Frequency domain functional near infrared spectroscopy (FD-fNIRS) is a tissue optical measurement technique used to measure absolute haemoglobin concentrations in brain tissue. This work is intended to be the first step in the development of a wearable, low-cost FD-fNIRS device for neurofeedback applications. The system requirements were generated from a review of relevant literature. A simplified system architecturewas developed based on the various instrumentation methodologies proposed by various authors. The functional blocks of this system were prototyped and their performance was evaluated. The developed vertical-cavity surface-emitting laser (VCSEL) current source was found to have a span of 10uA which meets the design specifications. Challenges exist in optimally biasing silicon photomultiplier (SiPM), which is susceptible to optical and electronic noise sources.

Silicon photon multipliers, or SiPMs, are single photon detectors that have grown increasing interest in the last decade as an alternative to photomultiplier tubes in many field of physics, engineering and medicine. Compared to PMTs, SiPMs are more compact, rugged and operate at much lower bias voltage, in the order of tens of volts. Moreover they are insensitive to magnetic field and can achieve a very high radiopurity SiPM detectors work on the principle of a diode operated above the breakdown voltage, in Geiger mode. In this condition, the electric field in the depletion region is high enough that the electron-hole pairs, generated by a single photon absorption through photoelectric effect, create secondary charges by impact ionization in a potentially diverging avalanche effect that can be exploited to generate a macroscopical current at the output of the diode. Thanks to this effect, the SiPM is capable of counting the number of impinging photons down to single photon level. Noise sources in the SiPM include dark counts and correlated noise. Dark counts are counts happening when an electron-hole pair is generated in the active volume of the device in absence of photon absorptions. These events are caused either by thermal generation, diffusion from the neutral region or by tunnel effect. Correlated noise events, or counts, on the other hand, are generated when a primary firing cell retriggers after a certain time or cause the triggering of another cell. All these noise sources introduce errors in the photon count by adding fake events to the output signal of the detector.Traditional SiPM application is 511 keV gamma-ray detection in PET machines, using scintillator LYSO crystals to convert a single gamma ray into a flash of visible photons. An application based on the same principle was studied in this thesis by coupling FBK RGB-HD SiPMs with CsI:Tl crystals in order to detect lower energy X and gamma-rays. This setup has proven to be effective in the detection of radiation with energy as low as 5.9 keV with a resolution of 38.3%, which is the minimum value of energy resolution measured with SiPMs coupled to scintillator crystals at such low energy. At the same time it was observed that large area detectors provided a dynamic range wide enough to simultaneously detect radiation ranging from 6.4 keV to 122 keV with minimal saturation. In another activity of this thesis it was developed a simulation software that reproduces the behaviour of a SiPM under different light conditions by taking into account the detector efficiency, the dead time and the recharge behaviour of its cells and theoretical modelizations of the noise parameters that affect the measurement. From a given light profile the simulation generates a waveform that reproduces the one measured during the operation of real SiPMs. This waveform was then analysed using FBK software developed for SiPM characterization and the results showed an excellent agreement between the simulated detector and a reference SiPM. This software will become a useful tool for the design of SiPMs for future experiments because it will allow to tune the properties of the detectors to specific applications and it will reduce the need of layout and process split to find the optimal configuration of the detector parameters.Among all FBK technologies, this work was focused on the position-sensitive LG-SiPM. Unlike standard SiPMs, which have a single output, the LG-SiPM employs a more complex structure that splits the current signal into four output channels with ratios depending on the position of the impinging light on its surface. Center of mass calculations are used to reconstruct the position of the firing cell with precision down to some tens of microns while maintaining the fast time response of SiPMs. An application of the LG-SiPM was studied in the framework of the ARIADNE experiment in collaboration with the university of Liverpool. In this work the LG-SiPM was used to detect scintillation light coming from ionization tracks generated by alpha particles inside a CF4 TPC chamber. The ionized electrons where drifted through the action of a high electric field in the TPC towards a THGEM where they created light with timing depending on the distance of each track segment from the scintillator. The LG detector was able to reconstruct the 3D track particle inside the chamber with an error below 8 mm RMS inside the 40 l chamber and, at the same time, to reconstruct the energy released by the particle as function of time and calculate the total energy of the interacting particle and its linear energy transfer. These results open a novel approach for the TPC position reconstruction that combines the low number of readout channels needed for the LG detector to its time-continuous response which allows to reconstruct the tree-dimensional track of a particle inside the chamber.During the experiment it emerged the presence of an artifact that drifted all the reconstructed tracks towards the centre of the detection area, at the end of the signal. This effect was studied by creating a second simulation software that recreates the electrical behaviour of the LG-SiPM equivalent circuit when one or more cells trigger. It was simulated the output of the circuit with different light conditions and different values of the circuit elements and it was observed that the presence of the artifact was related to low intensity currents flowing through the net of the LG-SiPM metal tracks and quenching resistors. Several simulations were run in order to identify the optimal configuration of parameters for the reduction of this unwanted effect and to implement improvements in future LG-SiPM productions.Another application of the LG-SiPM in the field of radiation detection is the position reconstruction of the scintillation light emitted by gamma-rays in a monolithic crystal. Using a thin CsI:Tl crystal and lowering the detector temperature it was possible to distinguish different positions of interaction on the surface of the detector with an error below 1 mm FWHM. This technology can be effective for the creation of monolithic, position sensitive X and gamma-ray detector with good energy resolution for low energy spectroscopy or medical imaging devices.

