An investigation was conducted focusing on how NOM affects coagulation in a United States south eastern coastal surface water. Current water treatment practice at Savannah Water I and D was investigated to determine the efficacy of NOM removal using existing coagulation methods. A robust assessment of alum and ferric sulfate for use as coagulants in the removal of disinfection byproduct (DBP) precursor material was conducted using composite water created from sample sites within the SWID watershed. Both coagulants were optimized for the removal of NOM. Pragmatic methods of NOM size analysis and its reactivity with chlorine was investigated. UF membranes were used in conjunction with a permeation coefficient model (PCM) to determine an apparent molecular weight distribution of NOM present in the watershed. Individual size classes were assessed for their potential to form trihalomethanes (THMs) upon chlorination. Coagulation using alum and ferric sulfate was assessed to determine removal efficiency of individual NOM size classes under various coagulation scenarios. Finally, UV254 absorbance (UVA) was assessed to determine its potential use as an indicator of DOC concentration in raw and treated water at SWID. Additionally, an investigation into the relationship between specific UVA (SUVA) and THM formation potential (THM-FP) was conducted.

About half a century ago, Főrster and Kasper discovered that traditional organic chromophore such as pyrene was weakened with an increase in its solution concentration. It was soon recognized that this was a general phenomenon for many aromatic compounds. This concentration-quenching effect was found to be caused by the formation of sandwich-shaped (disc-like) excimers and exciplexes aided by the collisional interactions between the aromatic molecules in the excited and ground states. In 2001, Tang¡¦group discovered such a system, in which luminogen aggregation played a constructive, instead of a destructive, role in the light-emitting process: a series of silole molecules were found to be non-luminescent in the solution state but emissive in the aggregated state. They coined the term ¡¥¡¥aggregation-induced emission¡¦¡¦ (AIE) or ¡§AIE enhancement¡¨ (AIEE) for this novel phenomenon which originated from the restricted intramolecular rotation (RIR) inherent from the chemical structures of the luminescent materials. To verify the effect of molecular structure on the AIE properties of organic and polymeric materials, four approaches were attempted in this research. (I) Aggregation-Induced Emission in Tetraphenylthiophene-Derived Organic Molecules and Vinyl Polymer Organic molecules of tetraphenylthiophene (TP) and the derived model compound of TP-Qu and vinyl polymer of PS-Qu with the pendant group of TP-Qu were prepared and characterized to identify their photoluminescent responses toward the effect of AIE. During aggregate formation, the corresponding TP solutions greatly gained the emission intensity. In contrast, TP-Qu and PS-Qu in isolated or aggregated states emitted strongly with nearly the same emission intensity. RIR is the key factor deciding the AIE effect in different states. With four small phenyl rotors around the central thiophene stator, the RIR of the TP molecules in dilute solution is low but increases upon aggregate formations. In contrast, the bulky C-2 quinoline rotor of the TP-Qu molecule enhances the RIR in isolated state. With the inherent TP-Qu pendant groups, the emissive behavior of vinyl polymer PS-Qu is similar to the TP-Qu molecule. (II) Aggregation-Induced Emission Enhancement of Diblock Copolymer Containing Tetraphenylthiophene-Quinoline Pendant Fluorphores by Selective Solvent Pairs In this study, diblock copolymer of PSQu-PBS containing 25 mol% of fluorescent PSQu segments was synthesized and its aggregation-induced emission enhancement (AIEE) behavior was characterized and compared to PSQu homopolymer with 100 mol% of fluorescent units. With fewer (25 %) fluorescent units, solutions of diblock PSQu-PBS copolymer actually have higher (or comparable) emission intensities than the homopolymer PSQu solutions. Solutions of PSQu-PBS in THF/H2O of varied compositions emit essentially with the same intensity but in contrast, emissions of PSQu-PBS in THF/hexane increase with the increasing hexane content. Copolymer micelles formed in THF/hexane mixtures are supposed to have higher extent of aggregation, leading to more pronounced AIEE effect than micelles formed in THF/H2O. (III) Tetraphenylthiophene-Functionalized Poly(N-isopropylacrylamide): Probing LCST with Aggregation-Induced Emission A hydrophobic TP center with novel AIE property was chemically linked to two poly(N-isopropylacrylamide) (PNIPAM) chains to obtain thermoresponsive polymers to study the relationships between the lower critical solution transitions (LCSTs) and the AIE-operative fluorenscence emission. Three ethynyl-terminated PNIPAMs with different molecular weights were synthesized via controlled atom transfer radical polymerization (ATRP) using ethynyl-functionalized initiator. The PNIPAMs were then coupled with diazide-funtionalized TP (TPN3) via click reaction to obtain the