One of the most important prerequisites in the drug development is to attain a reproducible and robust product in terms of its nature, and its chemical and physical properties. This can be challenging, since the crystalline form of drugs and excipients can be directly transformed into the amorphous one during normal pharmaceutical processing, referred to as process-induced amorphisation or process-induced disorder. The intention of this thesis was to address the mechanisms causing disorder during powder flow and milling and, in association with this, to evaluate, the ability of Raman spectroscopy and atomic force microscopy (AFM) to quantify and characterize process-induced disorder. The amorphisation mechanisms were controlled by stress energy distribution during processing, which in turn was regulated by a series of process parameters. Compression and shearing stress caused by sliding were stress types that acted on the particles during powder flow and ball milling process. However, sliding was the most important inter-particulate contact process giving rise to amorphisation and the transformation was proposed to be caused by vitrification. The plastic stiffness and elastic stiffness of the milling-induced particles were similar to a two-state particle model, however the moisture sorption characteristics of these particles were different. Thus the milled particles could not be described solely by a two-state particle model with amorphous and crystalline domains.  Raman spectroscopy proved to be an appropriate and effective technique in the quantification of the apparent amorphous content of milled lactose powder. The disordered content below 1% could be quantified with Raman spectroscopy. AFM was a useful approach to characterize disorder on the particle surfaces. In summary, this thesis has provided insight into the mechanisms involved in process-induced amorphisation of pharmaceutical powders and presented new approaches for quantification and characterization of disordered content by Raman spectroscopy and atomic force microscopy.

Small cantilevers with ultra-high resonant frequencies (1–3 MHz) have paved the way for high-speed atomic force microscopy. However, their potential for multi-frequency atomic force microscopy is unexplored. Because small cantilevers have small spring constants but large resonant frequencies, they are well-suited for the characterisation of delicate specimens with high imaging rates. We demonstrate their imaging capabilities in a bimodal frequency modulation mode in constant excitation on semi-crystalline polypropylene. The first two flexural modes of the cantilever were simultaneously excited. The detected frequency shift of the first eigenmode was held constant for topographical feedback, whereas the second eigenmode frequency shift was used to map the local properties of the specimen. High-resolution images were acquired depicting crystalline lamellae of approximately 12 nm in width. Additionally, dynamic force curves revealed that the contrast originated from different interaction forces between the tip and the distinct polymer regions. The technique uses gentle forces during scanning and quantified the elastic moduli Eam = 300 MPa and Ecr = 600 MPa on amorphous and crystalline regions, respectively. Thus, multimode measurements with small cantilevers allow one to map material properties on the nanoscale at high resolutions and increase the force sensitivity compared with standard cantilevers. / Dieser Beitrag ist aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The enhancement of strength of nanoscale materials such as face-centered cubic metal nanowires is well known and arises largely from processes mediated by high energy surface atoms. This leads to strong size effects in nanoscale plasticity; ,smaller is stronger. Yet, other factors, such as crystalline defects also contribute greatly to the mechanical properties. In particular, twin boundaries, which are pervasive and energetically favorable defects in face-centered cubic metal nanowires, have been shown to greatly enhance the strength, furthermore this increase in strength has been shown to be directly influenced by the twin density. However, attempts to control the introduction of beneficial defects remains challenging. Additionally, even minor local variations in the crystalline structure or size of metal nanowires may have drastic effects on the yielding of metal nanowires, which are difficult to measure through tensile and bending tests. In this study, atomic force microscopy based nanoindentation techniques are used to measure the local plasticity of Ni-Au bimetallic as well as Cu and Ag metallic nanowires. In the first part of the thesis the hardness of bimetallic nanowires synthesized through template-assisted electrodeposition is measured and found to show significant size-effects. It was found that the nanoindentation hardness was governed by materials properties, the observed indentation size effects were dependent on geometrical factors. The second part of this thesis presents a methodology to control the crystal structure of Ag and Cu nanowires through direct electrodeposition techniques, which were tested directly as grown on the substrate to limit effects of pre-straining. Ag nanowires showed marked size-effects as well as two distinct modes of deformation which we attribute to the defects that arise during crystalline growth. We also show control of the surface microstructure in Cu nanowires which leads to strengths that are more than doubled compared to single crystalline Cu nanowires. Finally, we present support from classic crystal growth theory to justify that the observed plasticity in Ag and Cu nanowires is largely dependent on defects that are nucleated through changes in the growth environment.

