Elena Zannoni

Neural stem cells (NSCs) show significant therapeutic potential for targeted delivery of agents to brain tumors due to their intrinsic tropism and ability to cross the blood-brain barrier. However, the lack of a reliable, high-sensitivity method for non-invasive, in vivo NSC monitoring and tracking hinders the development of NSC-based therapies. We present the characterization, optimization and in vivo validation of the CZT-microSPECT system for high-sensitivity tracking of small populations of radiolabeled NSCs. The stationary CZT-microSPECT scanner, based on solid-state detectors and a custom-designed tungsten collimator, has been tested for imaging ultra-low activities of iodine-125 (¹²⁵I; < 2.5 μCi) offering sub-keV energy resolution. Its unique design enables the system to act as 96 concurrent gamma cameras. We investigated the system’s high resolution and high sensitivity through Monte Carlo simulations and a preclinical longitudinal animal study. In the in vivo mouse study, the system successfully detected small clusters of radiolabeled NSCs with ultra-low injected activities (ranging between 0.6 and 2.56 μCi) in as little as 5 minutes imaging time. The system also captured the migration of NSCs from the injection site to distant metastatic locations. This work demonstrates the potential of ultra-low-dose SPECT imaging in developing and optimizing NSC-enabled theranostics of brain tumor.

This study presents an experimental evaluation of the Dynamic Extremity SPECT (DE-SPECT) system, specifically engineered for precise, regionselective gamma-ray spectroscopy in the diagnosis of Peripheral Vascular Disease (PVD) in lower extremities. The system incorporates Cadmium Zinc Telluride (CZT) imaging spectrometers and dynamic dual-field-of-view (FOV) collimators to facilitate comprehensive, multifunctional molecular imaging. The CZT detectors, with Depth of Interaction (DOI) capabilities, deliver an exceptional energy performance across a wide energy range up to 600 keV. The novel dual-FOV aperture system allows selective imaging with two configurations: a 28-cm diameter wide FOV suitable for dual-leg or scout imaging and a 16-cm diameter high-resolution, and high-sensitivity (HR-HS) FOV designed for single-leg or focused imaging. Utilizing uniform phantoms, resolution phantoms, and multi-tracer phantoms, we experimentally assessed the system’s sensitivity, spatial resolution, and multi-tracer imaging capabilities. Spatial resolutions were approximately 6 mm in HR-HS-FOV mode and between 8 mm to 10 mm in wide-FOV mode. Peak-to-Valley ratios, indicative of image clarity, improved with enhanced DOI resolutions, rising from 1.03 to 1.22. The system’s ability to perform multi-tracer imaging, essential for deriving multifunctional molecular information, further highlights its potential to significantly enhance diagnostic accuracy for PVD.

Over the past decade, alpha-emitter radiopharmaceutical therapy (<tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\alpha$</tex>-RPT) has attracted tremendous attention as a powerful cancer treatment approach in both preclinical and clinical applications. Dosimetry is the key to understanding the toxicity and efficacy profiles of αRPTs. Accurate knowledge of the distribution of the parent and daughter radionuclides is essential for precise dosimetry. For conventional radiopharmaceuticals, SPECT imaging provides a means to measure the in vivo biodistribution of radionuclides.

Robotic platforms are increasingly being integrated into medical imaging applications [1]. We propose a gantry-less SPECT imaging platform consisting of a collaborative high-articulated robotic manipulator (KUKA LBR Med 14 R820), a room-temperature semiconductor detector panel (<tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$3 \times 35-\text{mm}$</tex> thick CZT detectors), and a custom multi-pinhole tungsten collimator. The system first acquires a preliminary low-resolution image to determine an optimized trajectory around the object under examination. Then, the robotic manipulator dynamically places the detector panel to acquire projections and reconstruct a high-resolution tomographic image, according to the principle of adaptive imaging [2].

High-resolution radiation detectors are crucial for quantitative imaging in the medical, non-destructive testing, and high-energy physics fields. This study investigates the impact of charge sharing (CS) events in a 55-μm pixelated 2-mm CdTe detector. We then propose an energy-loss correction method to address high-multiplicity CS events, aiming to restore the detector's intrinsic capabilities. Utilizing the MiniPIX TPX3 Flex detector, we observed charge sharing events from Am-241 and Co-57 calibration sources and categorized the recorded events based on their multiplicity and circularity. Non-circular events exhibited energy peaks shifted towards lower energies due to extensive charge loss, impacting the overall spectrum. By emphasizing events with higher multiplicity and with circularity values close to unity, we achieved a more accurate estimation of true energy deposition. Finally, we used charge cloud dynamics to predict the charge propagation behavior. This will enable a more accurate categorization of clusters, and it will allow to obtain an unbiased estimation of the energy spectra, leading to a more robust energy calibration and spectroscopic performance.

