L'inclusione lavorativa tra accesso e partecipazione

La Convenzione delle Nazioni Unite sui Diritti delle Persone con Disabilità (UNCRPD) riconosce il diritto di tutte le persone al lavoro “gli Stati Parti adottano misure adeguate a garantire alle persone con disabilità, su base di uguaglianza con gli altri, l’accesso all’ambiente fisico, ai trasporti, all’informazione e alla comunicazione, compresi i sistemi e le tecnologie di informazione e comunicazione e ad altre attrezzature e servizi aperti o forniti al pubblico”(United Nation 2016 p.14). Nonostante i progressi (in ambito politico culturale) che si stanno compiendo in ambito internazionale in termini di pari opportunità e di inclusione, le persone in situazione di disabilità continuano a incontrare barriere che limitano la loro partecipazione attiva al mondo del lavoro. A partire da questo scenario, la ricerca si propone di indagare i bisogni (es. di accoglienza, di accesso al contesto fisico e digitale, di partecipazione nella vita dell’azienda ecc.) delle persone con disabilità e di sviluppare una applicazione digitale (web app), rivolta alle imprese, finalizzata a monitorare e a promuovere l'inclusione lavorativa. Ripercorrendo il modello di progettazione del design thinking e valorizzando un processo di ricerca basato su metodi misti (qualitativi e qualitativi) è stato ideato Job inclusion for all; un ambiente digitale fondato sull’adattamento di due strumenti di “metariflessione”: l’Index for inclusion job version e l’employment role mapping. Lo strumento digitale prototipato è stato testato e validato, durante l’ultimo anno di ricerca, da parte di una equipe multidisciplinare internazionale; tale processo ha consentito di raccogliere feedback (rispetto alla rilevanza e alla chiarezza degli item, rispetto ai punti di forza e di debolezza) che hanno consentito di migliorare e implementare la versione finale del prototipo di web app.

Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease

In this thesis is described the design and synthesis of potential agents for the treatment of the multifactorial Alzheimer’s disease (AD). Our multi-target approach was to consider cannabinoid system involved in AD, together with classic targets. In the first project, designed modifications were performed on lead molecule in order to increase potency and obtain balanced activities on fatty acid amide hydrolase and cholinesterases. A small library of compounds was synthesized and biological results showed increased inhibitory activity (nanomolar range) related to selected target. The second project was focused on the benzofuran framework, a privileged structure being a common moiety found in many biologically active natural products and therapeutics. Hybrid molecules were designed and synthesized, focusing on the inhibition of cholinesterases, Aβ aggregation, FAAH and on the interaction with CB receptors. Preliminary results showed that several compounds are potent CB ligands, in particular the high affinity for CB2 receptors, could open new opportunities to modulate neuroinflammation. The third and the fourth project were carried out at the IMS, Aberdeen, under the supervision of Prof. Matteo Zanda. The role of the cannabinoid system in the brain is still largely unexplored and the relationship between the CB1 receptors functional modification, density and distribution and the onset of a pathological state is not well understood. For this reasons, Rimonabant analogues suitable as radioligands were synthesized. The latter, through PET, could provide reliable measurements of density and distribution of CB1 receptors in the brain. In the fifth project, in collaboration with CHyM of York, the goal was to develop arginine analogues that are target specific due to their exclusively location into NOS enzymes and could work as MRI contrasting agents. Synthesized analogues could be suitable substrate for the transfer of polarization by p-H2 molecules through SABRE technique transforming MRI a more sensitive and faster technique.

System innovation and life cycle thinking in packaging value chain: the circularity of plastics.