Current state-of-the-art environmental, clinical, and in-vivo radiation sensing systems utilizing various inorganic and tissue-equivalent plastic scintillators are not user friendly, suffer from electron-beam-generated noise, and are difficult to deploy successfully for real-time dosimetry. A robust, real-time detection system using different scintillating materials coupled to solid-state detectors by optical fibers is developed. This system enables radiation monitors/clinicians to conduct meaningful real-time measurements using different inorganic scintillators or organic, tissue-equivalent plastic scintillators in harsh clinical and environmental environments. Recent solid state photomultiplier (SSPM) technology has matured, reaching a performance level that is suitable for replacement of the ubiquitous photomultiplier tube in selected applications for environmental radiation monitoring, clinical dosimetry, and medical imaging purposes. The objective of this work is laboratory and clinical testing of the Hamamatsu MPPC (S10362-11-050C), Photonique SSPM (0810G1), and Voxtel SiPM (SQBF-EKAA/SQBF-EIOA) SSPMs coupled to different inorganic scintillator crystals (Prelude 420, BGO), inorganic doped glass scintillator material SiO₂: Cu²⁺, and organic BCF-12 plastic scintillating fibers, used as detector elements. Both polymer optical fibers (POFs) and glass optical fibers (GOFs) are used as signal conduits for laboratory and clinical testing. Further, reduction of electron-beam-generated Cerenkov light in optical fibers is facilitated by the inclusion of metalized air-core capillary tubing between the BCF-12 plastic scintillating fiber and the POF. Dose linearity, percent depth dose, and angular measurements for 6 MV/18 MV photon beams and 9 MeV electron beams are compared using the Hamamatsu MPPC with-and without the use of the metalized air-core capillary tubing for BCF-12 plastic scintillating fiber. These same measurements are repeated for SiO₂: Cu²⁺ scintillator material without air-core capillary tubing. / Graduation date: 2012

L’exérèse des tumeurs cancéreuses est une procédure courante pour le traitement de nombreux cancers. L’enjeu est de réaliser une excision la plus complète possible pour éviter les récidives tout en épargnant le plus possible les tissus sains bordant la tumeur. La détection de positons est une modalité d’imagerie particulièrement adaptée au repérage de résidus tumoraux lors de l'éxerèse car sa forte sélectivité spatiale permet de s'affranchir du bruit provenant de la fixation non spécifique du radiotraceur dans les tissus situés en profondeur, offrant ainsi une meilleur sensibilité et un meilleur rapport signal sur bruit que la détection de photons gamma. L’utilisation pour le contrôle d’exérèse impose cependant une contrainte forte sur les dimensions du détecteur qui doit être manipulable facilement par le chirurgien et pouvoir être inséré dans des plaies opératoires potentiellement étroites. Une nouvelle génération de photodétecteurs appelés photomultiplicateurs silicium (SiPM) est particulièrement adaptée à cette application car ceux-ci allient la compacité et la robustesse des technologies silicium avec d'excellentes performances de détection. Mon travail de thèse porte sur le développement et la caractérisation de nouvelles sondes positon basées sur ces photodétecteurs. Dans un premier temps, un travail de caractérisation des SiPMs a été réalisé pour évaluer leurs performances pour la détection de positons. Deux prototypes de prototypes de détecteurs aux rôles complémentaires ont ensuite été réalisé: le premier est un imageur, basé sur l’assemblage de deux scintillateurs avec une ou deux matrices de SiPMs, qui permet de réaliser rapidement l'image de la distribution de traceur sur une large surface de tissus. Le second détecteur est une sonde de comptage, constituée de fibres scintillantes couplées à des SiPMs individuels via des fibres claires et capable d'être couplée à l'outil d'exérèse. Elle permet de guider l'outil du chirurgien vers les tissus repérés préalablement avec l'imageur. La caractérisation de l’imageur a montré sa capacité à détecter des résidus tumoraux de petite taille (15mg) avec une résolution submillimétrique. La sonde de comptage présente quant à elle, une efficacité de détection de 80%. / Excision of cancerous tumors is a common procedure for the treatment of numerous cancers. The stake is to perform the most complete excision to prevent recurrences while preserving as much as possible surrounding healthy tissues. Positron detection is a well suited imaging modality for detection of tumor remains