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Supplementary Methods from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

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Oncogenic kinase activity and the resulting aberrant growth and survival signaling are a common driving force of cancer. Accordingly, many successful molecularly targeted anticancer therapeutics are directed at inhibiting kinase activity. To assess kinase activity in minute patient samples, we have developed an immunocapture-based in vitro kinase assay on an integrated polydimethylsiloxane microfluidics platform that can reproducibly measure kinase activity from as few as 3,000 cells. For this platform, we adopted the standard radiometric 32P-ATP–labeled phosphate transfer assay. Implementation on a microfluidic device required us to develop methods for repeated trapping and mixing of solid-phase affinity microbeads. We also developed a solid-state beta-particle camera imbedded directly below the microfluidic device for real-time quantitative detection of the signal from this and other microfluidic radiobioassays. We show that the resulting integrated device can measure ABL kinase activity from BCR-ABL–positive leukemia patient samples. The low sample input requirement of the device creates new potential for direct kinase activity experimentation and diagnostics on patient blood, bone marrow, and needle biopsy samples. Cancer Res; 70(21); 8299–308. ©2010 AACR.

Objective. We propose a novel four-layer depth-of-interaction (DOI) encoding phoswich detector using lutetium–yttrium oxyothosilicate (LYSO) and bismuth germanate (BGO) scintillator crystal arrays for high sensitivity and high spatial resolution small animal PET imaging. Approach. The detector was comprised of a stack of four alternating LYSO and BGO scintillator crystal arrays coupled to an 8 × 8 multi-pixel photon counter (MPPC) array and read out by a PETsys TOFPET2 application specific integrated circuit. The four layers from the top (gamma ray entrance) to the bottom (facing the MPPC) consisted of a 24 × 24 array of 0.99 × 0.99 × 6 mm3 LYSO crystals, a 24 × 24 array of 0.99 × 0.99 × 6 mm3 BGO crystals, a 16 × 16 array of 1.53 × 1.53 × 6 mm3 LYSO crystals and a 16 × 16 array of 1.53 × 1.53 × 6 mm3 BGO crystals. Main results. Events that occurred in the LYSO and BGO layers were first separated by measuring the pulse energy (integrated charge) and duration (time over threshold (ToT)) from the scintillation pulses. Convolutional neural networks (CNNs) were then used to distinguish between the top and lower LYSO layers and between the upper and bottom BGO layers. Measurements with the prototype detector showed that our proposed method successfully identified events from all four layers. The CNN models achieved a classification accuracy of 91% for distinguishing the two LYSO layers and 81% for distinguishing the two BGO layers. The measured average energy resolution was 13.1% ± 1.7% for the top LYSO layer, 34.0% ± 6.3% for the upper BGO layer, 12.3% ± 1.3% for the lower LYSO layer, and 33.9% ± 6.9% for the bottom BGO layer. The timing resolution between each individual layer (from the top to the bottom) and a single crystal reference detector was 350 ps, 2.8 ns, 328 ps, and 2.1 ns respectively. Significance. In conclusion, the proposed four-layer DOI encoding detector achieved high performance and is an attractive choice for next-generation high sensitivity and high spatial resolution small animal positron emission tomography systems.

The suppression of leakage current via surface passivation plays a critical role for GaSb‐based optoelectronic devices. In this Letter the authors carefully optimise the sulfur passivation parameters for improving the performance of GaSb p–i–n devices. Two competing processes are evaluated during the sulfur passivation process: the hydrolysis of HS– ions that aide surface passivation and the re‐oxidation, respectively. Upon the optimisation of sulfur passivation parameters and subsequent encapsulation with atomic layer deposition Al2 O3, the surface resistivity significantly increased from 4.3 kΩ.cm to 28.6 kΩ.cm, leading to a 19.1 times drop in dark current at room temperature for the GaSb p–i–n structure. This Letter provides a repeatable and stable passivation approach for improving the optoelectronic performance of GaSb‐based devices.

We present the performance of a digital phoswich positron emission tomography (PET) detector, composed by layers of pixilated scintillator arrays, read out by solid state light detectors and an application specific integrated circuit (ASIC). We investigated the use of integrated charge from the scintillation pulses along with time-over-threshold (ToT) to determine the layer of interaction (DOI) in the scintillator. Simulations were performed to assess the effectiveness of the ToT measurements for separating the scintillator events and identifying cross-layer-crystal-scatter (CLCS) events. These simulations indicate that ToT and charge integration from such a detector provide sufficient information to determine the layer of interaction. To demonstrate this in practice, we used a pair of prototype LYSO/BGO detectors. One detector consisted of a 19 × 19 array of 7 mm long LYSO crystals (1.36 mm pitch) coupled to a 16 × 16 array of 8 mm long BGO crystals (1.63 mm pitch). The other detector was similar except the LYSO crystal pitch was 1.63 mm. These detectors were coupled to an 8 × 8 multi-pixel photon counter mounted on a PETsys TOFPET2 ASIC. This high performance ASIC provided digital readout of the integrated charge and ToT from these detectors. We present a method to separate the events from the two scintillator layers using the ToT, and also investigate the performance of this detector. All the crystals within the proposed detector were clearly resolved, and the peak to valley ratio was 11.8 ± 4.0 and 10.1 ± 2.9 for the LYSO and BGO flood images. The measured energy resolution was 9.9% ± 1.3% and 28.5% ± 5.0% respectively for the LYSO and BGO crystals in the phoswich layers. The timing resolution between the LYSO–LYSO, LYSO–BGO and BGO–BGO coincidences was 468 ps, 1.33 ns and 2.14 ns respectively. Results show ToT can be used to identify the crystal layer where events occurred and also identify and reject the majority of CLCS events between layers.

IntroductionRadio thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion when optimizing radiosynthesis processes. In applications where there are few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization. In a couple of studies, Cerenkov luminescence imaging (CLI) has been used for reading radio-TLC plates spotted with a variety of isotopes. We show that this approach can be extended to develop a high-throughput approach for radio-TLC analysis of many samples.MethodsThe high-throughput radio-TLC analysis was carried out by performing parallel development of multiple radioactive samples spotted on a single TLC plate, followed by simultaneous readout of the separated samples using Cerenkov imaging. Using custom-written MATLAB software, images were processed and regions of interest (ROIs) were drawn to enclose the radioactive regions/spots. For each sample, the proportion of integrated signal in each ROI was computed. Various crude samples of [18F]fallypride, [18F]FET and [177Lu]Lu-PSMA-617 were prepared for demonstration of this new method.ResultsBenefiting from a parallel developing process and high resolution of CLI-based readout, total analysis time for eight [18F]fallypride samples was 7.5min (2.5min for parallel developing, 5min for parallel readout), which was significantly shorter than the 48min needed using conventional approaches (24min for sequential developing, 24min for sequential readout on a radio-TLC scanner). The greater separation resolution of CLI enabled the discovery of a low-abundance side product from a crude [18F]FET sample that was not discernable using the radio-TLC scanner. Using the CLI-based readout method, we also observed that high labeling efficiency (99%) of [177Lu]Lu-PSMA-617 can be achieved in just 10min, rather than the typical 30min timeframe used.ConclusionsCerenkov imaging in combination with parallel developing of multiple samples on a single TLC plate proved to be a practical method for rapid, high-throughput radio-TLC analysis.