Compared to other, plastic materials have registered a strong acceleration in production and consumption during the last years. Despite the existence of waste management systems, plastic_based materials are still a pervasive presence in the environment, with negative consequences on marine ecosystem and human health. The recycling is still challenging due to the growing complexity of product design, the so-called overpackaging, the insufficient and inadequate recycling infrastructure, the weak market of recycled plastics and the high cost of waste treatment and disposal. The Circular economy package, the European Strategy for plastics in a circular economy and the recent European Green Deal include very ambitious programmes to rethink the entire plastic value chain. As regards packaging, all plastic packaging will have to be 100% recyclable (or reusable) and 55% recycled by 2030. Regions are consequently called upon to set up a robust plan able to fit the European objectives. It takes on greater importance in Emilia Romagna where the Packaging valley is located. This thesis supports the definition of a strategy aimed to establish an after-use plastics economy in the region. The PhD work has set the basis and the instruments to establish the so-called Circularity Strategy with the aim to turn about 92.000t of plastic waste into profitable secondary resources. System innovation, life cycle thinking and participative backcasting method have allowed to deeply analyse the current system, orientate the problem and explore sustainable solutions through a broad stakeholder participation. A material flow analysis, accompanied by a barrier analysis, has supported the identification of the gaps between the present situation and the 2030 scenario. Eco-design for and from recycling (and a mass _based recycling rate (based on the effective amount of plastic wastes turned into secondary plastics), valorized by a value_based indicator, are the key-points of the action plan.

Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis

In Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia. Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2. Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy.

New Synthetic Polyamines as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease and Cancer: Design, Synthesis and Biological Evaluation

Alzheimer's disease (AD) and cancer represent two of the main causes of death worldwide. They are complex multifactorial diseases and several biochemical targets have been recognized to play a fundamental role in their development. Basing on their complex nature, a promising therapeutical approach could be represented by the so-called "Multi-Target-Directed Ligand" approach. This new strategy is based on the assumption that a single molecule could hit several targets responsible for the onset and/or progression of the pathology. In particular in AD, most currently prescribed drugs aim to increase the level of acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase (AChE). However, clinical experience shows that AChE inhibition is a palliative treatment, and the simple modulation of a single target does not address AD aetiology. Research into newer and more potent anti-AD agents is thus focused on compounds whose properties go beyond AChE inhibition (such as inhibition of the enzyme β-secretase and inhibition of the aggregation of beta-amyloid). Therefore, the MTDL strategy seems a more appropriate approach for addressing the complexity of AD and may provide new drugs for tackling its multifactorial nature. In this thesis, it is described the design of new MTDLs able to tackle the multifactorial nature of AD. Such new MTDLs designed are less flexible analogues of Caproctamine, one of the first MTDL owing biological properties useful for the AD treatment. These new compounds are able to inhibit the enzymes AChE, beta-secretase and to inhibit both AChE-induced and self-induced beta-amyloid aggregation. In particular, the most potent compound of the series is able to inhibit AChE in subnanomolar range, to inhibit β-secretase in micromolar concentration and to inhibit both AChE-induced and self-induced beta-amyloid aggregation in micromolar concentration. Cancer, as AD, is a very complex pathology and many different therapeutical approaches are currently use for the treatment of such pathology. However, due to its multifactorial nature the MTDL approach could be, in principle, apply also to this pathology. Aim of this thesis has been the development of new molecules owing different structural motifs able to simultaneously interact with some of the multitude of targets responsible for the pathology. The designed compounds displayed cytotoxic activity in different cancer cell lines. In particular, the most potent compounds of the series have been further evaluated and they were able to bind DNA resulting 100-fold more potent than the reference compound Mitonafide. Furthermore, these compounds were able to trigger apoptosis through caspases activation and to inhibit PIN1 (preliminary result). This last protein is a very promising target because it is overexpressed in many human cancers, it functions as critical catalyst for multiple oncogenic pathways and in several cancer cell lines depletion of PIN1 determines arrest of mitosis followed by apoptosis induction. In conclusion, this study may represent a promising starting pint for the development of new MTDLs hopefully useful for cancer and AD treatment.