We present the DE-SPECT system, a region-selective clinical SPECT system designed for highperformance cardiovascular imaging. The system features six stationary CZT detector panels with dual-FOV collimators that enable rapid switching between a 28 cm wide field-of-view (FOV) and a 16 cm high-resolution, high-sensitivity (HR-HS) FOV. We evaluated DE-SPECT in large animal models of acute and chronic cardiovascular injury. Multi-isotope imaging with Tc-99m-tetrofosmin, I-123-MIBG, Ga-67 Citrate was used to visualize perfusion, sympathetic innervation and inflammation. A joint reconstruction algorithm was applied to combine a wide FOV with high resolution in the targeted region. We further demonstrated 1 -second dynamic imaging of tracer kinetics enabled by the system's high sensitivity and stationary geometry. These results establish the DE-SPECT as a versatile platform for dynamic, high-resolution, and multi-tracer imaging in cardiovascular disease.

Targeted Alpha Therapy (TAT) offers significant therapeutic potential in oncology, leveraging the high linear energy transfer (LET) and short path length of alpha particles to selectively eliminate micro-metastases and single cancer cells while sparing healthy tissue. However, clinical translation is limited by the lack of imaging tools capable of monitoring in vivo biodistribution and dosimetry of alpha-emitting isotopes. To address this gap, we have developed the Alpha-SPECT system—a high-sensitivity, high-resolution whole-body clinical SPECT scanner integrated with advanced CZT imaging spectrometers, specifically designed for simultaneous imaging of therapeutic alpha-emitters (such as Ac-225, Pb-212 and Ra-223) along with their decay daughters (including Fr-221, At-217, Bi-213, and Po-213 from Ac-225) in patients. The system integrates 496 micro-pinhole cameras across 31 detector panels in a cylindrical geometry, each comprising 16 CZT detectors <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$20 \times 20 \times 6 \text{mm}^{3}$</tex> with pixelated anodes and HEXITEC ASICs. A novel dual-FOV configuration is enabled by a precision CT-derived rotating gantry that switches between a large-field-of-view mode and a high-resolution mode. The system achieves sub-10-um gantry accuracy and a de-magnification ratio of 1:11, enhancing spatial resolution and angular sampling. Energy calibration with Ba-133 and Co-57 sources demonstrated average resolutions of 4-6 keV at 122 keV , further improved to 2.5-3 keV with machine learning-based charge-sharing correction. Ongoing geometric calibration and future NEMA-compliant performance evaluations aim to establish the Alpha-SPECT as a robust platform for clinical TAT imaging.

There is a rising interest in Single Photon Emission Computed Tomography (SPECT) imaging systems with improved energy resolution to facilitate multi-functional molecular imaging applications, such as alpha-emitter radiopharmaceutical therapy (α-RPT). In this paper, we report the design and evaluation of the Alpha-SPECT-Mini system that offers an ultrahigh energy resolution and high sensitivity for small animal studies. The Alpha-SPECT-Mini system is constructed based on small-pixel CdTe detectors that offers sub-1keV Full-Width-Half-Maximum (FWHM) energy resolution for single pixel events and an average ~2.5keV energy resolution at 122 keV and ~3.5 keV at 218 keV over 153600 pixels in the system. This allows to easily identify X- and gamma-ray contributions in densely populated spectra, such as from the Ac-225 decay chain. The system uses a 96-loft-hole collimator and six stationary detection panels in a full ring geometry. Finally, the system performance is demonstrated using Tc-99m- and Ac-225-filled resolution and image quality (IQ) phantoms. We have experimentally demonstrated that the Alpha-SPECT-Mini is a high-performance imaging system capable of imaging alpha-emitters in preclinical applications.

