Design and Characterization of Luminescent Silica Nanoparticles

The aim of this thesis was to design, synthesize and characterize dye-doped silica nanoparticles (DDSNPs) to be used as chemosensors or labels in bioanalytical applications. DDSNPs represent one of the most versatile and useful components in nanomedicine displaying important features such as high colloid stability in water, low toxicity, one-pot inexpensive synthesis and tunable fluorescence emission. Starting from the one-pot and highly reproducible synthesis of “silica-core/PEG shell” DDSNPs based on the use of micelles of Pluronic F127, in which take place both hydrolysis and condensation of the silica precursor and of the dyes functionalized with a triethoxysilane group, we developed DDSNPs suitable for optical and optoacustic imaging, drug loading and chemical sensing obtaining very interesting results for the further development of nanomedicine.

Design and Development of a Research Framework for Prototyping Control Tower Augmented Reality Tools

The purpose of the air traffic management system is to ensure the safe and efficient flow of air traffic. Therefore, while augmenting efficiency, throughput and capacity in airport operations, attention has rightly been placed on doing it in a safe manner. In the control tower, many advances in operational safety have come in the form of visualization tools for tower controllers. However, there is a paradox in developing such systems to increase controllers' situational awareness: by creating additional computer displays, the controller's vision is pulled away from the outside view and the time spent looking down at the monitors is increased. This reduces their situational awareness by forcing them to mentally and physically switch between the head-down equipment and the outside view. This research is based on the idea that augmented reality may be able to address this issue. The augmented reality concept has become increasingly popular over the past decade and is being proficiently used in many fields, such as entertainment, cultural heritage, aviation, military & defense. This know-how could be transferred to air traffic control with a relatively low effort and substantial benefits for controllers’ situation awareness. Research on this topic is consistent with SESAR objectives of increasing air traffic controllers’ situation awareness and enable up to 10 % of additional flights at congested airports while still increasing safety and efficiency. During the Ph.D., a research framework for prototyping augmented reality tools was set up. This framework consists of methodological tools for designing the augmented reality overlays, as well as of hardware and software equipment to test them. Several overlays have been designed and implemented in a simulated tower environment, which is a virtual reconstruction of Bologna airport control tower. The positive impact of such tools was preliminary assessed by means of the proposed methodology.

Design and characterization of Electrochemical Sensors for Organic Bioelectronics

This Ph.D. Thesis concerns the design and characterisation of functional electrochemical interfaces in organic electronic devices for bioelectronic applications. The Thesis is structured as follows: Chapter I – Technological context that has inspired the research, introduction to Organic Bioelectronics and literature review concerning Organic Electrochemical Transistors (OECTs) for sensing applications. Chapter II – Working principle of an all-polymeric OECT and operando microscopic characterization using scanning electrochemical techniques. Chapter III – Dopamine detection with all-polymeric OECT sensors. Development of a potentiodynamic approach to address selectivity issues in the presence of interfering species and design of a needle-type, sub-micrometric OECT sensor for spatially resolved detection of biological Dopamine concentrations. Chapter IV – Development of an OECT pH sensor. Characterization of the electrochemical transducer and functionalization of the OECT gate electrode with the sensing material. Potentiodynamic and potentiostatic operation modalities are explored and the sensing performances are assessed in both cases. The final device is realized on a flexible substrate and tested in Artificial Sweat. Chapter V – Study of two-terminal, electrochemically gated sensors inspired by the OECT configuration. Design and characterization of novel functional materials showing a potentiometric transduction of the chemical signal that can be exploited in the realization of electrochemical sensors with simplified geometry for wearable applications. Chapter VI – Conclusion.

Design and synthesis of (pro)electrophilic compounds for investigating the multifactorial nature of neurodegenerative diseases: focus on inflammation-driven events

Neuroinflammation constitutes a major player in the etiopathology of neurodegenerative diseases (NDDs), by orchestrating several neurotoxic pathways which in concert lead to neurodegeneration. A positive feedback loop occurs between inflammation, microglia activation and misfolding processes that, alongside excitotoxicity and oxidative events, represent crucial features of this intricate scenario. The multi-layered nature of NDDs requires a deepen investigation on how these vicious cycles work. This could further help in the search for effective treatments. Electrophiles are critically involved in the modulation of a variety of neuroprotective responses. Thus, we envisioned their peculiar ability to switch on/off biological activities as a powerful tool for investigating the neurotoxic scenario driven by inflammation in NDDs. In particular, in this thesis project, we wanted to dissect at a molecular level the functional role of (pro)electrophilic moieties of previously synthesized thioesters of variously substituted trans-cinnamic acids, to identify crucial features which could interfere with amyloid aggregation as well as modulate Nrf2 and/or NF-κB activation. To this aim, we first synthesized new compounds to identify bioactive cores which could specifically modulate the intended target. Then, we systematically modified their structure to reach additional pathogenic pathways which could in tandem contribute to the inflammatory process. In particular, following the investigation of the mechanistic underpinnings involving the catechol feature in amyloid binding through the synthesis of new dihydroxyl derivatives, we incorporated the identified antiaggregating nucleus into constrained frames which could contrast neuroinflammation also through the modulation of CB2Rs. In parallel, Nrf2 and/or NF-κB antinflammatory structural requirements were combined with the neuroprotective cores of pioglitazone, an antidiabetic drug endowed with MAO-B inhibitory properties, and memantine, which notably contrasts excitotoxicity. By acting as Swiss army knives, the new set of molecules emerge as promising tools to deepen our insights into the complex scenario regulating NDDs.