The use of graphene and conductive polyaniline nanomaterials in the field of electrochemistry is increasing due to their excellent conductivity, rapid electron transfer and high specific surface area. However, these properties are strongly dependent on the preparation processes. To accelerate the development of advanced electrochemical sensors for the simultaneous detection of trace amounts of heavy metal ions, two facile and green methods are proposed to improve their performance in this thesis. The first one was dedicated to make graphene-carbon nanotube hybrid nanocomposites. The introduction of carbon nanotubes not only greatly enhances the conductivity of graphene but also suppresses, to some degree, the aggregation between graphene nanosheets. Another method proposed in this thesis work was to synthesize a phytic acid doped polyaniline nanofiber based nanocomposite. The synergistic contribution from polyaniline nanofibers and phytic acid enhances the accumulation efficiency and the charge transfer rate of metal ions during the differential pulse anodic stripping voltammetry analysis. The above-mentioned nanocomposite modified electrodes were all successfully applied to real samples for the simultaneous detection of Cd2+ and Pb2+ with good recovery rates. Meanwhile, corrosion protection is another important branch in the field of electrochemistry. In this direction, an active alkyd-polyaniline composite coating with self-healing functionality was prepared. The polyaniline used in this thesis was doped with p-toluene sulfonic acid, which was employed to increase the conductivity of polyaniline, and 1 wt.% of as-prepared polyaniline nanoparticles were found to offer an effective conductive network for anticorrosion. Finally, the reasons that such low loading levels of nanomaterials can result in significantly reinforced properties in nanocomposites were studied with combined atomic force microscopy (AFM) techniques. The results demonstrated that the interphase for a 40-nm-sized silica particle could extend to 55–70 nm in poly(ethyl methacrylate) (PEMA) and poly(isobutyl methacrylate) (PiBMA) polymer matrix, and the interphase exhibited a gradient distribution in surface nanomechanical properties. / <p>QC 20170315</p>

This research concerns the development and characterization of methylene bis (p-cyclohexyl isocyanate/butanediol) (HMDI/BD) based polyurethanes used in connection with surface-active anti-microbial polyurethanes. Previously studied polyurethanes having an isophorone diisocyanate/butanediol (IPDI/BD) hard block contaminated water during dynamic contact angle (DCA) analyses. This contamination by unknown species confounds results from biocidal studies and jeopardizes the use of the polyurethane as a matrix polyurethane. By contrast, polyurethanes with methylene bis (p-cyclohexyl isocyanate)/butanediol hard block showed no contamination during DCA analysis. For this reason, further study of HMDI/BD/PTMO polyurethanes was conducted. HMDI/BD polyurethanes were synthesized with 15-50wt% hard block and a soft block of PTMO-2000 or PTMO-1000 where PTMO-2000 is poly (tetramethylene oxide) with a molecular weight of 2000g/mol and PTMO-1000 has a molecular weight of 1000g/mol. Characterization was performed with FT-IR and 1H NMR spectroscopy to verify polyurethane composition as well as hard block percentage. Thermal characterization was performed with modulated differential scanning calorimetry (MDSC). From MDSC, the glass transition temperatures of the soft and hard block for polyurethanes with PTMO-2000 as the soft block were -80°C and 86°C, respectively. For corresponding polyurethanes containing PTMO-1000 as the soft block, the measured Tgs for the soft and hard segments were -55°C and 65°C, respectively. The disparity between the respective soft and hard segment Tgs of these polyurethanes of differing soft block molecular weights is due to increased phase mixing that causes an increase in soft block Tg and a decrease in hard block Tg for the PTMO-1000 polyurethanes. From dynamic contact angle analyses of HMDI/BD/PTMO polyurethanes, the advancing and receding contact angles gradually decreased with each cycle but approached 80° and 60°, respectively. Results from force-distance curves with flamed glass slides obtained before and after immersion of the polyurethane coatings indicated that no water contamination occurred. Tensile tests demonstrated that hard block percentage, soft block molecular weight, and the amount of chain extender influences mechanical properties. For example, increasing hard block weight percentage increases the modulus. HMDI/BD(30)/PTMO-2000 (PU-1), HMDI/BD(25)/PTMO-2000, (PU-2) and HMDI/BD(35)/PTMO-2000 (PU-10) exhibited the best elastomeric properties. As the final outcome, lack of contamination and good mechanical properties made PU-2 and PU-9 (HMDI/BD(50)/PTMO-1000) suitable candidates as polyurethane matrices for polymer surface modifier evaluation.