This review explores the applications of room temperature semiconductor detectors, with a focus on Cd(Zn)Te based detection systems, in non-destructive testing and evaluation (NDT&E). Cd(Zn)Te detectors, which operate efficiently at ambient temperatures, eliminate the need for cryogenic cooling systems and offer high energy and spatial resolution, making them ideal for a wide range of NDT&E applications. Key performance parameters such as energy resolution, spatial resolution, time resolution, detector efficiency, and form factor are discussed. The paper highlights the utilization of Cd(Zn)Te detectors in various imaging and spectroscopic applications, including nuclear threat detection and non-proliferation, archaeological NDT, and Unmanned Aerial Vehicle radiological surveying. Cd(Zn)Te detectors hold significant promise in NDT&E due to their high-resolution imaging, superior spectroscopic capabilities, versatility, and portability.

This study introduces a novel maximum-likelihood-based data preconditioning method for a 3-D position sensitive cadmium zinc telluride (CZT) detector used in the dynamic extremity-single photon emission computed tomography imaging system, an organ-dedicated Single-Photon Emission computed tomography system optimized for imaging peripheral vascular diseases in lower extremities. The 3-D CZT detectors offer subpixel resolution of ~0.5 mm FWHM in X-Y-Z directions and an ultrahigh energy resolution of 3 keV at 200 keV, 4.5 keV at 450 keV, and 5.4 keV at 511 keV. Given the intrinsic challenges posed by pixel boundary issues, spatial distortions, and nonuniformity inherent in large-volume, high-resolution CZT detectors, we proposed a Maximum-Likelihood-based preconditioning technique to reconstruct the projection, which effectively mitigates the pixel boundary issue and deconvolves the distortions and nonuniformity in detector responses. To facilitate the preconditioning step, we used sheet-beam scanning to measure the distortion map of the CZT detectors. We have evaluated our data preconditioning technique through extensive experimental evaluations, including Tc-99m sheet-beam scanning and image reconstruction of an image quality phantom. These results not only demonstrated the efficacy of the technique in reducing the impact of pixel boundary issues and correcting for spatial distortions. The proposed data preconditioning technique could potentially be applied across various types of imaging sensors.

The Dynamic Extremity SPECT (DE-SPECT) system employs state-of-the-art technology for precise, region-selective gamma-ray spectroscopy using Cadmium Zinc Telluride (CZT) imaging spectrometers and dynamic dual-field-of-view (FOV) collimators. This clinical system is designed to enhance the diagnostic accuracy of Peripheral Vascular Disease (PVD) assessments in the lower extremities by providing comprehensive, multifunctional molecular imaging. The CZT detectors used in the system offer an excellent energy performance (2.6 keV FWHM at 220 keV, 3.3 keV at 440 keV) spanning a wide energy range of up to 600 keV. The uniquely designed dual-FOV aperture system enables region-selective imaging capabilities with two configurations: a 28-cm diameter FOV for dual-leg imaging and a 16-cm diameter FOV for focused, high-resolution, and high-sensitivity imaging. The system’s unmatched capability facilitates in vivo simultaneous multi-tracer theragnostics within user-selected targeted regions. We have fully assembled the system and conducted phantom studies using a series of uniform phantoms, custom-made image quality (IQ) phantoms, and a resolution phantom filled with multiple radiotracers (Tc-99m, I-123, In-111, etc.) to evaluate the imaging performance of the DE-SPECT system.

As one of the important multi-functional molecular imaging applications, the alpha-emitter radiopharmaceutical therapy attracts rising interest due to its great preclinical and clinical success. The Alpha-SPECT-mini system utilizes ultra-high energy resolution CdTe detectors to enable the ability to separate X- and gamma-rays emitted from the Ac-255 decay scheme. In vivo mice imaging studies with labeled Ac-225 injection has been demonstrated using Alpha-SPECT-mini. Energy peaks from Ac-225, Tl-209, Fr-221, Bi-213 can be used for tracing each element’s biological distribution. The Ac-225 washout processing and Bi-213 and Tl-209 accumulation in kidneys are observed during the In vivo mice imaging study.

In this paper, we report the design, development, and initial experimental evaluation of the Alpha-SPECT system, a full-body clinical SPECT scanner equipped with state-of-art CZT imaging spectrometers ideally suited to simultaneous imaging of therapeutic alpha-emitters (e.g., Ac-225, Ra-223, Lu-177, etc.) and their daughters (e.g., Fr.221, At-217, Bi-213, and Po-213 from the decay of Ac-225) in patients. Besides the potential for imaging alpha-labeled radiopharmaceutical therapy (a-RPT), the Alpha-SPECT system is intended to be a general-purpose clinical SPECT scanner for a wide variety of diagnostic and therapeutic applications. The system is equipped with a dual-aperture collimator that is installed on a CT-scanner-derived rotational gantry to allow the real-time switching between the two aperture configurations, as well as micro-swing of aperture in front of the CZT detectors with a sub- 15 mm precision to provide a variable FOV of 20-50 cm diameter and facilitate super-resolution sampling for further improved imagign resolution.