Design and Development of Network Monitoring Strategies in P4-enabled Programmable Switches

Network monitoring is of paramount importance for effective network management: it allows to constantly observe the network’s behavior to ensure it is working as intended and can trigger both automated and manual remediation procedures in case of failures and anomalies. The concept of SDN decouples the control logic from legacy network infrastructure to perform centralized control on multiple switches in the network, and in this context, the responsibility of switches is only to forward packets according to the flow control instructions provided by controller. However, as current SDN switches only expose simple per-port and per-flow counters, the controller has to do almost all the processing to determine the network state, which causes significant communication overhead and excessive latency for monitoring purposes. The absence of programmability in the data plane of SDN prompted the advent of programmable switches, which allow developers to customize the data-plane pipeline and implement novel programs operating directly in the switches. This means that we can offload certain monitoring tasks to programmable data planes, to perform fine-grained monitoring even at very high packet processing speeds. Given the central importance of network monitoring exploiting programmable data planes, the goal of this thesis is to enable a wide range of monitoring tasks in programmable switches, with a specific focus on the ones equipped with programmable ASICs. Indeed, most network monitoring solutions available in literature do not take computational and memory constraints of programmable switches into due account, preventing, de facto, their successful implementation in commodity switches. This claims that network monitoring tasks can be executed in programmable switches. Our evaluations show that the contributions in this thesis could be used by network administrators as well as network security engineers, to better understand the network status depending on different monitoring metrics, and thus prevent network infrastructure and service outages.

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.

Nanostructured piezoelectric materials for the design and development of self-sensing composite materials and energy harvesting devices

The work activities reported in this PhD thesis regard the functionalization of composite materials and the realization of energy harvesting devices by using nanostructured piezoelectric materials, which can be integrated in the composite without affecting its mechanical properties. The self-sensing composite materials were fabricated by interleaving between the plies of the laminate the piezoelectric elements. The problem of negatively impacting on the mechanical properties of the hosting structure was addressed by shaping the piezoelectric materials in appropriate ways. In the case of polymeric piezoelectric materials, the electrospinning technique allowed to produce highly-porous nanofibrous membranes which can be immerged in the hosting matrix without inducing delamination risk. The flexibility of the polymers was exploited also for the production of flexible tactile sensors. The sensing performances of the specimens were evaluated also in terms of lifetime with fatigue tests. In the case of ceramic piezo-materials, the production and the interleaving of nanometric piezoelectric powder limitedly affected the impact resistance of the laminate, which showed enhanced sensing properties. In addition to this, a model was proposed to predict the piezoelectric response of the self-sensing composite materials as function of the amount of the piezo-phase within the laminate and to adapt its sensing functionalities also for quasi-static loads. Indeed, one final application of the work was to integrate the piezoelectric nanofibers in the sole of a prosthetic foot in order to detect the walking cycle, which has a period in the order of 1 second. In the end, the energy harvesting capabilities of the piezoelectric materials were investigated, with the aim to design wearable devices able to collect energy from the environment and from the body movements. The research activities focused both on the power transfer capability to an external load and the charging of an energy storage unit, like, e.g., a supercapacitor.

Vulnerable users' protection with advanced recycling paving materials. Design and characterisation of rubber-based impact-absorbing pavement materials for bike lanes and sidewalks