Advanced signal and receiver design for next generation OFDM systems

This thesis deal with the design of advanced OFDM systems. Both waveform and receiver design have been treated. The main scope of the Thesis is to study, create, and propose, ideas and novel design solutions able to cope with the weaknesses and crucial aspects of modern OFDM systems. Starting from the the transmitter side, the problem represented by low resilience to non-linear distortion has been assessed. A novel technique that considerably reduces the Peak-to-Average Power Ratio (PAPR) yielding a quasi constant signal envelope in the time domain (PAPR close to 1 dB) has been proposed.The proposed technique, named Rotation Invariant Subcarrier Mapping (RISM),is a novel scheme for subcarriers data mapping,where the symbols belonging to the modulation alphabet are not anchored, but maintain some degrees of freedom. In other words, a bit tuple is not mapped on a single point, rather it is mapped onto a geometrical locus, which is totally or partially rotation invariant. The final positions of the transmitted complex symbols are chosen by an iterative optimization process in order to minimize the PAPR of the resulting OFDM symbol. Numerical results confirm that RISM makes OFDM usable even in severe non-linear channels. Another well known problem which has been tackled is the vulnerability to synchronization errors. Indeed in OFDM system an accurate recovery of carrier frequency and symbol timing is crucial for the proper demodulation of the received packets. In general, timing and frequency synchronization is performed in two separate phases called PRE-FFT and POST-FFT synchronization. Regarding the PRE-FFT phase, a novel joint symbol timing and carrier frequency synchronization algorithm has been presented. The proposed algorithm is characterized by a very low hardware complexity, and, at the same time, it guarantees very good performance in in both AWGN and multipath channels. Regarding the POST-FFT phase, a novel approach for both pilot structure and receiver design has been presented. In particular, a novel pilot pattern has been introduced in order to minimize the occurrence of overlaps between two pattern shifted replicas. This allows to replace conventional pilots with nulls in the frequency domain, introducing the so called Silent Pilots. As a result, the optimal receiver turns out to be very robust against severe Rayleigh fading multipath and characterized by low complexity. Performance of this approach has been analytically and numerically evaluated. Comparing the proposed approach with state of the art alternatives, in both AWGN and multipath fading channels, considerable performance improvements have been obtained. The crucial problem of channel estimation has been thoroughly investigated, with particular emphasis on the decimation of the Channel Impulse Response (CIR) through the selection of the Most Significant Samples (MSSs). In this contest our contribution is twofold, from the theoretical side, we derived lower bounds on the estimation mean-square error (MSE) performance for any MSS selection strategy,from the receiver design we proposed novel MSS selection strategies which have been shown to approach these MSE lower bounds, and outperformed the state-of-the-art alternatives. Finally, the possibility of using of Single Carrier Frequency Division Multiple Access (SC-FDMA) in the Broadband Satellite Return Channel has been assessed. Notably, SC-FDMA is able to improve the physical layer spectral efficiency with respect to single carrier systems, which have been used so far in the Return Channel Satellite (RCS) standards. However, it requires a strict synchronization and it is also sensitive to phase noise of local radio frequency oscillators. For this reason, an effective pilot tone arrangement within the SC-FDMA frame, and a novel Joint Multi-User (JMU) estimation method for the SC-FDMA, has been proposed. As shown by numerical results, the proposed scheme manages to satisfy strict synchronization requirements and to guarantee a proper demodulation of the received signal.

Design and fabrication of biocompatible scaffolds for the regeneration of tissues

Regenerative medicine and tissue engineering attempt to repair or improve the biological functions of tissues that have been damaged or have ceased to perform their role through three main components: a biocompatible scaffold, cellular component and bioactive molecules. Nanotechnology provide a toolbox of innovative scaffold fabrication procedures in regenerative medicine. In fact, nanotechnology, using manufacturing techniques such as conventional and unconventional lithography, allows fabricating supports with different geometries and sizes as well as displaying physical chemical properties tunable over different length scales. Soft lithography techniques allow to functionalize the support by specific molecules that promote adhesion and control the growth of cells. Understanding cell response to scaffold, and viceversa, is a key issue; here we show our investigation of the essential features required for improving the cell-surface interaction over different scale lengths. The main goal of this thesis has been to devise a nanotechnology-based strategy for the fabrication of scaffolds for tissue regeneration. We made four types of scaffolds, which are able to accurately control cell adhesion and proliferation. For each scaffold, we chose properly designed materials, fabrication and characterization techniques.