For decades, there has been immense progress in miniaturizing analytical methods based on electrophoresis to improve sensitivity, and to reduce sample volumes, separation times, and/or equipment cost and space requirements, in applications ranging from analysis of biological samples, to environmental analysis to forensics. In the field of radiochemistry, where radiation-shielded laboratory space is limited, there has been great interest in harnessing the compactness, high efficiency, and speed of microfluidics to synthesize short-lived radiolabeled compounds. We recently proposed that analysis of these compounds could also benefit from miniaturization, and have been investigating capillary electrophoresis (CE) and hybrid microchip electrophoresis (hybrid-MCE) as alternatives to the typically-used high-performance liquid chromatography (HPLC). We previously showed separation of the positron-emission tomography (PET) imaging tracer 3′-deoxy-3′-fluorothymidine (FLT) from its impurities in a hybrid-MCE device with UV detection, with similar separation performance to HPLC, but with improved speed and lower sample volumes. In this paper, we have developed an integrated radiation detector to enable measurement of the emitted radiation from radiolabeled compounds. Though conventional radiation detectors have been incorporated into CE systems in the past, these approaches cannot be readily integrated into a compact hybrid-MCE device. We instead employed a solid-state avalanche photodiode (APD)-based detector for real-time, high-sensitivity beta particle detection. The integrated system can reliably separate [(18)F]FLT from its impurities and perform chemical identification via co-injection with non-radioactive reference standard. This system can quantitate samples with radioactivity concentrations as low as 114 MBq/mL (3.1 mCi/mL), which is sufficient for analysis of radiochemical purity of radiopharmaceuticals.

Inflammatory bowel diseases (IBDs) in humans are characterized in part by aberrant CD4-positive (CD4+) T-cell responses. Currently, identification of foci of inflammation within the gut requires invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an antimouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a PET probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD. Methods: The DSS mouse model of IBD was validated by assessing changes in CD4+ T cells in the spleen and mesenteric lymph nodes (MLNs) using flow cytometry. Furthermore, CD4+ T cell infiltration in the colons of colitic mice was evaluated using immunohistochemistry. 89Zr-labeled GK1.5 cDb was used to image distribution of CD4+ T cells in the abdominal region and lymphoid organs of mice with DSS-induced colitis. Region-of-interest analysis was performed on specific regions of the gut to quantify probe uptake. Colons, ceca, and MLNs were removed and imaged ex vivo by PET. Imaging results were confirmed by ex vivo biodistribution analysis. Results: An increased number of CD4+ T cells in the colons of colitic mice was confirmed by anti-CD4 immunohistochemistry. Increased uptake of 89Zr-maleimide-deferoxamine (malDFO)-GK1.5 cDb in the distal colon of colitic mice was visible in vivo in PET scans, and region-of-interest analysis of the distal colon confirmed increased activity in DSS mice. MLNs from colitic mice were enlarged and visible in PET images. Ex vivo scans and biodistribution confirmed higher uptake in DSS-treated colons (DSS, 1.8 ± 0.40; control, 0.45 ± 0.12 percentage injected dose [%ID] per organ, respectively), ceca (DSS, 1.1 ± 0.38; control, 0.35 ± 0.09 %ID per organ), and MLNs (DSS, 1.1 ± 0.58; control, 0.37 ± 0.25 %ID per organ). Conclusion: 89Zr-malDFO-GK1.5 cDb detected CD4+ T cells in the colons, ceca, and MLNs of colitic mice and may prove useful for further investigations of CD4+ T cells in preclinical models of IBD, with potential to guide development of antibody-based imaging in human IBD.

Pulse pileup events degrade the signal-to-noise ratio (SNR) of nuclear medicine data. When such events occur in multiplexed detectors, they cause spatial misposition, energy spectrum distortion and degraded timing resolution, which leads to image artifacts. Pulse pileup is pronounced in PETbox4, a bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice. In that system, the combination of high absolute sensitivity, long scintillator decay time (BGO) and highly multiplexed electronics lead to a significant fraction of pulse pileup, reached at lower total activity than for comparable instruments. In this manuscript, a new pulse pileup rejection method named position shift rejection (PSR) is introduced. The performance of PSR is compared with a conventional leading edge rejection (LER) method and with no pileup rejection implemented (NoPR). A comprehensive digital pulse library was developed for objective evaluation and optimization of the PSR and LER, in which pulse waveforms were directly recorded from real measurements exactly representing the signals to be processed. Physical measurements including singles event acquisition, peak system sensitivity and NEMA NU-4 image quality phantom were also performed in the PETbox4 system to validate and compare the different pulse pile-up rejection methods. The evaluation of both physical measurements and model pulse trains demonstrated that the new PSR performs more accurate pileup event identification and avoids erroneous rejection of valid events. For the PETbox4 system, this improvement leads to a significant recovery of sensitivity at low count rates, amounting to about 1/4th of the expected true coincidence events, compared to the LER method. Furthermore, with the implementation of PSR, optimal image quality can be achieved near the peak noise equivalent count rate (NECR).

HiPET is a recently developed prototype preclinical PET scanner dedicated to high sensitivity and high resolution molecular imaging. The HiPET system employs a phoswich depth of interaction (DOI) detector design, which also allows identification of the large majority of the cross layer crystal scatter (CLCS) events. This work evaluates its performance characteristics following the National Electrical Manufacturers Association (NEMA) NU4-2008 protocol. The HiPET consists of twenty flat panel type detectors arranged in two rings. The inner diameter is 160 mm and the axial field of view (FOV) is 104 mm. Each detector is comprised of two layers of phoswich scintillator crystal arrays, a tapered, pixelated glass lightguide and a multi anode photomultiplier tube (MAPMT). The front (gamma ray entrance) layer is a 48 × 48 pixelated cerium doped lutetium yttrium orthosilicate (LYSO) scintillator array with individual crystals measuring 1.01 × 1.01 × 6.1 mm. The back (towards the PMT) layer is a 32 × 32 pixelated bismuth germanate (BGO) scintillator array with individual crystals measuring 1.55 × 1.55 × 8.9 mm. For energy windows of 250-650 keV and 350-650 keV, the peak absolute sensitivity at the center of the FOV was 13.5% and 10.4% including CLCS events, and 11.8% and 8.9% excluding CLCS events, respectively. The average detector energy resolution derived by averaging the individual crystal spectra was 11.7% ± 1.4% for LYSO and 17.0% ± 1.4% for BGO. The 3D ordered-subsets expectation maximization (OSEM) reconstructed image of a point source in air, ranged from 0.73 mm to 1.19 mm, with an average value of 0.93 ± 0.09 mm at all measured locations. The peak noise equivalent count rate (NECR) and scatter fraction were 179 kcps at 12.4 MBq and 6.9% for the mouse-sized phantom, and 63 kcps at 11.3 MBq and 18.3% for the rat-sized phantom. For the NEMA image quality phantom, the uniformity was 5.8%, and the spillover ratios measured in the water- and air-filled cold region chambers were 0.047 and 0.044, respectively. The recovery coefficients (RC) ranged from 0.31 to 0.92. These results and in vivo evaluation demonstrate that the HiPET can achieve high quality molecular imaging for biomedical applications.

