Hybrid gamma camera imaging: translation from bench to bedside

There is increasing interest in the use of small field of view (SFOV) portable gamma cameras in medical imaging. A novel hybrid optical-gamma camera (HGC) has been developed through a collaboration between the Universities of Leicester and Nottingham. This system offers high resolution gamma and optical imaging and shows potential for use at the patient bedside, or in the operating theatre. The aim of this thesis was to translate the HGC technology from in vitro laboratory studies to clinical use in human subjects. Pilot studies were undertaken with the HGC as part of this thesis. Furthermore, efforts have been made to transform the HGC technologies into a new medical device, known as Nebuleye. Initial physical evaluation of the pre-production prototype camera was carried out as part of the device developmental process, highlighting some aspects of the design that require further modification. A complete and rigorous testing scheme to assess the pre-production prototype camera has been developed and successfully implemented. The newly introduced tests enabled the system uniformity, system sensitivity, detector head shielding leakage, optical-gamma image alignment and optical image quality of the hybrid camera to be assessed objectively. This harmonised testing scheme allows characterisation and direct comparison of SFOV gamma cameras. In vitro and in vivo preclinical imaging was undertaken to examine the performance of the SFOV gamma cameras for experimental animal studies. The results of animal study have shown for the first time the feasibility and performance of these SFOV gamma cameras for imaging mice injected with a newly developed 111In labelled hybrid tracer. Further investigations are needed to improve the system resolution and prepare the camera system for combined gamma-near infrared fluorescence imaging in future. A systematic in vitro laboratory assessment method has been established to examine the imaging performance of the SFOV gamma camera in radioguided sentinel lymph node biopsy (SLNB) and radioactive seed localisation procedures for breast cancer surgery. Further preparatory work was undertaken to carry out a pilot clinical trial of the use of the pre-production prototype camera in sentinel node localisation procedures during breast cancer surgery. The clinical study protocol and routine quality control procedures have been established and are suitable for future use. Baseline data on the camera performance assessed using the routine quality control scheme have been obtained. Finally, the capabilities of the SFOV gamma camera were assessed. This has provided baseline data on user feedback and the imaging consequences on operator motion effects, as well as examining the detectability of a range of radionuclides, including 99mTc, 111In, 123I, 125I and 75Se. The first clinical results of the use of the HGC in clinical hybrid optical-gamma imaging in patients administered with 99mTc and 123I labelled radiopharmaceuticals have been reported. This clinical study has demonstrated the feasibility and capability of HGC in various clinical applications performed at the patient bedside, which included patients undergoing bone, thyroid, lacrimal drainage and lymphatic imaging as well as DaTscan studies. In conclusion, the work in this thesis has demonstrated the successful translation of an SFOV hybrid gamma camera for clinical use. This system would be ideally suited for use in the operating theatre for radioguided procedures such as sentinel node detection and tumour localisation. This system also offers potential for use with the new generation of hybrid fluorescent-radionuclide tracers currently under development