desired TP-embedded polymers of Px (x = 1, 2, and 3). All three polymers show AIE-property from their solution fluorescence behavior in THF/hexane mixtures. In the aqueous solution, the TP-center served as a fluorogenic probe that reveals the LCSTs of polymers and its relation to the degree of TP labeling in terms of polymer concentration. The thermoresponsiveness of Px was demonstrated by the complete emission quench when heated at temperatures above LCST. Dissociation of the TP aggregates above LCST is responsible for the emission quench. (IV) Influence of Molecular Weight on the Aggregation-Induced Emission of Vinyl Polymers Containing the Fluorescent 2,4,6-Triphenylpyridine Pendant Groups Molecular weight effect on the AIEE property of vinyl polymers containing fluorescent 2,4,6-triphenylpyridine (TPP) pendant groups was evaluated in the fourth topic. The high and low Mw vinyl polymers of PDMPS¡VL and ¡VH were prepared through Click chemistry between azide¡VTPP derivative and acetylene¡Vfunctionalized polystyrenes. Solutions of the low Mw PDMPS¡VL exhibited the normal AIEE effect with continuous emission gains with increasing extent of aggregation upon nonsolvent inclusion. On the contrast, the high Mw PDMPS¡VH solutions emitted with constant intensity on all solutions with different extent of aggregation. Despite the varied solution behavior, the solid PDMPS-L and ¡VH films are all strong deep-blue emitter with high quantum yields of 84 and 82.5%, respectively. The emission behavior was explained by the conformational difference between the PDMPS¡VL and ¡VH chains, which were approached by computer simulation in this topic.

Mixed matrix membranes (MMMs) have gained importance because they combine the desirable properties of the polymers and the organic/inorganic filler materials and they may have a very big potential. In this study polyethersulfone (PES) was used as polymeric material, and Zeolitic Imidazolate Framework-8 (ZIF-8) was used as porous filler material, and 2-hydroxy 5-methyl aniline(HMA), was used as a third component in membrane formulation. In this study, ZIF-8 crystals were synthesized with varying particle sizes, and a novel recycling methodology was developed to improve the efficiency of ZIF-8 production. ZIF-8 nano-crystals were synthesized by a 1-hour stirring method at room temperature and characterized by X-ray diffractometer, scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermal gravimetric analysis (TGA). In order to investigate the effect of ZIF-8 loading on the membrane performance, different types of membranes were prepared with varying amounts of ZIF-8 between 10-60% (w/w). Moreover, ternary mixed matrix membranes were synthesized consisting of different amounts of ZIF-8 between 10-30% (w/w) and HMA 1-10% (w/w). Gas transport properties of the membranes were investigated by single gas permeation experiments of H2, CO2 and CH4 at 3 bar feed pressure. In order to investigate the effect of feed pressure on the gas transport properties of the membranes, single gas experiments were conducted on 3, 6, 8, 10 and 12 bar feed pressures. Moreover, binary gas permeation experiments of CO2/CH4 pair were conducted through selected membranes at 3 bar and 12 bar feed pressures. In addition to gas permeation experiments, the morphology and thermal characteristics of the membranes were characterized by SEM, TGA and differential scanning calorimetry (DSC) analysis. The incorporation of ZIF-8 crystals into continuous PES matrix resulted in high performance gas separation membranes. The permeabilities of all studied gases increased with ZIF-8 loading while the ideal selectivities showed a slight decrease compared to neat PES membrane. Highly reproducible and repeatable results were obtained up to 30 % w/w ZIF-8 loading, while membrane formulation reproducibility was decreased for higher ZIF-8 contents (&gt / 30 w/w %). Addition of HMA improved the gas separation performances of the binary membranes significantly by decreasing permeabilities and increasing ideal selectivities. PES/ZIF-8(%20)/HMA(%7) membrane has the best separation performance for all gases among the ternary membranes. When 7 w/w % HMA was added to PES/ZIF-8(%20) membrane, H2 permeability decreased from 26.3 to 13.7 barrer, while H2/CH4 ideal selectivity increased from 61.8 to 103.7. Increasing feed pressures appreciably increased the separation performances of all membranes. While the H2 permeability is pressure independent, the CO2 and CH4 permeabilities were reduced with increasing feed pressures and the highest selectivity improvement was observed in H2/CH4 pair for all membrane compositions. For instance, when the feed pressure was increased from 3 bar to 12 bar, the percentage improvements in ideal selectivities through PES/ZIF-8(%10)/HMA(%4) membrane were calculated as 26, 69, 113 % for the H2/CO2, CO2/CH4 and H2/CH4 gas pairs / respectively. This results show that working at higher feed pressures will be more advantageous for separation of the studied gas pairs. The ideal selectivities and the separation factors were equal to each other for all membrane compositions both for 3 and 12 bar operating pressures.