G8 is a benchtop integrated PET/CT scanner dedicated to high-sensitivity and high-resolution imaging of mice. This work characterizes its National Electrical Manufacturers Association NU 4-2008 performance where applicable and also assesses the basic imaging performance of the CT subsystem. Methods: The PET subsystem in G8 consists of 4 flat-panel detectors arranged in a boxlike geometry. Each panel consists of 2 modules of a 26 × 26 pixelated bismuth germanate scintillator array with individual crystals measuring 1.75 × 1.75 × 7.2 mm. The crystal arrays are coupled to multichannel photomultiplier tubes via a tapered, pixelated glass lightguide. A cone-beam CT scanner consisting of a MicroFocus x-ray source and a complementary metal oxide semiconductor detector provides anatomic information. Sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance, and the capability of performing phantom and mouse imaging were evaluated for the PET subsystem. Noise, dose level, contrast, and resolution were evaluated for the CT subsystem. Results: With an energy window of 350–650 keV, the peak sensitivity was 9.0% near the center of the field of view. The crystal energy resolution ranged from 15.0% to 69.6% in full width at half maximum (FWHM), with a mean of 19.3% ± 3.7%. The average intrinsic spatial resolution was 1.30 and 1.38 mm FWHM in the transverse and axial directions, respectively. The maximum-likelihood expectation maximization reconstructed image of a point source in air averaged 0.81 ± 0.11 mm FWHM. The peak noise-equivalent count rate for the mouse-sized phantom was 44 kcps for a total activity of 2.9 MBq (78 μCi), and the scatter fraction was 11%. For the CT subsystem, the value of the modulation transfer function at 10% was 2.05 cycles/mm. Conclusion: The overall performance demonstrates that the G8 can produce high-quality images for molecular imaging–based biomedical research.

The most common positron emission tomography (PET) radio-labeled probe for molecular diagnostics in patient care and research is the glucose analog, 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). We report on an integrated microfluidics-chip/beta particle imaging system for in vitro 18F-FDG radioassays of glycolysis with single cell resolution. We investigated the kinetic responses of single glioblastoma cancer cells to targeted inhibitors of receptor tyrosine kinase signaling. Further, we find a weak positive correlation between cell size and rate of glycolysis.

III-(As, Sb) alloys are building blocks for various advanced optoelectronic devices, but the growth of their ternary or quaternary materials are commonly limited by spontaneous formation of clusters and phase separations during alloying. Recently, digital alloy growth by molecular beam epitaxy has been widely adopted in preference to conventional random alloy growth because of the extra degree of control offered by the ordered alloying. In this article, we provide a comparative study of the optical characteristics of AlAsSb alloys grown lattice-matched to GaSb using both techniques. The sample grown by digital alloy technique showed stronger photoluminescence intensity, narrower peak linewidth, and larger carrier activation energy than the random alloy technique, indicating an improved optical quality with lower density of non-radiative recombination centers. In addition, a relatively long carrier lifetime was observed from the digital alloy sample, consistent with the results obtained from the photoluminescence study.

This paper presents a deformable mouse atlas of the laboratory mouse anatomy. This atlas is fully articulated and can be positioned into arbitrary body poses. The atlas can also adapt body weight by changing body length and fat amount.A training set of 103 micro-CT images was used to construct the atlas. A cage-based deformation method was applied to realize the articulated pose change. The weight-related body deformation was learned from the training set using a linear regression method. A conditional Gaussian model and thin-plate spline mapping were used to deform the internal organs following the changes of pose and weight.The atlas was deformed into different body poses and weights, and the deformation results were more realistic compared to the results achieved with other mouse atlases. The organ weights of this atlas matched well with the measurements of real mouse organ weights. This atlas can also be converted into voxelized images with labeled organs, pseudo CT images and tetrahedral mesh for phantom studies.With the unique ability of articulated pose and weight changes, the deformable laboratory mouse atlas can become a valuable tool for preclinical image analysis.

Small animal positron emission tomography (PET) systems are often designed by employing close geometry configurations. Due to the different characteristics caused by geometrical factors, these tomographs require data acquisition protocols that differ from those optimized for conventional large diameter ring systems. In this work we optimized the energy window for data acquisitions with PETbox4, a 50 mm detector separation (box-like geometry) pre-clinical PET scanner, using the Geant4 Application for Tomographic Emission (GATE). The fractions of different types of events were estimated using a voxelized phantom including a mouse as well as its supporting chamber, mimicking a realistic mouse imaging environment. Separate code was developed to extract additional information about the gamma interactions for more accurate event type classification. Three types of detector backscatter events were identified in addition to the trues, phantom scatters and randoms. The energy window was optimized based on the noise equivalent count rate (NECR) and scatter fraction (SF) with lower-level discriminators (LLD) corresponding to energies from 150 keV to 450 keV. The results were validated based on the calculated image uniformity, spillover ratio (SOR) and recovery coefficient (RC) from physical measurements using the National Electrical Manufacturers Association (NEMA) NU-4 image quality phantom. These results indicate that when PETbox4 is operated with a more narrow energy window (350-650 keV), detector backscatter rejection is unnecessary. For the NEMA NU-4 image quality phantom, the SOR for the water chamber decreases by about 45% from 15.1% to 8.3%, and the SOR for the air chamber decreases by 31% from 12.0% to 8.3% at the LLDs of 150 and 350 keV, without obvious change in uniformity, further supporting the simulation based optimization. The optimization described in this work is not limited to PETbox4, but also applicable or helpful to other small inner diameter geometry scanners.

