponential AF decay is characterized from time-domain (TD) measurements on multiple nude mice and separated from the FP fluorescence using a linear fit to a priori basis functions. We illustrate this approach using an orthotopic mouse tumor model of breast adenocarcinoma. We also report that four commonly used FPs show distinct lifetimes, indicating their suitability for in vivo lifetime multiplexing. These results suggest the potential for exploiting fluorescence lifetime for imaging FPs for a variety of whole-body small-animal imaging applications.

Three-pinhole collimator to improve axial spatial resolution and sensitivity in pinhole SPECT

The aim of this study was to improve the uniformity of the axial spatial resolution and sensitivity in pinhole single-photon emission computed tomography (SPECT) and to extend the axial field of view, by using a dedicated three-pinhole collimator. A rectangular tungsten plate with three pinhole apertures of 1.5 mm diameter was designed to image a cylindrical field of view of 55 mm diameter and 160 mm axial length using a clinical gamma camera. To evaluate the non-uniformity of spatial resolution and noise, a multiple-disk phantom was built. The phantom was filled with Tc-99m, and data were acquired using a circular orbit and reconstructed with a dedicated iterative reconstruction algorithm. The axial spatial resolution together with the noise was measured in each disk. These measurements were compared to a single-pinhole system using an identical acquisition geometry and reconstruction. At the central slice, a spatial resolution of 2.7 mm was observed for both the three-pinhole and single-pinhole geometries. At 17.5 mm from the central slice, the axial spatial resolution deteriorated to 10.3 mm when using a single pinhole, while the spatial resolution remained 2.7 mm for the three-pinhole system. In the central slice, 19% noise was observed for both geometries. At 31.5 mm from this central slice, the noise remained 19% for the three-pinhole geometry, while it increased to 32% using a single pinhole. The presented three-pinhole collimator improves the uniformity of the axial spatial resolution and sensitivity in pinhole SPECT and consequently extends the axial field of view, a requirement for whole-body small-animal imaging.