Brain-dedicated imaging systems with high sensitivity and high spatial resolution have become an urgent requirement to facilitate improved understanding of several neurological disorders like Parkinson’s Disease, epilepsy, Alzheimer’s Disease and so on. In this paper, we present the design and preliminary simulation studies of our ultrahigh resolution brain Single Photon Emission Computed Tomography (SPECT) scanner with a hardware-implemented sampling enhancement strategies. The system is designed with 3202 -mm thick cadmium zinc telluride (CZT) detectors, arranged in a cylindrical geometry with dual field of view capability of 20 cm and 5 cm diameter. The whole brain imaging will be performed by coupling the detectors with a 2-mm diameter pinhole collimator, whereas, the microscopic imaging will be facilitated by using a nonconventional micro-ring aperture design with 0.15-mm ring opening. The micro-ring design offers an ultrahigh intrinsic spatial resolution with a reasonably adequate sensitivity. The collimator apertures are designed to be mounted with a precise single linear motor to shift the apertures slightly to improve the non-redundant angular sampling and thereby enhancing the spatial resolution of the system. The preliminary simulation study yields a peak sensitivity of $\sim 0.13 \%$ for larger FOV and $\sim 0.19 \%$ for the smaller FOV using micro-ring apertures.

Abstract Objective . Peripheral Vascular Disease (PVD) affects more than 230 million people worldwide and is one of the leading causes of disability among people over age 60. Nowadays, PVD remains largely underdiagnosed and undertreated, and requires the development of tailored diagnostic approaches. We present the full design of the Dynamic Extremity SPECT (DE-SPECT) system, the first organ-dedicated SPECT system for lower extremity imaging, based on 1 cm thick Cadmium Zinc Telluride (CZT) spectrometers and a dynamic dual field-of-view (FOV) synthetic compound-eye (SCE) collimator. Approach . The proposed DE-SPECT detection system consists of 48 1 cm thick 3D-position-sensitive CZT spectrometers arranged in a partial ring of 59 cm in diameter in a checkerboard pattern. The detection system is coupled with a compact dynamic SCE collimator that allows the user to select between two different FOVs at any time during an imaging study: a wide-FOV (28 cm diameter) configuration for dual-leg or scout imaging or a high-resolution and high-sensitivity (HR-HS) FOV (16 cm diameter) for single-leg or focused imaging. Main results. The preliminary experimental data show that the CZT spectrometer achieves a 3D intrinsic spatial resolution of &lt;0.75 mm FWHM and an excellent energy resolution over a broad energy range (2.6 keV FWHM at 218, 3.3 keV at 440 keV). From simulations, the wide-FOV configuration offers a 0.034% averaged sensitivity at 140 keV and &lt;8 mm spatial resolution, whereas the HR-HS configuration presents a peak central sensitivity of 0.07% at 140 keV and a ∼5 mm spatial resolution. The dynamic SCE collimator enables the capability to perform joint reconstructions that would ensure an overall improvement in imaging performance. Significance . The DE-SPECT system is a stationary and high-performance SPECT system that offers an excellent spectroscopic performance with a unique computer-controlled dual-FOV imaging capability, and a relatively high sensitivity for multi-tracer and multi-functional SPECT imaging of the extremities.

The advent of metal-based drugs and metal nanoparticles as therapeutic agents in anti-tumor treatment has motivated the advancement of X-ray fluorescence computed tomography (XFCT) techniques. An XFCT imaging modality can detect, quantify, and image the biodistribution of metal elements using the X-ray fluorescence signal emitted upon X-ray irradiation. However, the majority of XFCT imaging systems and instrumentation developed so far rely on a single or a small number of detectors. This work introduces the first full-ring benchtop X-ray fluorescence emission tomography (XFET) system equipped with 24 solid-state detectors arranged in a hexagonal geometry and a 96-pinhole compound-eye collimator. We experimentally demonstrate the system's sensitivity and its capability of multi-element detection and quantification by performing imaging studies on an animal-sized phantom. In our preliminary studies, the phantom was irradiated with a pencil beam of X-rays produced using a low-powered polychromatic X-ray source (90kVp and 60W max power). This investigation shows a significant enhancement in the detection limit of gadolinium to as low as 0.1 mg/mL concentration. The results also illustrate the unique capabilities of the XFET system to simultaneously determine the spatial distribution and accurately quantify the concentrations of multiple metal elements.