Hybrid gamma camera imaging: translation from bench to bedside

There is increasing interest in the use of small field of view (SFOV) portable gamma cameras in medical imaging. A novel hybrid optical-gamma camera (HGC) has been developed through a collaboration between the Universities of Leicester and Nottingham. This system offers high resolution gamma and optical imaging and shows potential for use at the patient bedside, or in the operating theatre. The aim of this thesis was to translate the HGC technology from in vitro laboratory studies to clinical use in human subjects. Pilot studies were undertaken with the HGC as part of this thesis. Furthermore, efforts have been made to transform the HGC technologies into a new medical device, known as Nebuleye. Initial physical evaluation of the pre-production prototype camera was carried out as part of the device developmental process, highlighting some aspects of the design that require further modification. A complete and rigorous testing scheme to assess the pre-production prototype camera has been developed and successfully implemented. The newly introduced tests enabled the system uniformity, system sensitivity, detector head shielding leakage, optical-gamma image alignment and optical image quality of the hybrid camera to be assessed objectively. This harmonised testing scheme allows characterisation and direct comparison of SFOV gamma cameras. In vitro and in vivo preclinical imaging was undertaken to examine the performance of the SFOV gamma cameras for experimental animal studies. The results of animal study have shown for the first time the feasibility and performance of these SFOV gamma cameras for imaging mice injected with a newly developed 111In labelled hybrid tracer. Further investigations are needed to improve the system resolution and prepare the camera system for combined gamma-near infrared fluorescence imaging in future. A systematic in vitro laboratory assessment method has been established to examine the imaging performance of the SFOV gamma camera in radioguided sentinel lymph node biopsy (SLNB) and radioactive seed localisation procedures for breast cancer surgery. Further preparatory work was undertaken to carry out a pilot clinical trial of the use of the pre-production prototype camera in sentinel node localisation procedures during breast cancer surgery. The clinical study protocol and routine quality control procedures have been established and are suitable for future use. Baseline data on the camera performance assessed using the routine quality control scheme have been obtained. Finally, the capabilities of the SFOV gamma camera were assessed. This has provided baseline data on user feedback and the imaging consequences on operator motion effects, as well as examining the detectability of a range of radionuclides, including 99mTc, 111In, 123I, 125I and 75Se. The first clinical results of the use of the HGC in clinical hybrid optical-gamma imaging in patients administered with 99mTc and 123I labelled radiopharmaceuticals have been reported. This clinical study has demonstrated the feasibility and capability of HGC in various clinical applications performed at the patient bedside, which included patients undergoing bone, thyroid, lacrimal drainage and lymphatic imaging as well as DaTscan studies. In conclusion, the work in this thesis has demonstrated the successful translation of an SFOV hybrid gamma camera for clinical use. This system would be ideally suited for use in the operating theatre for radioguided procedures such as sentinel node detection and tumour localisation. This system also offers potential for use with the new generation of hybrid fluorescent-radionuclide tracers currently under development

The application of the capacitive division technique to wide-field time-resolved fluorescence microscopy

Capacitive division and other charge-sharing techniques have become ubiquitous within modern technology. Almost all touchscreen devices depend on some form of charge sharing mechanism. The Capacitive-Division Imaging Readout, C-DIR, scheme developed for space/astronomy applications, is a proven concept which has benefited from widespread publication and several iterations of prototyping. In this study, we borrowed this idea and assessed its application in the field of life sciences, specifically, fluorescence lifetime imaging microscopy (FLIM). Firstly, the composite C-DIR camera system was developed using a prototype anode developed by Lapington et al in combination with advanced photomultiplier tube technology developed by Photek Limited, and ultra-fast NINO ASIC and high performance time-to-digital converter, HPTDC, readout electronics developed by CERN. Several issues like signal noise, timing jitter and image distortion required special attention to successfully tune the C-DIR system for obtaining FLIM measurements. The C-DIR was characterized in the context of current detector technologies used for time-resolved applications. The maximum achievable global event rate was determined to be a USB 2.0 hard limit of about 1MHz. The spatial resolution and timing performance were identified as 0.5 line-pairs/mm and 200ps FWHM, respectively, which was comparable to other wide-field fluorescence lifetime cameras. These results provided the basis for using the system in a real situation. Before this was possible, however, it was necessary to engineer a bespoke software platform for data acquisition which could cope with the data rates and reduce raw data emerging from the C-DIR system, producing a format compatible with widely used fitting software. The final stage of the project involved using the C-DIR for real science by reproducing real world experiments which allow for a fitness test of the system in the field. The first experiment involved a calcium calibration where the C-DIR system was calibrated using FLIM on a series of calcium buffers of known concentrations. This C-DIR was able accurately recover the lifetime values from the calcium buffers. The second shorter experiment involved using the calibrated system for the quantification of calcium within living tissue samples using fluorescence lifetime imaging. Results were consistent with those published in the literature which solidified the position of the C-DIR as a viable option for time-resolved fluorescence microscopy