Next-Generation Sequencing-Based Mutations Scanning Strategy of the BCR-ABL Kinase Domain in Patients with PhiladelPhia-Chromosome Positive Leukemias Treated with Tyrosine Kinase Inhibitors

In chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia patients resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL kinase domain mutation status is an essential component of the therapeutic decision algorithm. The recent development of Ultra-Deep Sequencing approach (UDS) has opened the way to a more accurate characterization of the mutant clones surviving TKIs conjugating assay sensitivity and throughput. We decided to set-up and validated an UDS-based for BCR-ABL KD mutation screening in order to i) resolve qualitatively and quantitatively the complexity and the clonal structure of mutated populations surviving TKIs, ii) study the dynamic of expansion of mutated clones in relation to TKIs therapy, iii) assess whether UDS may allow more sensitive detection of emerging clones, harboring critical 2GTKIs-resistant mutations predicting for an impending relapse, earlier than SS. UDS was performed on a Roche GS Junior instrument, according to an amplicon sequencing design and protocol set up and validated in the framework of the IRON-II (Interlaboratory Robustness of Next-Generation Sequencing) International consortium.Samples from CML and Ph+ ALL patients who had developed resistance to one or multiple TKIs and collected at regular time-points during treatment were selected for this study. Our results indicate the technical feasibility, accuracy and robustness of our UDS-based BCR-ABL KD mutation screening approach. UDS was found to provide a more accurate picture of BCR-ABL KD mutation status, both in terms of presence/absence of mutations and in terms of clonal complexity and showed that BCR-ABL KD mutations detected by SS are only the “tip of iceberg”. In addition UDS may reliably pick 2GTKIs-resistant mutations earlier than SS in a significantly greater proportion of patients.The enhanced sensitivity as well as the possibility to identify low level mutations point the UDS-based approach as an ideal alternative to conventional sequencing for BCR-ABL KD mutation screening in TKIs-resistant Ph+ leukemia patients

Design and Synthesis of Naphthalene Diimides Based Small Molecules as Anticancer Agents: Targeting the Polyamine Transporter, G-quadruplex Structures and HDAC

Cancer is a multifactorial disease characterized by a very complex etiology. Basing on its complex nature, a promising therapeutic strategy could be based by the “Multi-Target-Directed Ligand” (MTDL) approach, based on the assumption that a single molecule could hit several targets responsible for the pathology. Several agents acting on DNA are clinically used, but the severe deriving side effects limit their therapeutic application. G-quadruplex structures are DNA secondary structures located in key zones of human genome; targeting quadruplex structures could allow obtaining an anticancer therapy more free from side effects. In the last years it has been proved that epigenetic modulation can control the expression of human genes, playing a crucial role in carcinogenesis and, in particular, an abnormal expression of histone deacetylase enzymes are related to tumor onset and progression. This thesis deals with the design and synthesis of new naphthalene diimide (NDI) derivatives endowed with anticancer activity, interacting with DNA together with other targets implicated in cancer development, such as HDACs. NDI-polyamine and NDI-polyamine-hydroxamic acid conjugates have been designed with the aim to provide potential MTDLs, in order to create molecules able simultaneously to interact with different targets involved in this pathology, specifically the G-quadruplex structures and HDAC, and to exploit the polyamine transport system to get selectively into cancer cells. Macrocyclic NDIs have been designed with the aim to improve the quadruplex targeting profile of the disubstituted NDIs. These compounds proved the ability to induce a high and selective stabilization of the quadruplex structures, together with cytotoxic activities in the micromolar range. Finally, trisubstituted NDIs have been developed as G-quadruplex-binders, potentially effective against pancreatic adenocarcinoma. In conclusion, all these studies may represent a promising starting point for the development of new interesting molecules useful for the treatment of cancer, underlining the versatility of the NDI scaffold.

Analysis and design of high performance multiphase electric drives for vehicle and aircraft applications

The first part of this thesis has focused on the construction of a twelve-phase asynchronous machine for More Electric Aircraft (MEA) applications. In fact, the aerospace world has found in electrification the way to improve the efficiency, reliability and maintainability of an aircraft. This idea leads to the aircraft a new management and distribution of electrical services. In this way is possible to remove or to reduce the hydraulic, mechanical and pneumatic systems inside the aircraft. The second part of this dissertation is dedicated on the enhancement of the control range of matrix converters (MCs) operating with non-unity input power factor and, at the same time, on the reduction of the switching power losses. The analysis leads to the determination in closed form of a modulation strategy that features a control range, in terms of output voltage and input power factor, that is greater than that of the traditional strategies under the same operating conditions, and a reduction in the switching power losses.