Delineation of major torso organs is a key step of mouse micro-CT image analysis. This task is challenging due to low soft tissue contrast and high image noise, therefore anatomical prior knowledge is needed for accurate prediction of organ regions. In this work, we develop a deeply supervised fully convolutional network which uses the organ anatomy prior learned from independently acquired contrast-enhanced micro-CT images to assist the segmentation of non-enhanced images. The network is designed with a two-stage workflow which firstly predicts the rough regions of multiple organs and then refines the accuracy of each organ in local regions. The network is trained and evaluated with 40 mouse micro-CT images. The volumetric prediction accuracy (Dice score) varies from 0.57 for the spleen to 0.95 for the heart. Compared to a conventional atlas registration method, our method dramatically improves the Dice of the abdominal organs by 18%-26%. Moreover, the incorporation of anatomical prior leads to more accurate results for small-sized low-contrast organs (e.g. the spleen and kidneys). We also find that the localized stage of the network has better accuracy than the global stage, indicating that localized single organ prediction is more accurate than global multiple organ prediction. With this work, the accuracy and efficiency of mouse micro-CT image analysis are greatly improved and the need for using contrast agent and high x-ray dose is potentially reduced.

This work develops a (NH4)2S/Al2O3 passivation technique for photodiode-based GaSb/AlAsSb heterostructure. Surface-sulfurated GaSb/AlAsSb heterostructure mesas show a significant suppression of reversed-bias dark current by 4–5 orders of magnitude after they are further passivated by Al2O3 layers. So the mesa sidewalls treated with (NH4)2S/Al2O3 layers can effectively inhibit the shunt path of dark carriers. The activation energies for both bulk and surface components are extracted from temperature-dependent current–voltage characteristics, which suggest that the bulk characteristics remain unchanged, while Fermi-level pinning at surfaces is alleviated. Additionally, temperature coefficients of the breakdown voltage are extracted, confirming that the breakdown process is confined entirely in the large bandgap AlAsSb regions. This study shows that the implementation of (NH4)2S/Al2O3 passivation can lead to room temperature GaSb-based photodiodes and GaSb/AlAsSb-based avalanche photodiodes for highly efficient photodetection.

Demonstrated are antimony‐based (Sb‐based) separate absorption and multiplication avalanche photodiodes (SAM‐APDs) for X‐ray and gamma‐ray detection, which are composed of GaSb absorbers and large bandgap AlAsSb multiplication regions in order to enhance the probability of stopping high‐energy photons while drastically suppressing the minority carrier diffusion. Well‐defined X‐ray and gamma‐ray photopeaks are observed under exposure to 241Am radioactive sources, demonstrating the desirable energy‐sensitive detector performance. Spectroscopic characterizations show a significant improvement of measured energy resolution due to reduced high‐peak electric field in the absorbers and suppressed nonradiative recombination on surfaces. Additionally, the GaSb/AlAsSb SAM‐APDs clearly exhibit energy response linearity up to 59.5 keV with a minimum full‐width half‐maximum of 1.283 keV. A further analysis of the spectroscopic measurement suggests that the device performance is intrinsically limited by the noise from the readout electronics rather than that from the photodiodes. This study provides a first understanding of Sb‐based energy‐sensitive SAM‐APDs and paves the way to achieving efficient detection of high‐energy photons for X‐ray and gamma‐ray spectroscopy.

A beta camera has been developed that allows planar imaging of the spatial and temporal distribution of beta particles using a 14 × 14 mm^2 position sensitive avalanche photodiode (PSAPD). This camera system, which we call Betabox, can be directly coupled to microfluidic chips designed for cell incubation or other biological applications. Betabox allows for imaging the cellular uptake of molecular imaging probes labeled with charged particle emitters such as ^(18)F inside these chips. In this work, we investigate the quantitative imaging capabilities of Betabox for ^(18)F beta particles, in terms of background rate, efficiency, spatial resolution, and count rate. Measurements of background and spatial resolution are considered both at room temperature (21 °C ± 1 °C) and at an elevated operating temperature (37 °C ± 1 °C), as is often required for biological assays. The background rate measured with a 4 keV energy cutoff is below 2 cph mm^(−2) at both 21 and 37 °C. The absolute efficiency of Betabox for the detection of ^(18)F positron sources in contact with a PSAPD with the surface passivated from ambient light and damage is 46% ± 1%. The lower detection limit is estimated using the Rose Criterion to be 0.2 cps mm^(−2) for 1 min acquisitions and a 62 × 62 µm^2 pixel size. The upper detection limit is approximately 21 000 cps. The spatial resolution at both 21 and 37 °C ranges from 0.4 mm FWHM at the center of the field of view (FOV), and degrades to 1 mm at a distance of 5 mm away from center yielding a useful FOV of approximately 10 × 10 mm^2. We also investigate the effects on spatial resolution and sensitivity that result from the use of a polymer based microfluidic chip. For these studies we place varying layers of low-density polyethylene (LDPE) between the detector and the source and find that the spatial resolution degrades by ~180 µm for every 100 µm of LDPE film. Sensitivity is reduced by half with the inclusion of ~200 µm of additional LDPE film. Lastly, we demonstrate the practical utilization of Betabox, with an imaging test of its linearity, when coupled to a polydimethylsiloxane microfluidic chip designed for cell based assays.

The Genisys4 is a small bench-top preclinical PET scanner designed to enable imaging in biology, biochemistry, and pharmacology laboratories and imaging centers. Here, we compare its performance with that of a well-established preclinical PET scanner. Methods: Subcutaneous and lung tumor xenografts were used to compare lesion detectability and treatment responses to chemotherapy (gemcitabine) using 18F-FDG PET. The size of subcutaneous xenografts (L1210 and L1210-10K leukemia cells) and lung metastases (B-16 melanoma cells) was measured on small-animal CT images. Tumor 18F-FDG uptake was expressed as percentage injected dose per gram. Using list-mode data, serial images of the left ventricular blood pool were used to generate time–activity curves. Results: Subcutaneous xenografts (range, 4–12 mm; mean ± SD, 6.1 ± 1.7 mm) and lung metastases (range, 1–5 mm; mean, 2.1 ± 1.2 mm) were detected equally well with both scanners. Tumor 18F-FDG uptake measured with both scanners was highly correlated for subcutaneous xenografts (r2 = 0.93) and lung metastases (r2 = 0.83). The new Genisys4 scanner and the established scanner provided comparable treatment response information (r2 = 0.93). Dynamic imaging sequences permitted the generation of left ventricular blood-pool time–activity curves with both scanners. Conclusion: Using subcutaneous and lung xenografts, a novel and an established preclinical PET scanner provided equivalent information with regard to lesion detection, tumor 18F-FDG uptake, tumor response to treatment, and generation of time–activity curves. Thus, the Genisys4 provides a small, efficient bench-top preclinical PET alternative for quantitatively studying murine tumor models in biology, biochemistry, and pharmacology laboratories and preclinical imaging centers.