Optimization of the Parameters of the YAP-(S)PETII Scanner for SPECT Acquisition

Abstract Single Photon Emission Computed Tomography (SPECT) could be considered as a milestone in terms of biomedical imaging technique, which visualizes Functional processes in-vivo, based on the emission of gamma rays produced within the body. The most distinctive feature of SPECT from other imaging modalities is that it is based on the tracer principle, discovered by George Charles de Hevesy in the first decade of the twentieth century. As known by everyone, the metabolism of an organism is composed of atoms within a molecule which can be replaced by one of its radioactive isotopes. By using this principle, we are able to follow and detect pathways of the photons which are emitted from the radioactive element inside the metabolism. SPECT produces images by using a gamma camera which consists of two major functional components, the collimator and the radiation detector. The collimator is a thick sheet of a heavy metal like lead, tungsten of gold with densely packed small holes and is put just in front of the photon detector. The radiation detector converts the gamma rays into scintillation light photons. In conventional SPECT, scanners utilize a parallel hole collimator. Defining a small solid angle, each collimator hole is located somewhere along this line and the photons might reach the detector by passing through these holes. Subsequently, we can create projection images of the radioisotope distribution. The quantity of photons which come to the radiation detector through the collimator holes specifies the image quality regarding signal to noise ratio. One of the crucial parts of all SPECT scanners is the collimator design. The main part of this dissertation is to investigate performance characteristics of YAP-(S)PETII scanner collimator and to obtain collimator characteristics curves for optimization purposes. Before starting the collimator performance investigation of YAP-(S)PETII scanner, we first performed simulation of it in SPECT mode with point source Tc-99m to measure collimator and system efficiency by using GATE–the Geant4 Application for Emission Tomography. GATE is an advanced, flexible, precise, opensource Monte Carlo toolkit developed by the international OpenGATE collaboration and dedicated to the numerical simulations in medical imaging. We obtained the results of collimator and system efficiency in terms of collimator length, radius and septa by using GATE_v4. Then, we compared our results with analytical formulation of efficiency and resolution. For those simulation experiments, we found that the difference between the simulated and the analytical results with regard to approximated geometrical collimator efficiency formulation of H. Anger, is within 20%. Then, we wrote a new ASCII sorter algorithm, which reads ASCII output of GATE_v4 and then creates a sinogram and reconstructs it to see the final simulation results. At the beginning, we used the analytical reconstruction method, filtered back projection (FBP), but this method produces severely blurred images. To solve this problem and increase our image quality, we tried different mathematical filters, like ramp, sheep-logan, low-pass cosine filters. After all of those studies mentioned above, we learned that GATE_v4 is not practical to measure collimator efficiency and resolution. On the other hand, the results of GATE_v4 did not show directly septal penetrated photon ratio. Under the light of these findings, we decided to develop a new user-friendly ray tracing program for optimization of low energy general purpose (LEGP) parallelhole collimators. In addition, we tried to evaluate the image quality and quantify the impact of high-energy contamination for I-123 isotope imaging. Due to its promising chemical characteristics, Iodine-123 is increasingly used in SPECT studies. 159 keV photons are used for imaging, however, high-energy photons result in an error in the projection data primarily by penetration of the collimator and scattering inside the crystal with energy close to the photons used for imaging. One of the way to minimize this effect is using a double energy window (DEW) method, because, it decreases noise in main (sensitive) energy window. By using this method, we tried to determine the difference between simulated and experimental projection results and scattered photon ratio (Sk) value of YAP-(S)PETII scanner for I-123 measurements. The main drawback of GATE simulations is that they are CPU-intensive. In this dissertation to handle this problem, we did the feasibility study of the Fully Monte Carlo based implementation of the system matrix derivation of YAP-(S)PETII scanner by using XtreemOS platform. To manage lifecycle of the simulation on the top XtreemOS, we developed a set of scripts. The main purpose of our study is to integrate a distributed platform like XtreemOS to reduce the overall simulation completion time and increase the feasibility of SPECT simulations in a research environment and establish an accurate and fast method for deriving the system matrix of the YAP-(S)PETII scanner by using Monte Carlo simulation approach. We developed also the ML-EM Algorithm to the reconstruct our GATE simulation results and to derive the system matrix directly from GATE output. In addition to the accuracy consideration, we intend to develop a flexible matrix derivation method and GATE output reconstruction tool

PLANETCAM-UPV/EHU: A dual channel lucky imaging camera for solar system studies. Performance, Calibration and Scientific applications.

