Reduced-order modelling, circuit-level design and SOI fabrication of microelectromechanical resonators

This thesis deals with two important research aspects concerning radio frequency (RF) microresonators and switches. First, a new approach for compact modeling and simulation of these devices is presented. Then, a combined process flow for their simultaneous fabrication on a SOI substrate is proposed. Compact models for microresonators and switches are extracted by applying mathematical model order reduction (MOR) to the devices finite element (FE) description in ANSYS c° . The behaviour of these devices includes forms of nonlinearities. However, an approximation in the creation of the FE model is introduced, which enables the use of linear model order reduction. Microresonators are modeled with the introduction of transducer elements, which allow for direct coupling of the electrical and mechanical domain. The coupled system element matrices are linearized around an operating point and reduced. The resulting macromodel is valid for small signal analysis around the bias point, such as harmonic pre-stressed analysis. This is extremely useful for characterizing the frequency response of resonators. Compact modelling of switches preserves the nonlinearity of the device behaviour. Nonlinear reduced order models are obtained by reducing the number of nonlinearities in the system and handling them as input to the system. In this way, the system can be reduced using linear MOR techniques and nonlinearities are introduced directly in the reduced order model. The reduction of the number of system nonlinearities implies the approximation of all distributed forces in the model with lumped forces. Both for microresonators and switches, a procedure for matrices extraction has been developed so that reduced order models include the effects of electrical and mechanical pre-stress. The extraction process is fast and can be done automatically from ANSYS binary files. The method has been applied for the simulation of several devices both at devices and circuit level. Simulation results have been compared with full model simulations, and, when available, experimental data. Reduced order models have proven to conserve the accuracy of finite element method and to give a good description of the overall device behaviour, despite the introduced approximations. In addition, simulation is very fast, both at device and circuit level. A combined process-flow for the integrated fabrication of microresonators and switches has been defined. For this purpose, two processes that are optimized for the independent fabrication of these devices are merged. The major advantage of this process is the possibility to create on-chip circuit blocks that include both microresonators and switches. An application is, for example, aswitched filter bank for wireless transceiver. The process for microresonators fabrication is characterized by the use of silicon on insulator (SOI) wafers and on a deep reactive ion etching (DRIE) step for the creation of the vibrating structures in single-crystal silicon and the use of a sacrificial oxide layer for the definition of resonator to electrode distance. The fabrication of switches is characterized by the use of two different conductive layers for the definition of the actuation electrodes and by the use of a photoresist as a sacrificial layer for the creation of the suspended structure. Both processes have a gold electroplating step, for the creation of the resonators electrodes, transmission lines and suspended structures. The combined process flow is designed such that it conserves the basic properties of the original processes. Neither the performance of the resonators nor the performance of the switches results affected by the simultaneous fabrication. Moreover, common fabrication steps are shared, which allows for cheaper and faster fabrication.

Electrothermal characterization and nonlinear modelling of GaN transistors for telecommunication circuit design

This thesis starts showing the main characteristics and application fields of the AlGaN/GaN HEMT technology, focusing on reliability aspects essentially due to the presence of low frequency dispersive phenomena which limit in several ways the microwave performance of this kind of devices. Based on an equivalent voltage approach, a new low frequency device model is presented where the dynamic nonlinearity of the trapping effect is taken into account for the first time allowing considerable improvements in the prediction of very important quantities for the design of power amplifier such as power added efficiency, dissipated power and internal device temperature. An innovative and low-cost measurement setup for the characterization of the device under low-frequency large-amplitude sinusoidal excitation is also presented. This setup allows the identification of the new low frequency model through suitable procedures explained in detail. In this thesis a new non-invasive empirical method for compact electrothermal modeling and thermal resistance extraction is also described. The new contribution of the proposed approach concerns the non linear dependence of the channel temperature on the dissipated power. This is very important for GaN devices since they are capable of operating at relatively high temperatures with high power densities and the dependence of the thermal resistance on the temperature is quite relevant. Finally a novel method for the device thermal simulation is investigated: based on the analytical solution of the tree-dimensional heat equation, a Visual Basic program has been developed to estimate, in real time, the temperature distribution on the hottest surface of planar multilayer structures. The developed solver is particularly useful for peak temperature estimation at the design stage when critical decisions about circuit design and packaging have to be made. It facilitates the layout optimization and reliability improvement, allowing the correct choice of the device geometry and configuration to achieve the best possible thermal performance.