BackgroundAutomated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes with particular focus on fluorine-18 ((18)F).MethodsThe key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes.ResultsThe combined system demonstrates volume variation to be within 5% for dispensing volumes of 20μL or greater. When considering volumes of 20μL or greater, the delivered radioactivity is in agreement with the requested amount as measured independently with a dose calibrator to within 2% on average.ConclusionsThe integration of the detector and pump in an in-line system leads to a flexible and compact approach that can accurately dispense solutions containing radioactivity concentrations ranging from the high values typical of [(18)F]fluoride directly produced from a cyclotron (~0.1-1mCiμL(-1)) to the low values typical of batches of [(18)F]fluoride-labeled radiotracers intended for preclinical mouse scans (~1-10μCiμL(-1)).

Semiconductor radiation detectors offer direct absorption of a high-energy photon by the detector material, and promise the lowest energy resolution for x-ray and gamma-ray spectroscopy. The enhanced energy resolution for x-rays or gamma-rays could be very attractive for monitoring hazardous industrial waste, sensing radiological weapons or nuclear threats, and medical imaging. High stopping power (photoelectric absorption efficiency, ∝ Z4–5) semiconductor radiation detectors that operate at room temperature with a performance approaching the energy resolution of cooled high purity germanium detectors (HPGe) is desirable, but have yet been realized. Large bandgap materials with lower noise tend to have low Z and thus poor efficiency for stopping gamma radiation. On the other hand, high Z materials, which are efficient at stopping gamma radiation, present low bandgaps resulting in large dark currents and require cooling to achieve good energy resolution. CdTe is by far the most promising material that has both large bandgap and high Z, but it also suffers from hole tailing effect for photon energy >100 keV due to the poor hole transport [1, 2].

This paper introduces a mouse atlas registration system (MARS), composed of a stationary top-view x-ray projector and a side-view optical camera, coupled to a mouse atlas registration algorithm. This system uses the x-ray and optical images to guide a fully automatic co-registration of a mouse atlas with each subject, in order to provide anatomical reference for small animal molecular imaging systems such as positron emission tomography (PET). To facilitate the registration, a statistical atlas that accounts for inter-subject anatomical variations was constructed based on 83 organ-labeled mouse micro-computed tomography (CT) images. The statistical shape model and conditional Gaussian model techniques were used to register the atlas with the x-ray image and optical photo. The accuracy of the atlas registration was evaluated by comparing the registered atlas with the organ-labeled micro-CT images of the test subjects. The results showed excellent registration accuracy of the whole-body region, and good accuracy for the brain, liver, heart, lungs and kidneys. In its implementation, the MARS was integrated with a preclinical PET scanner to deliver combined PET/MARS imaging, and to facilitate atlas-assisted analysis of the preclinical PET images.

This study investigates methodologies for the estimation of small animal anatomy from non-tomographic modalities, such as planar X-ray projections, optical cameras, and surface scanners. The key goal is to register a digital mouse atlas to a combination of non-tomographic modalities, in order to provide organ-level anatomical references of small animals in 3D.A 2D/3D registration method was developed to register the 3D atlas to the combination of non-tomographic imaging modalities. Eleven combinations of three non-tomographic imaging modalities were simulated, and the registration accuracy of each combination was evaluated.Comparing the 11 combinations, the top-view X-ray projection combined with the side-view optical camera yielded the best overall registration accuracy of all organs. The use of a surface scanner improved the registration accuracy of skin, spleen, and kidneys.The methodologies and evaluation presented in this study should provide helpful information for designing preclinical atlas-based anatomical data acquisition systems.

An integrated β-camera and microfluidic chip was developed that is capable of quantitative imaging of glycolysis radioassays using 18F-FDG in small cell populations down to a single cell. This paper demonstrates that the integrated system enables digital control and quantitative measurements of glycolysis in B-RafV600E–mutated melanoma cell lines in response to specific B-Raf inhibition. Methods: The β-camera uses a position-sensitive avalanche photodiode to detect charged particle–emitting probes within a microfluidic chip. The integrated β-camera and microfluidic chip system was calibrated, and the linearity was measured using 4 different melanoma cell lines (M257, M202, M233, and M229). Microfluidic radioassays were performed with cell populations ranging from hundreds of cells down to a single cell. The M229 cell line has a homozygous B-RafV600E mutation and is highly sensitive to a B-Raf inhibitor, PLX4032. A microfluidic radioassay was performed over the course of 3 days to assess the cytotoxicity of PLX4032 on cellular 18F-FDG uptake. Results: The β-camera is capable of imaging radioactive uptake of 18F-FDG in microfluidic chips. 18F-FDG uptake for a single cell was measured using a radioactivity concentration of 37 MBq/mL during the radiotracer incubation period. For in vitro cytotoxicity monitoring, the β-camera showed that exposure to 1 μM PLX4032 for 3 days decreased the 18F-FDG uptake per cell in highly sensitive M229 cells, compared with vehicle controls. Conclusion: The integrated β-camera and microfluidic chip can provide digital control of live cell cultures and allow in vitro quantitative radioassays for multiple samples simultaneously.

The purpose of this study was to investigate the influence of combined inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) and bone morphogenetic protein (BMP) activity in a mixed lytic/blastic prostate cancer lesion in bone. Human prostate cancer cells (C4 2b) were injected into immunocompromised mice using an intratibial injection model to create mixed lytic/blastic lesions. RANK-Fc, a recombinant RANKL antagonist, was injected subcutaneously three times a week (10 mg/kg) to inhibit RANKL and subsequent formation, function and survival of osteoclasts. Inhibition of BMP activity was achieved by transducing prostate cancer cells ex vivo with a retroviral vector expressing noggin (retronoggin; RN). There were three treatment groups (RANK-Fc treatment, RN treatment and combined RN and RANK-Fc treatment) and two control groups (untreated control and empty vector control for the RN treatment group). The progression of bone lesion and tumor growth was evaluated using plain radiographs, hindlimb tumor size, 18F-Fluorodeoxyglucose and 18F-fluoride micro PET-CT, histology and histomorphometry. Treatment with RANK-Fc alone inhibited osteolysis and transformed a mixed lytic/blastic lesion into an osteoblastic phenotype. Treatment with RN alone inhibited the osteoblastic component in a mixed lytic/blastic lesion and resulted in formation of smaller osteolytic bone lesion with smaller soft tissue size. The animals treated with both RN and RANK-Fc demonstrated delayed development of bone lesions, inhibition of osteolysis, small soft tissue tumors and preservation of bone architecture with less tumor induced new bone formation. This study suggests that combined inhibition of the RANKL and the BMP pathway may be an effective biologic therapy to inhibit the progression of established mixed lytic/blastic prostate cancer lesions in bone.