200 p.PlanetCam-UPV/EHU es una cámara astronómica `lucky imaging¿ diseñada para la obtención de imágenes de alta resolución de objetos del Sistema Solar, principalmente como apoyo a la investigación científica en dinámica atmosférica y estudios de estructura vertical de nubes en las atmósferas planetarias. El instrumento trabaja simultáneamente en dos canales, cada uno con su propio detector y filtros del interés en el rango Visible (0.38 - 1 ¿m) e infrarrojo cercano SWIR (1 - 1.7 ¿m). El instrumento contiene varios filtros seleccionados para imágenes de color y una amplia serie de filtros correspondientes a las bandas de absorción de metano y CO2, así como sus longitudes de onda adyacentes, todos ellos seleccionados por su interés en los estudios planetarios. El objetivo principal dentro del alcance de esta tesis ha sido caracterizar el funcionamiento radiométrico y astronómico de PlanetCam, así como su calibración en reflectividad absoluta, proporcionando valores de la reflectividad absoluta de Júpiter y de Saturno a lo largo de cuatro años de observación. Por otra parte, se ha realizado una serie de estudios científicos de los principales planetas del Sistema Solar en términos de dinámica atmosférica así como un modelo de transferencia radiativa para el análisis de la estructura vertical de la atmósfera de Júpiter

PLANETCAM-UPV/EHU: A dual channel lucky imaging camera for solar system studies. Performance, Calibration and Scientific applications.

200 p.PlanetCam-UPV/EHU es una cámara astronómica `lucky imaging¿ diseñada para la obtención de imágenes de alta resolución de objetos del Sistema Solar, principalmente como apoyo a la investigación científica en dinámica atmosférica y estudios de estructura vertical de nubes en las atmósferas planetarias. El instrumento trabaja simultáneamente en dos canales, cada uno con su propio detector y filtros del interés en el rango Visible (0.38 - 1 ¿m) e infrarrojo cercano SWIR (1 - 1.7 ¿m). El instrumento contiene varios filtros seleccionados para imágenes de color y una amplia serie de filtros correspondientes a las bandas de absorción de metano y CO2, así como sus longitudes de onda adyacentes, todos ellos seleccionados por su interés en los estudios planetarios. El objetivo principal dentro del alcance de esta tesis ha sido caracterizar el funcionamiento radiométrico y astronómico de PlanetCam, así como su calibración en reflectividad absoluta, proporcionando valores de la reflectividad absoluta de Júpiter y de Saturno a lo largo de cuatro años de observación. Por otra parte, se ha realizado una serie de estudios científicos de los principales planetas del Sistema Solar en términos de dinámica atmosférica así como un modelo de transferencia radiativa para el análisis de la estructura vertical de la atmósfera de Júpiter

Wide-Field InfrarRed Survey Telescope-Astrophysics Focused Telescope Assets WFIRST-AFTA 2015 Report

This report describes the 2014 study by the Science Definition Team (SDT) of the Wide-Field Infrared Survey Telescope (WFIRST) mission. It is a space observatory that will address the most compelling scientific problems in dark energy, exoplanets and general astrophysics using a 2.4-m telescope with a wide-field infrared instrument and an optical coronagraph. The Astro2010 Decadal Survey recommended a Wide Field Infrared Survey Telescope as its top priority for a new large space mission. As conceived by the decadal survey, WFIRST would carry out a dark energy science program, a microlensing program to determine the demographics of exoplanets, and a general observing program utilizing its ultra wide field. In October 2012, NASA chartered a Science Definition Team (SDT) to produce, in collaboration with the WFIRST Study Office at GSFC and the Program Office at JPL, a Design Reference Mission (DRM) for an implementation of WFIRST using one of the 2.4-m, Hubble-quality telescope assemblies recently made available to NASA. This DRM builds on the work of the earlier WFIRST SDT, reported by Green et al. (2012) and the previous WFIRST-2.4 DRM, reported by Spergel et. (2013). The 2.4-m primary mirror enables a mission with greater sensitivity and higher angular resolution than the 1.3-m and 1.1-m designs considered previously, increasing both the science return of the primary surveys and the capabilities of WFIRST as a Guest Observer facility. The addition of an on-axis coronagraphic instrument to the baseline design enables imaging and spectroscopic studies of planets around nearby stars.Comment: This report describes the 2014 study by the Science Definition Team of the Wide-Field Infrared Survey Telescope mission. 319 pages; corrected a misspelled name in the authors list and a typo in the abstrac