Biomolecules on cell surfaces play critical roles in diverse biological and physiological processes. However, conventional bulk scale techniques are unable to clarify the density and distribution of specific biomolecules in situ on single, living cell surfaces at the micro or nanoscale. In this work, a single cell analysis technique based on Atomic Force Microscopy (AFM) is developed to spatially identify biomolecules and characterize nanomechanical properties on single cell surfaces. The unique advantage of these AFM-based techniques lies in the ability to operate in situ (in a non-destructive fashion) and in real time, under physiological conditions or controlled micro-environments. First, AFM-based force spectroscopy was developed to study the fundamental biophysics of the heparin/thrombin interaction at the molecular level. Based on force spectroscopy, a force recognition mapping strategy was developed and optimized to spatially detect single protein targets on non-biological surfaces. This platform was then translated to the study of complex living cell surfaces. Specific carbohydrate compositions and changes in their distribution, as well as elasticity change were obtained by monitoring Bacillus cells sporulation process. The AFM-based force mapping technique was applied to different cellular systems to develop a cell surface biomolecule library. Nanoscale imaging combined with carbohydrate mapping was used to evaluate inactivation methods and growth temperatures effects on Yersinia pestis surface. A strategy to image cells in real time was coupled with hydrophobicity mapping technique to monitor the effect of antimicrobials (antimicrobial polymer and copper) on Escherichia coli and study their killing mechanisms. The single spore hydrophobicity mapping was used to localize the exosporium structure and potentially reconstruct culture media. The descriptions of cell surface DNA on single human epithelial cells potentially form a novel tool for forensic identification. Overall, these nanoscale tools to detect and assess changes in cell behavior and function over time, either as a result of natural state changes or when perturbed, will further our understanding of fundamental biological processes and lead to novel, robust methods for the analysis of individual cells. Real time analysis of cells can be used for the development of lab-on-chip type assays for drug design and testing or to test the efficacy of antimicrobials.

Phospholipase Cβ (PLCβ) cleaves phosphatidylinositol-4,5-bisphosphate (PIP₂) into the second messengers inositol-1,4,5-triphosphate (IP₃) and diacylglycerol (DAG). IP₃ increases intracellular Ca²⁺, while DAG remains in the membrane, and together with increased Ca²⁺, activates protein kinase C (PKC). PLCβ has low basal activity but is activated following stimulation of G_i- and G_q-coupled receptors through direct interactions with Gα_q and Gβγ. PLCβ is essential for normal cardiomyocyte and vascular smooth muscle function and regulates cell proliferation, survival, migration, and differentiation. However, increased PLCβ activity and expression results in arrhythmias, hypertrophy, and heart failure. PLCβ must interact with the cell membrane for its activity. While heterotrimeric G proteins stimulate PLCβ, they are insufficient for full activation, suggesting the membrane itself contributes to increased lipid hydrolysis, potentially via interfacial activation. However, how the composition of the membrane and its resulting properties, such as surface charge, contribute to adsorption and interfacial activation is not well-established. Furthermore, whether or how interfacial activation also impacts other regulatory elements in PLCβ and Gα_q-dependent activation is unknown. Using an innovative combination of atomic force microscopy on compressed lipid monolayers and biochemical assays, we are beginning to understand how the membrane itself, PLCβ autoinhibitory elements and Gα_q regulate PLCβ activation. These studies provide the first structure-based approach to understanding how the cell membrane regulates the activity of this essential effector enzyme.