Bio-physical interactions and feedbacks in a global climate model

This PhD thesis addresses the topic of large-scale interactions between climate and marine biogeochemistry. To this end, centennial simulations are performed under present and projected future climate conditions with a coupled ocean-atmosphere model containing a complex marine biogeochemistry model. The role of marine biogeochemistry in the climate system is first investigated. Phytoplankton solar radiation absorption in the upper ocean enhances sea surface temperatures and upper ocean stratification. The associated increase in ocean latent heat losses raises atmospheric temperatures and water vapor. Atmospheric circulation is modified at tropical and extratropical latitudes with impacts on precipitation, incoming solar radiation, and ocean circulation which cause upper-ocean heat content to decrease at tropical latitudes and to increase at middle latitudes. Marine biogeochemistry is tightly related to physical climate variability, which may vary in response to internal natural dynamics or to external forcing such as anthropogenic carbon emissions. Wind changes associated with the North Atlantic Oscillation (NAO), the dominant mode of climate variability in the North Atlantic, affect ocean properties by means of momentum, heat, and freshwater fluxes. Changes in upper ocean temperature and mixing impact the spatial structure and seasonality of North Atlantic phytoplankton through light and nutrient limitations. These changes affect the capability of the North Atlantic Ocean of absorbing atmospheric CO2 and of fixing it inside sinking particulate organic matter. Low-frequency NAO phases determine a delayed response of ocean circulation, temperature and salinity, which in turn affects stratification and marine biogeochemistry. In 20th and 21st century simulations natural wind fluctuations in the North Pacific, related to the two dominant modes of atmospheric variability, affect the spatial structure and the magnitude of the phytoplankton spring bloom through changes in upper-ocean temperature and mixing. The impacts of human-induced emissions in the 21st century are generally larger than natural climate fluctuations, with the phytoplankton spring bloom starting one month earlier than in the 20th century and with ~50% lower magnitude. This PhD thesis advances the knowledge of bio-physical interactions within the global climate, highlighting the intrinsic coupling between physical climate and biosphere, and providing a framework on which future studies of Earth System change can be built on.

Dynamic identification of structures: experimental assessment of modal parameteres through methods in frequency domain, in time-frequency domain and model updating

Among the experimental methods commonly used to define the behaviour of a full scale system, dynamic tests are the most complete and efficient procedures. A dynamic test is an experimental process, which would define a set of characteristic parameters of the dynamic behaviour of the system, such as natural frequencies of the structure, mode shapes and the corresponding modal damping values associated. An assessment of these modal characteristics can be used both to verify the theoretical assumptions of the project, to monitor the performance of the structural system during its operational use. The thesis is structured in the following chapters: The first introductive chapter recalls some basic notions of dynamics of structure, focusing the discussion on the problem of systems with multiply degrees of freedom (MDOF), which can represent a generic real system under study, when it is excited with harmonic force or in free vibration. The second chapter is entirely centred on to the problem of dynamic identification process of a structure, if it is subjected to an experimental test in forced vibrations. It first describes the construction of FRF through classical FFT of the recorded signal. A different method, also in the frequency domain, is subsequently introduced; it allows accurately to compute the FRF using the geometric characteristics of the ellipse that represents the direct input-output comparison. The two methods are compared and then the attention is focused on some advantages of the proposed methodology. The third chapter focuses on the study of real structures when they are subjected to experimental test, where the force is not known, like in an ambient or impact test. In this analysis we decided to use the CWT, which allows a simultaneous investigation in the time and frequency domain of a generic signal x(t). The CWT is first introduced to process free oscillations, with excellent results both in terms of frequencies, dampings and vibration modes. The application in the case of ambient vibrations defines accurate modal parameters of the system, although on the damping some important observations should be made. The fourth chapter is still on the problem of post processing data acquired after a vibration test, but this time through the application of discrete wavelet transform (DWT). In the first part the results obtained by the DWT are compared with those obtained by the application of CWT. Particular attention is given to the use of DWT as a tool for filtering the recorded signal, in fact in case of ambient vibrations the signals are often affected by the presence of a significant level of noise. The fifth chapter focuses on another important aspect of the identification process: the model updating. In this chapter, starting from the modal parameters obtained from some environmental vibration tests, performed by the University of Porto in 2008 and the University of Sheffild on the Humber Bridge in England, a FE model of the bridge is defined, in order to define what type of model is able to capture more accurately the real dynamic behaviour of the bridge. The sixth chapter outlines the necessary conclusions of the presented research. They concern the application of a method in the frequency domain in order to evaluate the modal parameters of a structure and its advantages, the advantages in applying a procedure based on the use of wavelet transforms in the process of identification in tests with unknown input and finally the problem of 3D modeling of systems with many degrees of freedom and with different types of uncertainty.