Our cities are constantly evolving, and the necessity to improve the condition and safety of the urban infrastructures is fundamental. However, on the roads, the specific needs of cyclists and pedestrians are often neglected. The Vulnerable Road Users (VRUs), among whom cyclists and pedestrians are, rarely benefit from the most innovative safety measures. Inspired by playgrounds and aiming to reduce VRUs injuries, the Impact-Absorbing Pavements (IAP) developed as novel sidewalks, and bike lanes surface layers may help decrease injuries, fatalities, and the related societal costs. To achieve this goal, the End-of-Life Tyres (ELTs) crumb rubber (CR) is used as a primary resource, bringing its elastic properties into the surface layer. The thesis is divided into five main chapters. The first concerns the formulation and the definition of a feasible mix. The second explores the mechanical and environmental properties in detail, and the ageing effect is also assessed. The third describes the modelling of the material to simulate accidents and measure the injury reduction, especially on the head. The fourth chapter is reserved for the field trial. The last gives some perspectives on the research and proposes a way to optimize and improve the data and results collected during the doctoral research. It was observed that the specimens made with cold protocol have noticeable performances and reduce the overall carbon footprint impact of this material. The material modelling and the accident simulation proved the performance of the IAP against head injuries, and the field trial confirmed the good results obtained in the laboratory for the cold-made material. Finally, the outcomes of this thesis opened many prospective to the IAP development, such as the use of a plant-based binder or recycled aggregates and gave a positive prospect of an innovative material to the urban road infrastructures.

Design and evaluation of aerosol and liquid separation systems

Conventional chromatographic columns are packed with porous beads by the universally employed slurry-packing method. The lack of precise control of the particle size distribution, shape and position inside the column have dramatic effects on the separation efficiency. In the first part the thesis an ordered, three-dimensional, pillar-array structure was designed by a CAD software. Several columns, characterized by different fluid distributors and bed length, were produced by a stereolithographic 3D printer and compared in terms of pressure drop and height equivalent to a theroretical plate (HETP). To prevent the release of unwanted substances and to provide a surface for immobilizing a ligand, pillars were coated with one or more of the following materials: titanium dioxide, nanofibrillated cellulose (NFC) and polystyrene. The external NFC layer was functionalized with Cibacron Blue and the dynamic binding capacity of the column was measured by performing three chromatographic cycles, using bovine serum albumin (BSA) as target molecule. The second part of the thesis deals with Covid-19 pandemic related research activities. In early 2020, due to the pandemic outbreak, surgical face masks became an essential non-pharmaceutical intervention to limit the spread. To address the consequent shortage and to support the reconversion of the Italian industry, in late March 2020 a multidisciplinary group of the University of Bologna created the first Italian laboratory able to perform all the tests required for the evaluation and certification of surgical masks. More than 1200 tests were performed on about 350 prototypes, according to the standard EN 14683:2019. The results were analyzed to define the best material properties and masks composition for the production of masks with excellent efficiency. To optimize the usage of surgical masks and to reduce their environmental burden, the variation of their performance over time of usage were investigated as to determine the maximum lifetime.

Design and characterization of wideband Hall current sensors in BCD technology for smart power and metering applications

Power electronic circuits are moving towards higher switching frequencies, exploiting the capabilities of novel devices to shrink the dimension of passive components. This trend demands sensors capable enough to operate at such high frequencies. This thesis aims to demonstrate through experimental characterization, the broadband capability of a fully integrated CMOS X-Hall current sensor in current mode interfaced with a transimpedance amplifier (TIA), chip CH09, realized in CMOS technology for power electronics applications such as power converters. The system exploits a common-mode control system to operate the dual supply system, 5-V for the X-Hall probe and 1.2-V for the readout. The developed prototype achieves a maximum acquisition bandwidth of 12 MHz, a power consumption of 11.46 mW, resolution of 39 mArms, a sensitivity of 8 % /T, and a FoM of 569-MHz/A2mW, significantly higher than current state-of-the-art. Further enhancements were proposed to CH09 as a new chip CH100, aiming for accuracy levels prerequisite for a real-time power electronic application. The TIA was optimized for a wider bandwidth of 26.7 MHz with nearly 30% reduction of the integrated input referred noise of 26.69 nArms at the probe-AFE interface in the frequency band of DC-30 MHz, and a 10% improvement in the dynamic range. The expected input range is 5-A. The chip incorporates a dual sensing chain for differential sensing to overcome common mode interferences. A novel offset cancellation technique is proposed that would require switching of polarity of bias currents. Thermal gain drift was improved by a factor of 8 and will be digitally calibrated utilizing a new built-in temperature sensor with a post calibration measurement accuracy greater than 1%. The estimated power consumption of the entire system is 55.6 mW. Both prototypes have been implemented through a 90-nm microelectronic process from STMicroelectronics and occupy a silicon area of 2.4 mm2.