Novel dual D3R/GSK-3β modulators: an innovative multitarget strategy for bipolar disorder

Among the psychiatric diseases, bipolar disorder (BD) is the sixth leading cause of disability with a prevalence up to 4 % worldwide. BD is a complex neuropsychiatric condition which alternates episodes of mania with symptoms of depression. Although the neurobiological pathways are not completely clarified, the dopamine (DA) hypothesis, recognized as the leading theory explaining the pathophysiology of the malady, states that the dramatically compromised homeostatic regulation of dopaminergic circuits leads to alternated changes in DA neurotransmission. Modulation of D2 and D3 receptors (D2/3R) through partial agonists represents the first-line therapeutic strategy for psychiatric diseases. Moreover, a deregulation of the enzyme glycogen synthase kinase-3β (GSK-3β) has been reported as peculiar feature of BD. In this scenario, the concomitant modulation of D3R and GSK-3β, by employing multitarget compounds, could offer promises to achieve an effective cure of this illness. In the light of these findings, we rationally envisaged the pharmacophoric model at the basis of the design of several D3R partial agonists, suitable to be exploited for the dual D3R/GSK-3β ligand design. Thus, synthetic efforts were addressed to develop a first set of hybrid molecules able to concurrently modulate the selected targets. For a chemical structure point of view, we employed different spacers to combine a substituted aryl-piperazine moiety, reported in previously discovered D3R modulators, with a pyrazole-based fragment, already identified in GSK-3β inhibitors. A fluorescent and a cellular functional assays were carried out to assess the activity of all synthetized compounds against GSK-3β and on D3R, respectively. Most of the derivatives proved to effectively modulate both GSK-3β and D3R with potencies in the low-µM and low-nM range, respectively. The consistent biological data allowed us to identify some lead candidates worth to be further modified with the aim to optimize their biological profile and to perform a structure-activity relationship (SAR) study.

Peptidomimetic ligands for tuning integrin-mediated signalling: rational design, synthesis and theranostic applications

Integrins are α/β-heterodimeric transmembrane adhesion receptors that mediate cell-cell and cell-ECM interactions. Integrins are bidirectional signalling receptors that respond to external signals (“outside-in” signalling) and in parallel, transduce internal signals to the matrix (“inside-out” signalling), to regulate vital cellular functions including migration, survival, growth and differentiation. Therefore, dysregulation of these tightly regulated processes often results in uncontrolled integrin activation and abnormal tissue expression that is responsible for many diseases. Because of their important roles in physiological and pathological events, they represent a validated target for therapeutic and diagnostic purposes. The aim of the present Thesis was focused on the development of peptidic ligands for α4β1 and αvβ3 integrin subtypes, involved in inflammatory responses (leukocytes recruitment and extravasation) and cancer progression (angiogenesis, tumor growth, metastasis), respectively. Following the peptidomimetic strategy, we designed and synthesized a small library of linear and cyclic hybrid α/β-peptidomimetics based on the phenylureido-LDV scaffolds for the treatment of chronic inflammatory autoimmune diseases. In order to implement a fast and non-invasive diagnostic method for monitoring the course of the inflammatory processes, a flat glass-surface of dye-loaded Zeolite L-crystal nanoparticles was coated with bioactive α4β1-peptidomimetics to detect specific integrin-expressing cells as biomarkers of inflammatory diseases. Targeted drug delivery has been considered a promising alternative to overcome the pharmacokinetic limitations of conventional anticancer drugs. Thus, a novel Small-Molecule Drug Conjugate was synthesized by connecting the highly cytotoxic Cryptophycin to the tumor-targeting RGDfK-peptide through a protease-cleavable linker. Finally, in view to making the peptide synthesis more sustainable and greener, we developed an alternative method for peptide bonds formation employing solvent-free mechanochemistry and ultra-mild minimal solvent-grinding conditions in common, inexpensive laboratory equipment. To this purpose, standard amino acids, coupling agents and organic-green solvents were used in the presence of nanocrystalline hydroxyapatite as a reusable, bio-compatible inorganic basic catalyst.