Low molecular weight organic acids (LMWOAs) are important nutrients for microbes. However, most LMWOAs do not exist freely in the environment but are bound to macromolecular organic matter, e.g. kerogen, lignite and coal. During burial and geological maturation of sedimentary macromolecular organic matter biological and abiological processes promote the liberation of LMWOAs into the surrounding sediment. Through this process, microbes in sedimentary subsurface environments are supplied with essential nutrients. To estimate the feedstock potential of buried macromolecular organic matter to many environments it is important to determine the amount of LMWOAs that are bound to such a matrix. However, high-pressure and high temperature are a key feature of deep subsurface environments, and these physical parameters have a profound influence on chemical reaction kinetics. Therefore it is essential for the estimation of the feedstock potential to generate high-pressure and high temperature for the liberation of LMWOAs to recreate true in-situ conditions. This work presents a newly developed, inexpensive incubation system for biological and geological samples. It allows the application of high-pressure and high temperature as well as a subsampling of the liquid phase without loss of pressure, thereby not disturbing the on-going processes. When simulating the liberation of LMWOAs from sedimentary organic matter, the newly developed incubation system produces more realistic results than other extraction systems like Soxhlet. The extraction products remain in the extraction medium throughout the extraction, influencing the chemical conditions of the extraction medium. Sub-bituminous coal samples from New Zealand as well as lignite samples from Germany were extracted at elevated temperature (90˚C) and pressure (5 MPa). The main LMWOAs released from these low rank coals were formate, acetate and oxalate. Extraction efficiency was increased by two to four times for formate, acetate and oxalate in comparison to existing extraction methods without pressurisation and with demineralised water. This shows the importance of pressure for the simulation of true in-situ conditions and suggests that the amount of bioavailable LMWOAs is higher than previously thought. With the increase in carbon capture and storage (CCS) and the enhanced recovery of oil and gas (EOR/EGR), more and more CO2 becomes injected into the underground. However, the effects of elevated concentrations of carbon dioxide on sedimentary organic matter are rarely investigated. As the incuabtion system allows the manipulation of the composition and partial pressure of dissolved gasses, the effect of highly gas-enriched (CO2, CO2/SO2, CO2/NO2; to simulate flue gas conditions) waters on the extraction yield of LMWOAs from macromolecular organic matter was evaluated. For sub-bituminous coal the concentrations of all LMWAOs decreased upon the addition of gas, irrespective of its composition, whereas for lignite formate always and acetate mostly increased, while oxalate decreased. This suggests an positive effect on the nutrient supply for the subsurface microbiota of lignite layers, as formate and acetate are the most common LMWOAs used for microbial metabolism. In terrestrial mud volcanoes (TMVs), sedimentary material is rapidly ascending from great depth to the surface. Therefore LMWOAs that were produced from buried macromolecular organic matter at depth are also brought up to the surface, and fuel heterotrophic microbial ecosystems at the surface. TMVs represent geochemically and microbiologically diverse habitats, which are supplied with organic substrates and electron acceptors from deep-seated hydrocarbon-generating systems and intersected shallow aquifers, respectively. The main electron donor in TMVs in Azerbaijan is sulphate, and microbial sulphate reduction leads to the production of a wide range of reduced sulphur species that are key players in several biological processes. In our study we estimated the effect of LMWOAs on the sulphur metabolising activity of microorganims in TMVs from Azerbaijan. The addition of a mixture of volatile fatty acids containing acetate and other LMWOAs showed significant positive response to the sulphate reduction rate (SRR) of samples of several mud volcanoes. Further investigations on the temperature dependency of the SRR and the characterisation of thermophilic sulphate-reducing bacteria (SRB) showed a connection between the deep hot subsurface and the surface. / Niedermolekulare organische Säuren (nachfolgend als LMWOAs - low molecular weight organic acids - bezeichnet) stellen wichtige mikrobielle Substrate dar. Jedoch liegen die meisten LMWOAs nicht in freier, bioverfügbarer Form vor, sondern