Purpose: The traditional figures of merit used in the evaluation of positron emission tomography(PET)systems, including system sensitivity and spatial resolution, do not directly reflect the minimum detectable activity (MDA) performance, despite the fact that it is one of the most important tasks for a PETsystem. MDA, as a combination of the more traditional PETsystem parameters, is directly related to lesion detection. However, MDA evaluation is task specific and cannot be done by a single measurement. Therefore, a simple method to evaluate system detectability needs to be developed. Methods: In this work, an analytical method of MDA estimation was developed, taking into account system sensitivity, spatial resolution, source properties, and noise propagation in image reconstruction by using the Rose criterion and/or the Curie equation as the detection standard. In the implementation, the source background, as well as the intrinsic activity background from the scintillation material of the system, was also taken into consideration. The accuracy of this method was evaluated in two commercially available preclinical PETsystems, with phantom experiments that were designed to closely mimicin vivo tumor uptake without introducing finite boundaries between the source and the background. Results: The lesion contrast-to-noise ratio calculated by the analytical evaluation showed good agreement with that obtained from the experiments. Visual assessment of the reconstructed images at the detection limit (based on analytical evaluation) also was in agreement with the Rose criterion. The MDA performance was quantitatively compared between the two preclinical PETsystems and showed different detection limits under different imaging conditions, suggesting that the detection limit of a PETsystem strongly depends on the lesion properties and acquisition settings. Conclusions: An analytical method of evaluating the PETsystem detectability was developed and validated by experiments. Overall, the analytical MDA calculation provides a simple way to evaluate the signal detectability of a PETsystem and can be used for comparing different systems. It also provides guidelines for designing new PET tomographs as well as optimizing data acquisition protocols.

PETbox is a low-cost benchtop PET scanner dedicated to high throughput preclinical imaging that is currently under development at our institute. This paper presents the design and characterization of the detectors that are used in the PETbox system. In this work, bismuth germanate scintillator was used for the detector, taking advantage of its high stopping power, high photoelectric event fraction, lack of intrinsic background radiation and low cost. The detector block was segmented into a pixelated array consisting of 20 × 44 elements, with a crystal pitch of 2.2 mm and a crystal cross section of 2 mm × 2 mm. The effective area of the array was 44 mm × 96.8 mm. The array was coupled to two Hamamatsu H8500 position sensitive photomultiplier tubes, forming a flat-panel type detector head with a sensitive area large enough to cover the whole body of a typical laboratory mouse. Two such detector heads were constructed and their performance was characterized. For one detector head, the energy resolution ranged from 16.1% to 38.5% full width at half maximum (FWHM), with a mean of 20.1%; for the other detector head, the energy resolution ranged from 15.5% to 42.7% FWHM, with a mean of 19.6 %. The intrinsic spatial resolution was measured to range from 1.55 mm to 2.39 mm FWHM along the detector short axis and from 1.48 mm to 2.33 mm FWHM along the detector long axis, with an average of 1.78 mm. Coincidence timing resolution for the detector pair was measured to be 4.1 ns FWHM. These measurement results show that the detectors are suitable for our specific application.

Dual-energy x-ray computed tomography (DECT) has the capability to decompose attenuation coefficients using two basis functions and has proved its potential in reducing beam-hardening artifacts from reconstructed images. The method typically involves two successive scans with different x-ray tube voltage settings. This work proposes an approach to dual-energy imaging through x-ray beam filtration that requires only one scan and a single tube voltage setting. It has been implemented in a preclinical microCT tomograph with minor modifications. Retrofitting of the microCT scanner involved the addition of an automated filter wheel and modifications to the acquisition and reconstruction software. Results show that beam-hardening artifacts are reduced to noise level. Acquisition of a mu-Compton image is well suited for attenuation-correction of PET images while dynamic energy selection (4D viewing) offers flexibility in image viewing by adjusting contrast and noise levels to suit the task at hand. All dual-energy and single energy reference scans were acquired at the same soft tissue dose level of 50 mGy.

It has been observed that microfluidic chips used for synthesizing (18)F-labeled compounds demonstrate visible light emission without nearby scintillators or fluorescent materials. The origin of the light was investigated and found to be consistent with the emission characteristics from Cerenkov radiation. Since (18)F decays through the emission of high-energy positrons, the energy threshold for beta particles, i.e. electrons or positrons, to generate Cerenkov radiation was calculated for water and polydimethylsiloxane (PDMS), the most commonly used polymer-based material for microfluidic chips. Beta particles emitted from (18)F have a continuous energy spectrum, with a maximum energy that exceeds this energy threshold for both water and PDMS. In addition, the spectral characteristics of the emitted light from (18)F in distilled water were also measured, yielding a broad distribution from 300 nm to 700 nm, with higher intensity at shorter wavelengths. A photograph of the (18)F solution showed a bluish-white light emitted from the solution, further suggesting Cerenkov radiation. In this study, the feasibility of using this Cerenkov light emission as a method for quantitative measurements of the radioactivity within the microfluidic chip in situ was evaluated. A detector previously developed for imaging microfluidic platforms was used. The detector consisted of a charge-coupled device (CCD) optically coupled to a lens. The system spatial resolution, minimum detectable activity and dynamic range were evaluated. In addition, the calibration of a Cerenkov signal versus activity concentration in the microfluidic chip was determined. This novel method of Cerenkov radiation measurements will provide researchers with a simple yet robust quantitative imaging tool for microfluidic applications utilizing beta particles.

The ability to reproducibly and repeatedly image rodents in noninvasive imaging systems, such as small-animal positron emission tomography (PET) and computed tomography (CT), requires a reliable method for anesthetizing, positioning, and heating animals in a simple reproducible manner. In this paper, we demonstrate that mice and rats can be reproducibly and repeatedly imaged using an imaging chamber designed to be rigidly mounted on multiple imaging systems.Mouse and rat imaging chambers were made of acrylic plastic and aluminum. MicroCT scans were used to evaluate the positioning reproducibility of the chambers in multimodality and longitudinal imaging studies. The ability of the chambers to maintain mouse and rat body temperatures while anesthetized with gas anesthesia was also evaluated.Both the mouse and rat imaging chambers were able to reproducibly position the animals in the imaging systems with a small degree of error. Placement of the mouse in the mouse imaging chamber resulted in a mean distance of 0.23 mm per reference point in multimodality studies, whereas for longitudinal studies the mean difference was 1.11 mm. The rat chamber resulted in a mean difference of 0.46 mm in multimodality studies and a mean difference of 4.31 mm in longitudinal studies per reference point. The chambers maintained rodent body temperatures at the set point temperature of 38 degrees C.The rodent imaging chambers were able to reproducibly position rodents in tomographs with a small degree of variability and were compatible with routine use. The embedded anesthetic line and heating system was capable of maintaining the rodent's temperature and anesthetic state, thereby enhancing rodent health and improving data collection reliability.