Design and Synthesis of Novel Kinase Inhibitors for the Treatment of Chronic Respiratory Diseases

In 2017, Chronic Respiratory Diseases accounted for almost four million deaths worldwide. Unfortunately, current treatments are not definitive for such diseases. This unmet medical need forces the scientific community to increase efforts in the identification of new therapeutic solutions. PI3K delta plays a key role in mechanisms that promote airway chronic inflammation underlying Asthma and COPD. The first part of this project was dedicated to the identification of novel PI3K delta inhibitors. A first SAR expansion of a Hit, previously identified by a HTS campaign, was carried out. A library of 43 analogues was synthesised taking advantage of an efficient synthetic approach. This allowed the identification of an improved Hit of nanomolar enzymatic potency and moderate selectivity for PI3K delta over other PI3K isoforms. However, this compound exhibited low potency in cell-based assays. Low cellular potency was related to sub optimal phys-chem and ADME properties. The analysis of the X-ray crystal structure of this compound in human PI3K delta guided a second tailored SAR expansion that led to improved cellular potency and solubility. The second part of the thesis was focused on the rational design and synthesis of new macrocyclic Rho-associated protein kinases (ROCKs) inhibitors. Inhibition of these kinases has been associated with vasodilating effects. Therefore, ROCKs could represent attractive targets for the treatment of pulmonary arterial hypertension (PAH). Known ROCK inhibitors suffer from low selectivity across the kinome. The design of macrocyclic inhibitors was considered a promising strategy to obtain improved selectivity. Known inhibitors from literature were evaluated for opportunities of macrocyclization using a knowledge-based approach supported by Computer Aided Drug Design (CADD). The identification of a macrocyclic ROCK inhibitor with enzymatic activity in the low micro molar range against ROCK II represented a promising result that validated this innovative approach in the design of new ROCKs inhibitors.

Design of experiment in drug development: optimal allocations in multi-arm clinical trials and design space for multi-step processes

In this thesis, we deal with the design of experiments in the drug development process, focusing on the design of clinical trials for treatment comparisons (Part I) and the design of preclinical laboratory experiments for proteins development and manufacturing (Part II). In Part I we propose a multi-purpose design methodology for sequential clinical trials. We derived optimal allocations of patients to treatments for testing the efficacy of several experimental groups by also taking into account ethical considerations. We first consider exponential responses for survival trials and we then present a unified framework for heteroscedastic experimental groups that encompasses the general ANOVA set-up. The very good performance of the suggested optimal allocations, in terms of both inferential and ethical characteristics, are illustrated analytically and through several numerical examples, also performing comparisons with other designs proposed in the literature. Part II concerns the planning of experiments for processes composed of multiple steps in the context of preclinical drug development and manufacturing. Following the Quality by Design paradigm, the objective of the multi-step design strategy is the definition of the manufacturing design space of the whole process and, as we consider the interactions among the subsequent steps, our proposal ensures the quality and the safety of the final product, by enabling more flexibility and process robustness in the manufacturing.

Development of numerical tools for the simulation, design and optimization of a Helicon Plasma Thruster

This work thesis focuses on the Helicon Plasma Thruster (HPT) as a candidate for generating thrust for small satellites and CubeSats. Two main topics are addressed: the development of a Global Model (GM) and a 3D self-consistent numerical tool. The GM is suitable for preliminary analysis of HPTs with noble gases such as argon, neon, krypton, and xenon, and alternative propellants such as air and iodine. A lumping methodology is developed to reduce the computational cost when modelling the excited species in the plasma chemistry. A 3D self-consistent numerical tool is also developed that can treat discharges with a generic 3D geometry and model the actual plasma-antenna coupling. The tool consists of two main modules, an EM module and a FLUID module, which run iteratively until a steady state solution is converged. A third module is available for solving the plume with a simplified semi-analytical approach, a PIC code, or directly by integration of the fluid equations. Results obtained from both the numerical tools are benchmarked against experimental measures of HPTs or Helicon reactors, obtaining very good qualitative agreement with the experimental trend for what concerns the GM, and an excellent agreement of the physical trends predicted against the measured data for the 3D numerical strategy.