during excision because its strong spatial selectivity makes it insensitive to the noise coming from the non-specific accumulation of the radiotracer in healthy tissues located far from the detector, leading to a better sensitivity and a better signal-to-noise ratio than gamma photon detection. Its use for the control of excision implies however strong constraints on detector dimensions which must be easy to handle by the surgeon and easy to insert in tight surgical wound. A new generation of photodetectors called Silicon Photmultipliers (SiPMs) is particularly suited for this application because they present the compactness and robustness of silicon technologies and very good detection performances. My thesis aims to develop and characterize a new generation of new positron probes based on these photodetectors. Two prototypes of detectors with complementary roles were realized: the first one is an imaging device based on the assembly of two scintillators with one or two SiPMs arrays which allows to quickly make an image of tracer distribution along a wide surface of tissues. The second detector is a counting probe made of scintillating fibers associated with individual SiPMs through clear optical fibers and can be associated to the excision tool. It guides the surgeon tool to the tissues previously localized with the imaging probe. Characterization of the imaging probe showed its ability to detect small tumor remains (15mg) with a submillimetric resolution. The counting probe showed a detection efficiency of 80%.

MicroRNAs are a class of small non-coding RNAs involved in post-transcriptional regulation. Their role in almost all processes of the cell, make microRNAs ubiquitary players of cell development, growth, differentiation, cell to cell communication and cell death. Thus, cells’ physiological or pathological conditions are reflected by variations in the levels of expression of microRNAs, enabling them to be used as biomarkers of such states. In the past decade, there has been an exponential increase of studies using microRNAs as potential biomarkers for cancer, neurodegenerative diseases, inflammation and cardiac diseases, from tissues and liquid biopsies. However, none of them has reached the clinics yet, due to inconsistency of results through the literature and lack of assay standardization and reproducibility. Technological limitations of microRNAs detection have been, to date, the biggest challenge for using these molecules in clinical settings. In fact, although microarrays, RT-qPCR and RNA-seq are well-established technologies, they all require complex procedures and trained personnel, for performing RNA extraction, labelling of the target and PCR amplification. All these steps introduce variability and, in addition, since no universally standardized protocol – from sample extraction to analyte detection - has been produced yet, methodological procedures are difficult to reproduce. For this reason, we developed a new platform for the rapid detection of microRNAs in biofluids composed of an innovative silicon-photomultiplier (SiPM) based detector and a new chemistry for nucleic acid testing (Chem-NAT). Chem-NAT exploits a dynamic labelling chemistry which allows the sensitive detection of nucleic acids till single base level. On the other hand, SiPM-based device, compared to normal vacuum photomultipliers, grants miniaturization and higher capacity of fitting in a bench-top solution for clinical settings, among other advantages. The new platform – ODG – has been validated for the direct detection – neither RNA extraction nor PCR amplification needed - of microRNA-21 in plasma of lung cancer patients. In this work, we also explored the use of microRNAs as biomarkers in metastatic castration resistant prostate cancer (mCRPC). We collected plasma samples from mCRPC patients before and after abiraterone acetate treatment – androgen deprivation type of drug – and performed a miRnome analysis for discovering microRNAs predicting the efficacy of the drug. We chose miR-103a-3p and miR-378a-5p and we validated them via TaqMan RT-qPCR. We discovered that the ratio between the two microRNAs is able to predict the efficacy of abiraterone acetate and follow the responsiveness in time. In liquid biopsies, extracellular vesicles are getting increasing importance for diagnostic and prognostic purposes. Therefore, in this work we also explored the expression of some microRNAs in extracellular vesicles from plasma, isolated via nickel-based method. We discovered that microRNA-21 and microRNA-223 are not enriched in vesicles from healthy individuals.