In this work, we have developed the CdTe detector-based alpha-SPECT-mini system for preclinical studies. The system is designed to have ultrahigh energy resolution <3keV on average and sensitivity to accommodate the low dose of the targeted alpha therapy applications in mice studies. Machine learning charge sharing reconstruction algorithms are used to achieve the best energy resolution and sensitivity simultaneously. We have performed the Derenzo resolution and Image Quality phantom studies with Tc-99m to evaluate the intrinsic resolution <0.75mm and with Ac-225 to evaluate the multi-isotope imaging capabilities (Ac-225, Fr-221, Bi-213, Tl-209) of the system. Soon, we will also perform the in vivo mice imaging study to further evaluate the system performance for low dose imaging and to study the biological reaction of mice to Ac-225 and toxicity effects on surrounding healthy tissues.

The Dynamic Extremity SPECT (DE-SPECT) system is a hyperspectral organ-dedicated SPECT system based on 1-cm thick Cadmium Zinc Telluride (CZT) imaging spectrometers and dynamic dual-field-of-view (FOV) compound-eye collimators. The objective of the project is to develop a non-invasive imaging technique for comprehensive assessment of peripheral vascular disease (PVD) in lower extremities.The DE-SPECT system is a stationary and high-performance SPECT system that offers an excellent energy performance (2.6 keV FWHM at 220 keV, 3.3 keV at 440 keV) over a wide energy range up to 600 keV, an optimized imaging geometry with a numerically-controlled dual-FOV aperture (offering 28-cm diameter FOV for dual-leg imaging and 16-cm diameter FOV for focused high-resolution and high-sensitivity imaging), and a relatively high sensitivity for multi-tracer SPECT imaging in the lower extremities. The system offers an unmatched ability to perform in vivo voxel-by-voxel gamma-ray spectrometry to derive the concentrations of multiple commonly used radiotracers (Tl-201, Tc-99m, I-123, In-111, etc.) and therapeutic radionuclides (Ac-225, Ra-223, and Lu-177, etc.) in user-selected targeted regions. This capability makes it particularly attractive for molecularly-guided interventions.

We present a maximum-likelihood (ML) -based data preconditioning method for a 3-D position sensitive CZT detector used in the DE-SPECT imaging system, a clinical SPECT system dedicated for imaging the peripheral vascular diseases (PVD) in lower extremities. The 3-D CZT detectors offer subpixel resolution of <0.5 mm FWHM in X-Y-Z directions and an ultrahigh energy resolution of 3 keV at 200 keV, 4.5 keV at 450 keV, and 5.4 keV at 511 keV. Due to pixel edge effects and distortion issues, we utilized sheet beam scanning to measure the detector response, and then used an ML-based algorithm to reconstruct the projection, which effectively deconvolve the distortions in detector linear responses. As we showed in the experimental results, this technique produces corrected positions of interactions. Additionally, we anticipate that this approach can be applied to other solid-state and scintillation detectors with known distortion due to imperfections in detectors and electronics. Future work includes phantom studies to evaluate the effect of the data preconditioning approach on experimental SPECT imaging studies.

Optogenetics is a biological technique which aims to modulate the neuronal activities of target cells through activation of light-sensitive proteins. X-ray induced optogenetics is an approach to generate visible light in deep tissues using radioluminescence of scintillating micro-particles through x-ray irradiation. The increase in the penetration depth, reduction in tissue heating, and absence of invasive surgical procedure are the major advantages of x-ray induced optogenetic approach. Previous studies have shown that Ce:GAGG (Ce: Gd<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</inf>Al<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf>Ga<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</inf>O<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">12</inf>) scintillating particles/crystals are biocompatible and non-cytotoxic with one of the brightest light yield which makes them a suitable candidate for X-Optogenetics. In this study, we demonstrate the feasibility of imaging Ce:GAGG micro-scintillating particles in mouse brain and gut region using our full-ring benchtop x-ray fluorescence emission tomography (XFET) system. Our preliminary experimental studies with pulverized Ce:GAGG micro-particles demonstrate an excellent detection limit of 14 mg in a small animal-sized phantom. We would further explore the improvement in signal-to-noise ratio and detection limit for remote optogenetic application by preparing a GEANT4 model of the multi-slit XFET system and simulating for different source configurations and detection angles.