sind vielmehr an hochmolekulare organische Substanzen gebunden, z.B. Kerogen, Lignit und Kohle. Während der geologischen Verbringung in tiefe Erdschichten und der geologischen Reifung von sedimentären hochmolekularen organischen Substanzen, führen biologische und abiologische Prozesse zu einer Freisetzung von LMWOAs in die umgebenden Sedimente. Durch diesen Prozess werden Mikroorganismen in unterirdischen sedimentären Ökosystemen mit essentiellen Nährstoffen versorgt. Um das Nährstoffpotential tief liegender hochmolekularer organischer Substanzen für diverse Ökosystemen abschätzen zu können, ist es notwendig, die Menge an LMWOAs, die an solch eine hochmolekulare Matrix gebunden ist, zu bestimmen. Dabei stellen hoher Druck sowie hohe Temperatur entscheidende Faktoren in tiefen unterirdischen Ökosystemen dar, welche einen signifikanten Einfluss auf chemische Reaktionen haben. Daher ist es für die Abschätzung des Nährstoffpotentials entscheidend, hohen Druck und hohe Temperatur bei der Freisetzung von LMWOAs zu erzeugen, um wahre in situ Bedingungen zu schaffen. In der vorliegenden Arbeit wird ein neu entwickeltes, preiswertes Inkubationssystem für biologische und geologische Proben präsentiert. Es erlaubt die Verwendung von hohem Druck als auch hoher Temperatur sowie eine Unterprobennahme der flüssigen Phase ohne Druckverlust, um den fortlaufende Prozess nicht zu unterbrechen. Bei der Simulierung der Freisetzung von LMWOAs aus sedimentären organischen Substanzen erhält man mit dem neu entwickelten Inkubationssystem realistischere Resultate als mit anderen Extraktionssystemen, wie z.B. eine Soxhlet-Apparatur. Die Extraktionsprodukte verbleiben während der Extraktion im Extraktionsmedium, wodurch die chemischen Bedingungen verändert werden. Kohleproben aus Neuseeland sowie aus Deutschland wurden mittels erhöhter Temperatur (90°C) und Druck (5 MPa) extrahiert. Die wichtigsten LMWOAs, die aus diesen Kohlen freigesetzt wurden, waren Formiat, Acetat und Oxalat. Die Extraktionseffizienz für diese LMWOAs konnte im Vergleich zu existierenden Extraktionsmethoden ohne Druck um den Faktor 2 bis 4 gesteigert werden. Dies zeigt die Bedeutung von Druck bei der Simulation von in situ Bedingungen und legt nahe, dass die Menge an bioverfügbaren LMWOAs größer ist als bisher angenommen. Durch die Zunahme der CO2-Speicherung im Untergrund (carbon capture and storage, CCS) sowie der erweiterten Förderung von Öl und Gas (enhanced recovery of oil and gas, EOR/EGR) wird immer mehr CO2 in den Untergrund gepresst. Jedoch sind die Auswirkungen von erhöhten CO2-Konzentrationen auf sedimentäre organische Materie noch unerforscht. Da mit dem Inkubationssystem die Veränderung der Zusammensetzung und des Partialdruckes von gelösten Gasen möglich ist, wurde der Effekt von hoch mit Gasen (CO2, CO2/SO2, CO2/NO2; um Kraftwerksabgase zu simulieren) angereicherten Wässern auf die Extraktionsausbeute von LMWOAs untersucht. Bei der subbituminösen Kohle zeigte sich eine Abnahme aller LMWOAs-Konzentrationen durch die Lösung von Gas im Extraktionsmedium, wobei die Art des Gases keine Rolle spielte. Bei Lignit konnte hingegen festgestellt werden, dass die Extraktionsausbeute an Formiat immer und an Acetat meistens erhöht wurde, während sie sich bei Oxalat verringerte. Dies deutet auf einen positiven Effekt für die Nährstoffversorgung von Mikroorganismen um Lignit-Lagerstätten an, da Formiat und Acetat die am häufigsten verwendeten LMWOAs im mikrobiellen Stoffwechsel darstellen. In terrestrischen Schlammvulkanen (terrestrial mud volcanoes, TMVs) steigt sedimentäres Material aus großen Tiefen an die Erdoberfläche. Somit werden auch LMWOAs, welche aus hochmolekularen organischen Substanzen freigesetzt werden, an die Oberfläche verbracht, und ermöglichen dort heterotrophe Ökosysteme. TMVs stellen dabei geochemisch und mikrobiell unterschiedliche Habitate dar, welche mit organischen Substraten und Elektronenakzeptoren aus tief liegenden, Kohlenwasserstoffe erzeugenden Systemen versorgt werden. In TMVs in Aserbaidschan stellt Sulfat den Hauptelektronenakzeptor dar, wobei mikrobielle Sulfatreduktion zu einer Vielzahl an reduzierten Schwefelspezies führt. In der vorliegenden Arbeit wurde der Effekt von LMWOAs auf die Aktivität von Mikroorganismen bei der Umsetzung von Schwefel in TMVs in Aserbaidschan untersucht. Die Zugabe einer Mischung verschiedener kurzkettiger Fettsäuren zu Schlammproben verschiedener TMVs erzeugte eine signifikant positive Reaktion in Bezug auf die Sulfat-Reduktionsraten. Weiterführende Untersuchungen zur Temperaturabhängigkeit der Sulfat-Reduktionsraten und die Charakterisierung thermophiler, Sulfat-Reduzierender Bakterien zeigte eine Verbindung zwischen der tiefen, heißen Biosphäre und der Erdoberfläche auf.