Use of VEGFR-2 targeted microbubbles (BR55, Bracco imaging) for the early ultrasound evaluation of response to antiangiogenic treatment in a xenograft model of hepatocarcinoma

Aim: To evaluate the early response to treatment to an antiangiogenetic drug (sorafenib) in a heterotopic murine model of hepatocellular carcinoma (HCC) using ultrasonographic molecular imaging. Material and Methods: the xenographt model was established injecting a suspension of HuH7 cells subcutaneously in 19 nude mice. When tumors reached a mean diameter of 5-10 mm, they were divided in two groups (treatment and vehicle). The treatment group received sorafenib (62 mg/kg) by daily oral gavage for 14 days. Molecular imaging was performed using contrast enhanced ultrasound (CEUS), by injecting into the mouse venous circulation a suspension of VEGFR-2 targeted microbubbles (BR55, kind gift of Bracco Swiss, Geneve, Switzerland). Video clips were acquired for 6 minutes, then microbubbles (MBs) were destroyed by a high mechanical index (MI) impulse, and another minute was recorded to evaluate residual circulating MBs. The US protocol was repeated at day 0,+2,+4,+7, and +14 from the beginning of treatment administration. Video clips were analyzed using a dedicated software (Sonotumor, Bracco Swiss) to quantify the signal of the contrast agent. Time/intensity curves were obtained and the difference of the mean MBs signal before and after high MI impulse (Differential Targeted Enhancement-dTE) was calculated. dTE represents a numeric value in arbitrary units proportional to the amount of bound MBs. At day +14 mice were euthanized and the tumors analyzed for VEGFR-2, pERK, and CD31 tissue levels using western blot analysis. Results: dTE values decreased from day 0 to day +14 both in treatment and vehicle groups, and they were statistically higher in vehicle group than in treatment group at day +2, at day +7, and at day +14. With respect to the degree of tumor volume increase, measured as growth percentage delta (GPD), treatment group was divided in two sub-groups, non-responders (GPD>350%), and responders (GPD<200%). In the same way vehicle group was divided in slow growth group (GPD<400%), and fast growth group (GPD>900%). dTE values at day 0 (immediately before treatment start) were higher in non-responders than in responders group, with statistical difference at day 2. While dTE values were higher in the fast growth group than in the slow growth group only at day 0. A significant positive correlation was found between VEGFR-2 tissue levels and dTE values, confirming that level of BR55 tissue enhancement reflects the amount of tissue VEGF receptor. Conclusions: the present findings show that, at least in murine experimental models, CEUS with BR55 is feasable and appears to be a useful tool in the prediction of tumor growth and response to sorafenib treatment in xenograft HCC.