The accurate assessment of nodal involvement in prostate cancer is crucial to planning treatment, yet there is a shortage of noninvasive imaging techniques capable of visualizing nodal lesions directly. This study demonstrates the feasibility of using recombinant human adenoviral vectors to detect nodal metastases in a human prostate cancer model. This was achieved by the prostate-restricted expression of optical and positron emission tomography (PET) imaging reporter genes by the viral vector coupled with the innate lymphotropic properties of adenovirus. We show that peritumoral administration of these vectors results in the direct detection of reporter gene expression in metastatic lesions within sentinel lymph nodes. Notably, this approach parallels the current lymphoscintigraphy method but enables the direct PET visualization of sentinel lymph node metastases, eliminating the need for invasive lymphadenectomy. These findings may lead to more effective diagnostic and therapeutic strategies for individuals with advanced-stage prostate cancer.

The combination of small-animal PET/CT scans and conventional imaging methods may enhance the evaluation of in vivo biologic interactions of murine models in the study of prostate cancer metastasis to bone.Small-animal PET/CT scans using (18)F-fluoride ion and (18)F-FDG coregistered with high-resolution small-animal CT scans were used to longitudinally assess the formation of osteoblastic, osteolytic, and mixed lesions formed by human prostate cancer cell lines in a severe combined immunodeficient (SCID) mouse tibial injection model. These scans were correlated with plain radiographs, histomorphometry, and soft-tissue measurements.Small-animal PET/CT scans were able to detect biologic activity of cells that induced an osteoblastic lesion 2 wk earlier than on plain radiographs. Furthermore, both the size and the activity of the lesions detected on PET/CT images significantly increased at each successive time point (P0.05). (18)F-FDG lesions strongly correlated with soft-tissue measurements, whereas (18)F-fluoride ion activity correlated with bone volume measured on histomorphometric analysis (P0.005). Osteolytic lesions were successfully quantified using small-animal CT, whereas lesion sizes measured on (18)F-FDG PET scans also strongly correlated with soft-tissue tumor burden (P0.05). In contrast, for mixed lesions, (18)F-fluoride ion and (18)F-FDG PET/CT scans detected only minimal activity.(18)F-FDG and (18)F-fluoride ion PET/CT scans can be useful tools in characterizing pure osteolytic and osteoblastic lesions induced by human prostate cancer cell lines. The value of this technology needs further evaluation to determine whether these studies can be used effectively to detect more subtle responses to different treatment regimens in animal models.

We report here on a technique to implement high-resolution objects with voxels having variable dimensions (compressed) for the reduction of memory and central processing unit (CPU) requirements in Monte Carlo simulations. The technique, which was implemented in GATE, the GEANT4 application for positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging simulations, was developed in response to our need for realistic high-resolution phantoms for dosimetry calculations. A compression algorithm similar to run-length encoding for one-dimensional data streams, was used to fuse together adjacent voxels with identical physical properties. The algorithm was verified by conducting dosimetric calculations and imaging experiments on compressed and uncompressed phantoms. Depending on the initial phantom size and composition, compression ratios of up to 99.9% were achieved allowing memory and CPU reductions of up to 85% and 70%, respectively. The output of the simulations was consistent with respect to the goals for each type of simulation performed (dosimetry and imaging). The implementation of compressed voxels in GATE allows for significant memory and CPU reduction and is suitable for dosimetry as well as for imaging experiments.

Currently available diagnostic techniques can be unreliable in the diagnosis of delayed fracture healing in certain clinical situations, which can lead to increased complication rates and costs to the health care system. This study sought to determine the utility of positron emission tomography (PET) scanning with (18)F-fluoride ion, which localizes in regions of high osteoblastic activity, and (18)F-fluorodeoxyglucose (FDG), an indicator of cellular glucose metabolism, in assessing bone healing in a rat femur fracture model.Fractures were created in the femurs of immunocompetent rats. Animals in group I had a fracture produced via a manual three-point bending technique. Group II animals underwent a femoral osteotomy with placement of a 2-mm silastic spacer at the fracture site. Fracture healing was assessed with plain radiographs, (18)F-fluoride, and (18)F-FDG PET scans at 1, 2, 3, and 4-week time points after surgery. Femoral specimens were harvested for histologic analysis and manual testing of torsional and bending strength 4 weeks after surgery.All fractures in group I revealed abundant callus formation and bone healing, while none of the nonunion femurs were healed via assessment with manual palpation, radiographic, and histologic evaluation at the 4-week time point. (18)F-fluoride PET images of group I femurs at successive 1-week intervals revealed progressively increased signal uptake at the union site during fracture repair. In contrast, minimal tracer uptake was seen at the fracture sites in group II at all time points after surgery. Data analysis revealed statistically significant differences in mean signal intensity between groups I and II at each weekly interval. No significant differences between the two groups were seen using (18)F-FDG PET imaging at any time point.This study suggests that (18)F-fluoride PET imaging, which is an indicator of osteoblastic activity in vivo, can identify fracture nonunions at an early time point and may have a role in the assessment of longitudinal fracture healing. PET scans using (18)F-FDG were not helpful in differentiating metabolic activity between successful and delayed bone healing.

The purpose of this study was to calculate internal absorbed dose distribution in mice from preclinical small animal PET imaging procedures with fluorine-18 labeled compounds ({sup 18}FDG, {sup 18}FLT, and fluoride ion). The GATE Monte Carlo software and a realistic, voxel-based mouse phantom that included a subcutaneous tumor were used to perform simulations. Discretized time-activity curves obtained from dynamic in vivo studies with each of the compounds were used to set the activity concentration in the simulations. For {sup 18}FDG, a realistic range of uptake ratios was considered for the heart and tumor. For each simulated time frame, the biodistribution of the radionuclide in the phantom was considered constant, and a sufficient number of decays were simulated to achieve low statistical uncertainty. Absorbed dose, which was scaled to take into account radioactive decay, integration with time, and changes in biological distribution was reported in mGy per MBq of administered activity for several organs and uptake scenarios. The mean absorbed dose ranged from a few mGy/MBq to hundreds of mGy/MBq. Major organs receive an absorbed dose in a range for which biological effects have been reported. The effects on a given investigation are hard to predict; however, investigators should be awaremore » of potential perturbations especially when the studied organ receives high absorbed dose and when longitudinal imaging protocols are considered.« less

In this study, we developed a simple and robust semi-automatic method to measure the right ventricle to left ventricle (RV-to-LV) transit time (TT) in mice using 2-[/sup 18/F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). The accuracy of the method was first evaluated using a 4-D digital dynamic mouse phantom. The RV-to-LV TTs of twenty-nine mouse studies were measured using the new method and compared to those obtained from the conventional ROI-drawing method. The results showed that the new method correctly separated different structures (e.g., RV, lung, and LV) in the PET images and generated corresponding time activity curve (TAC) of each structure. The RV-to-LV TTs obtained from the new method and ROI method were not statistically different (p=0.20; r=0.76). We expect that this fast and robust method is applicable to the pathophysiology of cardiovascular diseases using small animal models such as rats and mice.