Design and testing of innovative, artificial intelligence-based techniques to model and control the combustion process and to reduce the Co2 emissions in modern, high-performance, gasoline direct injection engines

This work deals with the development of calibration procedures and control systems to improve the performance and efficiency of modern spark ignition turbocharged engines. The algorithms developed are used to optimize and manage the spark advance and the air-to-fuel ratio to control the knock and the exhaust gas temperature at the turbine inlet. The described work falls within the activity that the research group started in the previous years with the industrial partner Ferrari S.p.a. . The first chapter deals with the development of a control-oriented engine simulator based on a neural network approach, with which the main combustion indexes can be simulated. The second chapter deals with the development of a procedure to calibrate offline the spark advance and the air-to-fuel ratio to run the engine under knock-limited conditions and with the maximum admissible exhaust gas temperature at the turbine inlet. This procedure is then converted into a model-based control system and validated with a Software in the Loop approach using the engine simulator developed in the first chapter. Finally, it is implemented in a rapid control prototyping hardware to manage the combustion in steady-state and transient operating conditions at the test bench. The third chapter deals with the study of an innovative and cheap sensor for the in-cylinder pressure measurement, which is a piezoelectric washer that can be installed between the spark plug and the engine head. The signal generated by this kind of sensor is studied, developing a specific algorithm to adjust the value of the knock index in real-time. Finally, with the engine simulator developed in the first chapter, it is demonstrated that the innovative sensor can be coupled with the control system described in the second chapter and that the performance obtained could be the same reachable with the standard in-cylinder pressure sensors.

Design and characterization of polymorphs and co-crystals of organic molecular semiconductors

In the last decades, organic semiconductors have attracted attention due to their possible employment in solution-processed optoelectronic and electronic devices. One of the advantages of solution processing is the possibility to process into flexible substrates at low cost. Organic molecular materials tend to form polymorphs, which can exhibit very different properties. In most cases, the control of the crystal structure is decisive to maximize the performance of the final device. Although organic electronics have progressed a lot, n-type organic semiconductors still lag behind p-type, presenting challenges such as air instability and poor solubility. NDI derivatives are promising candidates for applications in organic electronics due to their characteristics. Recently, the structure-properties relationship and the polymorphism of these molecules have gained attention. In the first part of this thesis, NDI-C6 thermal behavior was extensively explored which revealed two different behaviors depending on the annealing process. This study allowed to define the stability ranking of the NDI-C6 bulk forms and to determine the crystal structure of Form γ at 54°C. Additionally, the polymorphic and thermal behavior of thin films of NDI-C6 was also explored. It was possible to isolate pure Form α, Form β, Form γ and a new metastable Form ε. It was also possible to determine the stability ranking of the phases in thin films. OFETs were fabricated having different polymorphs as active layer, unfortunately the performance was not ideal. During the second part of this thesis, core-chlorinated NDIs with fluoroalkyl chains were studied. Initially, the focus was on the polymorphism of CF3-NDI that revealed a solvate form with a very interesting molecular arrangement suggesting the possibility to form charge transfer co-crystals. In the last part of the thesis, the synthesis and characterization of CT co-crystal with different NDI derivatives, and acceptor and as donor BTBT and ditBu-BTBT were explored.

Strategies to hijack MTs dysfunction in neurodegenerative tauopathies: Design and synthesis of novel CNS-disease-modifying tools

Neuronal microtubules assembly and dynamics are regulated by several proteins including (MT)-associated protein tau, whose aberrant hyperphosphorylation promotes its dissociation from MTs and its abnormal deposition into neurofibrillary tangles, a common neurotoxic hallmarks of neurodegenerative tauopathies. To date, no disease-modifying drugs have been approved to combat CNS tau-related diseases. The multifactorial etiology of these conditions represents one of the major limits in the discovery of effective therapeutic options. In addition, tau protein functions are orchestrated by diverse post-translational modifications among which phosphorylation mediated by PKs plays a leading role. In this context, conventional single-target therapies are often inadequate in restoring perturbed networks and fraught with adverse side-effects. This thesis reports two distinct approaches to hijack MT defects in neurons. The first is focused on the rational design and synthesis of first-in-class triple inhibitors of GSK-3β, FYN, and DYRK1A, three close-related PKs, which act as master regulators of aberrant tau hyperphosphorylation. A merged multi-target pharmacophore strategy was applied to simultaneously modulate all three targets and achieve a disease-modifying effect. Optimization of ARN25068 by a computationally and crystallographic driven SAR exploration, allowed to rationalize the key structural modifications to maintain a balanced potency against all three targets and develop a new generation of quite well-balanced analogs exhibiting improved physicochemical properties, a good in vitro ADME profile, and promising cell-based anti-tau phosphorylation activity. In Part II, MT-stabilizing compounds have been developed to compensate MT defects in tau-related pathologies. Intensive chemical effort has been devoted to scaling up BL-0884, identified as a promising MT-normalizing TPD, which exhibited favorable ADME-PK, including brain penetration, oral bioavailability, and brain pharmacodynamic activity. A suitable functionalization of the exposed hydroxyl moiety of BL-0884 was carried out to generate corresponding esters and amides possessing a wide range of applications as prodrugs and active targeting for cancer chemotherapy.