Changes in tumor stiffness for early prediction of tumor response to sorafenib: a proof-of-concept study with elastosonography in an animal model of Hepatocellular Carcinoma (HCC)

Background and aims: Sorafenib is the reference therapy for advanced Hepatocellular Carcinoma (HCC). No method exists to predict in the very early period subsequent individual response. Starting from the clinical experience in humans that subcutaneous metastases may rapidly change consistency under sorafenib and that elastosonography a new ultrasound based technique allows assessment of tissue stiffness, we investigated the role of elastonography in the very early prediction of tumor response to sorafenib in a HCC animal model. Methods: HCC (Huh7 cells) subcutaneous xenografting in mice was utilized. Mice were randomized to vehicle or treatment with sorafenib when tumor size was 5-10 mm. Elastosonography (Mylab 70XVG, Esaote, Genova, Italy) of the whole tumor mass on a sagittal plane with a 10 MHz linear transducer was performed at different time points from treatment start (day 0, +2, +4, +7 and +14) until mice were sacrified (day +14), with the operator blind to treatment. In order to overcome variability in absolute elasticity measurement when assessing changes over time, values were expressed in arbitrary units as relative stiffness of the tumor tissue in comparison to the stiffness of a standard reference stand-off pad lying on the skin over the tumor. Results: Sor-treated mice showed a smaller tumor size increase at day +14 in comparison to vehicle-treated (tumor volume increase +192.76% vs +747.56%, p=0.06). Among Sor-treated tumors, 6 mice showed a better response to treatment than the other 4 (increase in volume +177% vs +553%, p=0.011). At day +2, median tumor elasticity increased in Sor-treated group (+6.69%, range –30.17-+58.51%), while decreased in the vehicle group (-3.19%, range –53.32-+37.94%) leading to a significant difference in absolute values (p=0.034). From this time point onward, elasticity decreased in both groups, with similar speed over time, not being statistically different anymore. In Sor-treated mice all 6 best responders at day 14 showed an increase in elasticity at day +2 (ranging from +3.30% to +58.51%) in comparison to baseline, whereas 3 of the 4 poorer responders showed a decrease. Interestingly, these 3 tumours showed elasticity values higher than responder tumours at day 0. Conclusions: Elastosonography appears a promising non-invasive new technique for the early prediction of HCC tumor response to sorafenib. Indeed, we proved that responder tumours are characterized by an early increase in elasticity. The possibility to distinguish a priori between responders and non responders based on the higher elasticity of the latter needs to be validated in ad-hoc experiments as well as a confirmation of our results in humans is warranted.

Staphylococcus aureus bones and joints infections: in vivo studies and host immune response

Abstract The aim of this work was the development of a murine model of septic arthrosynovitis and osteomyelitis caused by Staphylococcus aureus, which could mimic the natural disease occurring in humans and which could be suitable for testing preventive and therapeutic interventions. This model could be particularly useful since S. aureus-mediated joints and bones infections are relevant in humans, both in terms of frequency and severity. Our attention focused in tracking bacterial infiltration in joints and bones over time using different microbiological and hystopathological tools, which allowed us to have a complete overview of the situation and to evaluate the immunological actions undertaken by the host to contain or eradicate the bacterial infection. Antibodies and cytokines profiles, as well as recruitment of host immune cells at joints of immunized and infected mice were therefore monitored for a time period that allowed us to study both the acute and the chronic phases of the disease in situ. Finally the Novartis vaccine formulation proposed against S. aureus infections was tested for its capacity to protect immunized mice from joints infections, and the preventive immunization was compared to a standard antibiotic prophylaxis. The availability of powerful tools to study specific bacterial-mediated diseases is nowadays an important requirement for the scientific community to shed light on the complex interactions between host and pathogens and to test treatments for preventing or contrasting infections. We believe that our work significantly contributes to the overall knowledge in the field of S. aureus-dependent pathologies, opening the possibility for further investigations in several fields of study.

Evaluation of the transcriptomic response of an Alzheimer's disease murine model induced at different ages: searching for predictors

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disease, characterized by the impairment of mnesic and cognitive functions, that represents the most frequent type of dementia in older people worldwide. Aging is the most important risk factor for the sporadic form of the pathology and it is associated to the progressive impairment of the proteostasis network. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of β-amyloid (Aβ) protein and phosphorylated-tau protein. Increasing proteins misfolding activates a specific cellular response known as Unfolded Protein response (UPR) which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR and aging process in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomers at 3 or 18 months. The oligomers injection in aged animals caused the increased of memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA-sequencing analysis was performed and the bioinformatic analysis showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The following analysis highlighted the significant dysregulation of the three branches of the UPR, the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker of the neurodegenerative process, which regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.