A phoswich depth of interaction (DOI) detector composed by two layers of scintillator arrays (LYSO and BGO) has been proposed. To use this design for building practical systems, a tapered multiple-element glass lightguide is necessary to couple the scintillator arrays to a PSPMT. The complete individual detector module offers an overall dimension of 52×52 mm2 that matches the external dimensions of the PSPMT package, allowing continuous positioning of the scintillator arrays for creating flat panel detectors without introducing gaps between detector modules. In this work, we define the elements adjacent to the edge in an array as “edge+” elements. Both of the layers of the phoswich detector and the lightguide have such edge+ elements. The lightguide was modified according to the photodetector geometry, aiming at improving edge and corner crystal identification and energy resolution: In an assembled detector, the optimized edge+ lightguide elements superimpose on top of both edge and edge+ anodes of the PSPMT. In that case, the edge+ lightguide elements distribute light onto both the edge and edge+ anodes, while edge lightguide elements primarily distribute light onto the edge anodes. This different light sharing scheme improves the capability of identifying edge+ crystals from edge crystals. In addition, the edge lightguide elements were enlarged to improve the light collection and corresponding energy resolution for the edge crystals. Flood images were acquired and energy resolution was calculated for individual crystals. All the edge and edge+ crystals were clearly resolved. Energy resolution was improved from 24.4 ± 4.4% to 20.0 ± 1.7% for edge crystals. The new proposed lightguide successfully improved edge crystal identification and energy resolution in the proposed pixelated scintillator detector.

A new phoswich detector is being developed at the Crump Institute, aiming to provide improvements in sensitivity, and spatial resolution for PET. The detector configuration is comprised of two layers of pixelated scintillator crystal arrays, a glass lightguide and a light detector. The annihilation photon entrance (top) layer is a $48\times48$ array of $1.01 \times 1.01 \times7 ~\hbox{mm}^{3}$ LYSO crystals. The bottom layer is a $32 \times 32$ array of $1.55 \times1.55 \times 9~\hbox{mm}^{3}$ BGO crystals. A tapered, multiple-element glass lightguide is used to couple the exit end of the BGO crystal array ( $52 \times 52~\hbox{mm}^{2}$ ) to the photosensitive area of the Position Sensitive Photomultiplier Tube ( $46 \times 46~\hbox{mm}^{2}$ ), allowing the creation of flat panel detectors without gaps between the detector modules. Both simulations and measurements were performed to evaluate the characteristics and benefits of the proposed design. The GATE Monte Carlo simulation indicated that the total fraction of the cross layer crystal scatter (CLCS) events in singles detection mode for this detector geometry is 13.2%. The large majority of these CLCS events (10.1% out of 13.2%) deposit most of their energy in a scintillator layer other than the layer of first interaction. Identification of those CLCS events for rejection or correction may lead to improvements in data quality and imaging performance. Physical measurements with the prototype detector showed that the LYSO, BGO and CLCS events were successfully identified using the delayed charge integration (DCI) technique, with more than 95% of the LYSO and BGO crystal elements clearly resolved. The measured peak-to-valley ratios (PVR) in the flood histograms were 3.5 for LYSO and 2.0 for BGO. For LYSO, the energy resolution ranged from 9.7% to 37.0% full width at half maximum (FWHM), with a mean of $13.4 \pm 4.8\%$ . For BGO the energy resolution ranged from 16.0% to 33.9% FWHM, with a mean of $18.6\pm 3.2\%$ . In conclusion, these results demonstrate that the proposed detector is feasible and can potentially lead to a high spatial resolution, high sensitivity and DOI PET system.

The Optical Positron Emission Tomography (OPET) system will provide the capabilities of bioluminescence and PET modalities in one combined imaging system. Bioluminescence light emitted in vivo has a spectrum ranging from 550–700 nm. The optical photon signals detected are approximately two orders lower in amplitude and one order shorter in duration compared to scintillation light pulses from a 511 keV γ-event. In this study the performance characteristics of the OPET detectors for bioluminescence imaging were evaluated. The detection uniformity was measured for wavelengths between 400–700 nm and normalization maps were used to correct the acquired images. The spatial resolution along the transaxial and axial directions was 2.30 and 2.38 mm FWHM, respectively. The average dark counts for the detector was 76±30 cps at an ambient temperature of 20°.

The X-ray spectrum from a small-animal computed tomography (CT) device directly influences the dose delivered to the animal as well as the image quality. For any given imaging task, the spectrum needs to be optimized. The aim of this study is to present a model of a small animal microCT X-ray source and to calculate practical spectra for different anode and filter combinations by using the Monte Carlo method. The GATE simulation package was used for this work. The X-ray source of the MicroCAT II scanner was modeled as a tungsten enclosure containing the X-ray tube with dielectric oil and a thin carbon exit window. The anode was a tungsten or molybdenum cylinder block tilted with respect to the electron-beam axis. Beam filtration was achieved through a disk of variable thickness and composition positioned at the exit window. Photon detection was performed with a thick (1 cm) cylindrical tungsten plate (20 cm diameter). Simulated spectra were compared with spectra measured with a CdTe detector for three beams: 50, 70 and 80 kVp with 2 mm of aluminum filtration. There was a reasonable agreement between measurements and calculations. Identified features of the measured spectra were: K absorption edges of Cd and Te (from the detector itself) and characteristic X-rays from Te (Kα and Kβ) and possibly Sb (Kα). Discrepancies between simulations and measurements can be attributed to elements that have been left out of simulations, imperfect detector alignment, and uncertainty in elemental composition of simulated materials. The Monte Carlo method is a convenient and fast tool allowing the calculation of spectra possessing the essential features of real spectra. These and other spectra will be used in future work to study the influence of X-ray spectrum on dose and image quality for various X-ray CT system configurations.

The design of a dual modality imaging system for small animal optical and positron emission tomography imaging (OPET) is underway. Its detector must be capable of imaging high energy γ-rays from PET while also resolving optical wavelength photons from bioluminescence. GSO, high purity GSO, BGO, LSO, LYSO, and LaBr scintillators were investigated for their use in the OPET detector. Of specific interest were scintillators with low afterglow, since afterglow photons in the decay of the larger γ-ray events are indistinguishable from the photons generated by bioluminescence. Samples from these crystals were coupled to a photomultiplier tube (PMT) and produced scintillation light from γ-ray events originating from a positron source. The PMT output was directed to a special signal processing circuit that allowed measurement of single photons at different times in the decay of the scintillation. GSO and BGO exhibited optimal performance for use in the OPET system due to their low afterglow. LSO, LYSO, and LaBr were determined unsuitable for use with the current OPET design due to their significant afterglow components. The effect of the afterglow of GSO on the detection of the bioluminescence signal-to-noise ratio (SNR) was evaluated for the OPET system.