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex

Desenvolvimento de câmaras gama de alta resolução baseadas em foto-sensores de silício

Doutoramento em Engenharia FísicaThe development of a compact gamma camera with high spatial resolution is of great interest in Nuclear Medicine as a means to increase the sensitivity of scintigraphy exams and thus allow the early detection of small tumours. Following the introduction of the wavelength-shifting fibre (WSF) gamma camera by Soares et al. and evolution of photodiodes into highly sensitive silicon photomultipliers (SiPMs), this thesis explores the development of a WSF gamma camera using SiPMs to obtain the position information of scintillation events in a continuous CsI(Na) crystal. The design is highly flexible, allowing the coverage of different areas and the development of compact cameras, with very small dead areas at the edges. After initial studies which confirmed the feasibility of applying SiPMs, a prototype with 5 5 cm2 was assembled and tested at room temperature, in an active field-of-view of 10 10 mm2. Calibration and characterisation of intrinsic properties of this prototype were done using 57Co, while extrinsic measurements were performed using a high-resolution parallel-hole collimator and 99mTc. In addition, a small mouse injected with a radiopharmaceutical was imaged with the developed prototype. Results confirm the great potential of SiPMs when applied in a WSF gamma camera, achieving spatial resolution performance superior to the traditional Anger camera. Furthermore, performance can be improved by an optimisation of experimental conditions, in order to minimise and control the undesirable effects of thermal noise and non-uniformity of response of multiple SiPMs. The development and partial characterisation of a larger SiPM WSF gamma camera with 10 10 cm2 for clinical application are also presented.O desenvolvimento de uma câmara gama compacta com alta resolução espacial é de grande interesse em Medicina Nuclear, como meio de aumentar a sensibilidade dos exames de cintigrafia e assim permitir a deteção precoce de pequenos tumores. Na sequência da introdução da câmara gama com fibras óticas por Soares et al. e da evolução dos fotodiodos para fotomultiplicadores de silício (SiPMs) altamente sensíveis, esta tese explora o desenvolvimento de uma câmara gama com fibras óticas usando SiPMs para obter a informação da posição dos eventos de cintilação num cristal de CsI(Na) contínuo. O design é altamente flexível permitindo cobrir diferentes áreas e desenvolver câmaras compactas, com muito pouca área morta na periferia. Após testes iniciais que confirmaram a viabilidade da aplicação dos SiPMs, um protótipo com 5 5 cm2 foi montado e testado à temperatura ambiente, num campo de visão ativo de 10 10 mm2. A calibração e caracterização de propriedades intrínsecas deste protótipo foram efetuadas utilizando 57Co, enquanto que medições extrínsecas foram realizadas com um colimador de buracos paralelos de alta resolução e 99mTc. Adicionalmente, o protótipo desenvolvido foi usado para produzir a imagem de um ratinho injetado com um radiofármaco. Os resultados confirmam o grande potencial dos SiPMs quando aplicados numa câmara gama com fibras óticas, atingindo uma performance em resolução espacial superior à da câmara Anger tradicional. Além disso, a performance pode ser melhorada por uma otimização das condições experimentais, no sentido de minimizar e controlar os efeitos indesejáveis do ruído térmico e da não-uniformidade de resposta de múltiplos SiPMs. O desenvolvimento e caracterização parcial de uma câmara com 10 10 cm2 para aplicação clínica são também apresentados