Les événements biochimiques de l'activation T ont été décrits depuis longtemps et sont bien connus. A l'échelle moléculaire la liaison du Récepteur des Cellules T (TCR) présent à la surface du lymphocyte T avec un peptide (du soi ou non soi), ce dernier étant chargé sur le Complexe Majeur d'Histocompatibilité (MHC), présent à la surface des Cellules Présentatrices d'Antigène (CPA) conduit à l'initiation de la réponse immunitaire. La réponse des lymphocytes T est extrêmement spécifique, sensible, robuste et semble présenter des caractéristiques de mécano-transduction. En effet, il a été démontré récemment que le TCR agirait comme un mécanosenseur alors que le lymphocyte T peut sentir la mécanique de son environnement à une échelle cellulaire. Cependant, la majorité de ces études ont été réalisées en opposant un lymphocyte T à un substrat inerte limitant la compréhension sur la contribution éventuelle de chaque partenaire cellulaire car la présence de l'APC peut induire des changements dans l'organisation du lymphocyte T.Le but de cette thèse a été de mettre en place un suivi de l’activation des lymphocytes T pat une APC modèle, sous force grâce à l’utilisation de la microscopie à force atomique. Il a mené à plusieurs développements méthodologiques originaux validés de manière expérimentale avec un système cellulaire modèle (hybridomes murins vs. Cellules COS modifiées pour être des APC pouvant être modifiées à souhait grâce à l’expression d’une grande variété de molécules impliquées dans la réponse immunitaire). / The biochemical events of T activation have been described for a long time and are well known. At the molecular level, the binding of the T-cell receptor (TCR) present on the surface of the T-cell with a peptide (self or non-self) loaded on the Major Histocompatibility Complex (MHC), present on the surface of the Antigen Presenting Cells (APC), leads to the initiation of the immune response. In addition, the T cell response is extremely specific, sensitive, robust and appears to have mechano-transduction characteristics. Indeed, it has recently been demonstrated that the TCR would act as a mechanosensor while the T lymphocyte can feel the mechanics of its environment on a cellular scale. However, the majority of these studies were performed by opposing/facing a T cell to an inert substrate (e.g., bead, functionnlized glass slides molecularly decorated or not), limiting the understanding of the possible contribution of each cell partner because the presence of APC can induce changes in the organization of the T cell. The aim of this thesis was to set up a follow-up of the activation, under force, between a model APC and a T lymphocyte. It has led to several original methodological developments experimentally validated with a model cell system (mouse hybridomas vs. COS cells modified to be complexifiable APCs).

Neste trabalho investigamos a dinâmica de crescimento de filmes de diamante sintetizados por meio de deposição química a vapor ativada por plasma de microondas (CVD). A caracterização foi feita utilizando, fundamentalmente, microscopia de força atômica (AFM). Analisamos o comportamento da rugosidade dos filmes como função da escala de observação e do tempo de deposição. Dessa maneira verificamos a existência de leis de potência para o crescimento e determinamos os expoentes críticos associados a essas leis. Os resultados obtidos estão em bom acordo com o processo de crescimento descrito pela equação estocástica KPZ. Os mecanismos principais são a deposição aleatória de partículas na superfície, o crescimento lateral e a dessorção. / Diamond films have been grown by Microwave Plasma assisted Chemical Vapor Deposition (CVD). The characterization has been made mainly by Atomic Force Microscopy (AFM). We could analyze the roughness behavior with the scale of observation and with the deposition time. We could determine the critical exponents associated with these laws. The results suggest that the growth process is in good agreement with the stochastic growth equation known as KPZ. The most important mechanisms are the random deposition, the lateral growth and the desorption.

by Choy Wing Hong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 95-102). / Text in English; abstract also in Chinese. / by Choy Wing Hong. / ABSTRACT --- p.vi / ACKNOWLEDGEMENTS --- p.x / LIST OF FIGURES --- p.xi / LIST OF TABLES --- p.xiii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Background --- p.1 / Chapter 1.2 --- Surface passivation techniques --- p.2 / Chapter 1.2.1 --- Sulfide solution passivation --- p.2 / Chapter 1.2.2 --- Gas-phase sulfide passivation --- p.3 / Chapter 1.2.3 --- Ultra-violet and ozone exposure --- p.4 / Chapter 1.3 --- Surface structure of sulfide-passivated surface --- p.5 / Chapter 1.4 --- Surface structure of ultra-violet/ozone oxidation --- p.8 / Chapter 1.5 --- Objectives of present study --- p.10 / Chapter Chapter 2 --- Instrumentation --- p.12 / Chapter 2.1 --- Introduction --- p.12 / Chapter 2.2 --- Atomic force microscopy (AFM) --- p.12 / Chapter 2.2.1 --- The development of AFM --- p.12 / Chapter 2.2.2 --- Basic principles of AFM --- p.12 / Chapter 2.2.3 --- Forces and their relevance to atomic force microscopy --- p.13 / Chapter 2.2.3.1 --- Van Der Waals forces --- p.15 / Chapter 2.2.3.2 --- Repulsive forces --- p.15 / Chapter 2.2.3.3 --- Capillary forces --- p.15 / Chapter 2.2.4 --- Displacement sensor of AFM --- p.15 / Chapter 2.2.4.1 --- Electron tunneling --- p.16 / Chapter 2.2.4.2 --- Optical interference --- p.16 / Chapter 2.2.4.3 --- Laser beam deflection --- p.16 / Chapter 2.2.5 --- Instrument specification --- p.17 / Chapter 2.2.5.1 --- Contact mode AFM --- p.17 / Chapter 2.3 --- X-ray photoelectron spectroscopy --- p.19 / Chapter 2.3.1 --- The development of XPS --- p.19 / Chapter 2.3.2 --- Basic principles of XPS --- p.19 / Chapter 2.3.3 --- XPS experiments --- p.23 / Chapter 2.3.4 --- Quantitative analysis --- p.26 / Chapter 2.3.4.1 --- Atomic concentration of a homogenous materials --- p.26 / Chapter 2.3.4.2 --- Layer structure --- p.27 / Chapter 2.4 --- Rutherford backscattering spectrometry (RBS) --- p.29 / Chapter 2.4.1 --- Basic principles --- p.29 / Chapter 2.4.2 --- Kinematics --- p.29 / Chapter 2.4.3 --- Channeling --- p.31 / Chapter Chapter 3 --- Surface treatments --- p.32 / Chapter 3.1 --- Semiconductor wafer --- p.32 / Chapter 3.2 --- Cleaning procedures --- p.32 / Chapter 3.3 --- Polysulfide passivation --- p.34 / Chapter 3.4 --- UV/Ozone oxidation --- p.39 / Chapter Chapter 4 --- Surface roughness and oxide contents of sulfide passivation --- p.41 / Chapter 4.1 --- Introduction --- p.41 / Chapter 4.2 --- Experimental methodology --- p.42 / Chapter 4.3 --- Etching --- p.44 / Chapter 4.3.1 --- Etching effect of polysulfide solution --- p.45 / Chapter 4.3.2 --- Possible consequences of the etching effect --- p.45 / Chapter 4.4 --- Oxide contents --- p.47 / Chapter 4.4.1 --- Oxide gained during polysulfide solution treatment --- p.47 / Chapter 4.4.2 --- Oxide gained after polysulfide passivation --- p.47 / Chapter 4.5 --- Surface roughness --- p.49 / Chapter 4.5.1 --- Surface roughness after different passivation methods --- p.49 / Chapter 4.5.2 --- The sticking probability after different passivations --- p.51 / Chapter 4.6 --- The spiral ladder of solution-phase passivation --- p.55 / Chapter 4.7 --- Conclusions --- p.58 / Chapter Chapter 5 --- Sulfide on Ge/GaAs heterojunction --- p.59 / Chapter 5.1 --- Introduction --- p.59 / Chapter 5.1.1 --- Band structure of Ge/GaAs heteroj unction --- p.59 / Chapter 5.1.2 --- Lattice match of Ge/GaAs heteroj unction --- p.60 / Chapter 5.1.3 --- The growth of Ge on GaAs using molecular beam epitaxy --- p.62 / Chapter 5.2 --- The growth of Ge on GaAs using thermal pulse annealing --- p.63 / Chapter 5.3 --- Sulfide as an atomic interdiffusion barrier --- p.65 / Chapter 5.3.1 --- Experimental methodology --- p.65 / Chapter 5.3.2 --- Crystallinity of Ge --- p.67 / Chapter 5.3.3 --- Results and discussions --- p.67 / Chapter 5.3.3.1 --- RBS and XPS results --- p.67 / Chapter 5.3.3.2 --- AFM and I-V results --- p.71 / Chapter 5.4 --- Conclusions --- p.71 / Chapter Chapter 6 --- UV/03 on Ge/GaAs heterojunction --- p.72 / Chapter 6.1 --- Introduction of UV/o3 oxidation --- p.72 / Chapter 6.2 --- UV/o3 oxidation on GaAs --- p.74 / Chapter 6.3 --- Ge on UV/o3 treated GaAs --- p.76 / Chapter 6.3.1 --- Experimental methodology --- p.76 / Chapter 6.3.2 --- Crystallinity of Ge --- p.77 / Chapter 6.3.3 --- AFM results --- p.77 / Chapter 6.3.4 --- RBS results --- p.80 / Chapter 6.4 --- Diodes --- p.82 / Chapter 6.4.1 --- Fabrication of diode --- p.82 / Chapter 6.4.2 --- Diode characteristics --- p.84 / Chapter 6.4.3 --- I-V characteristics --- p.90 / Chapter 6.5 --- Conclusions --- p.90 / Chapter Chapter 7 --- Conclusion and future work --- p.93 / Chapter 7.1 --- Conclusions --- p.93 / Chapter 7.2 --- Future works --- p.94 / Reference --- p.95