The microstructure of polyolefins determines their macroscopic properties. Consequently, it is essential to predict how polymerization conditions will affect polyolefin microstructure. The most important microstructural distributions of ethylene/alfa-olefin copolymers made with coordination catalysts are their molecular weight (MWD), chemical composition (CCD), and comonomer sequence length (CSLD). Several mathematical models have been developed to predict these microstructural distributions; reliable techniques to estimate parameters for these models, however, are still poorly developed, especially for catalysts that have multiple site types, such as heterogeneous Ziegler-Natta complexes. Most commercial polyolefins are made with heterogeneous Ziegler-Natta catalysts, which make polyolefins with broad MWD, CCD, and CSLD. This behavior is attributed to the presence of several active site types, leading to a final product that can be seen as a blend of polymers made on the different catalyst site types. The main objective of this project is to develop a methodology to estimate the most important parameters needed to describe the microstructure of ethylene/alfa-olefin copolymers made with these multiple site-type catalysts. To accomplish this objective, we developed the Integrated Deconvolution Estimation Model (IDEM). IDEM estimates ethylene/alf-olefin reactivity ratios for each site type in two-steps. In the first step, the copolymer MWD, measured by high-temperature gel permeation chromatography, is deconvoluted into several Flory’s most probable distributions to determine the number of site types and the weight fractions of copolymer made on each of them. In the second estimation step, the model uses the MWD deconvolution information to fit the copolymer triad distributions measured by 13C NMR and estimate the reactivity ratios per site type. This is the first time that MWD and triad distribution information is integrated to estimate the reactivity ratio per site type of multiple site-type catalysts used to make ethylene/alfa-olefin copolymers. IDEM was applied to two sets of ethylene-co-1-butene copolymers made with a commercial Ziegler-Natta catalyst, covering a wide range of 1-butene fractions. In the first set of samples (EBH), hydrogen was used as a chain transfer agent, whereas it was absent in the second set (EB). Comparison of the reactivity ratio estimates for the sets of samples permitted the quantification of the hydrogen effect on the reactivity ratios of the different site types present in the Ziegler-Natta catalyst used in this thesis. Since 13C NMR it is an essential analytical step in IDEM, triad distributions for the EB and EBH copolymers were measured in two different laboratories (Department of Chemistry at the University of Waterloo, and Dow Chemical Research Center at Freeport, Texas). IDEM was applied to both set of triad measurements to find out the effect of interlaboratory 13C NMR analysis on reactivity ratio estimation.

Rice starch contains two types of glucose polymers, mainly linear amylose and hyper-branched amylopectin. Waxy rice has been characterised by the lack of amylose, the proportion of which being one of the most important parameters measured for rice quality. Germplasm collection work conducted in the Lao People’s Democratic Republic has previously demonstrated the diversity of this type of rice in terms of quality. The definition of a waxy rice variety is dependent on the meaning of amylose. The conventional method for determining amylose content has shown that waxy rice could have up to 5% amylose. However, including a 0% amylose standard in the standard curve causes the amylose content of these varieties to become 0-2%. In this work, the absence of amylose in waxy rice has been determined through three different approaches. Granule-bound starch synthase I (GBSS1), the enzyme which synthesises amylose, was not detected in waxy rice. Long linear chains associated with amylose were also not detected by size exclusion chromatography (SEC). The absence of these long chains affected functional properties of waxy rice, as indicated by the differences in viscosity curves between waxy and non-waxy rice. Moreover, these waxy varieties themselves exhibit differences in their viscosity curves, another indication of the diversity in coking properties in these varieties. A new approach, the ‘lnP(N) technique’, in analysing chain length distributions was applied to varieties with known mutations in two of the enzymes involved in the synthesis of amylopectin, and in determining gelatinisation temperature. It was determined that the presence of a novel feature, an interruption to linearity at DP 18-24, of the lnP(N) plot was found in rice samples with mutations in the alk gene, which codes for starch synthase (SS) IIa, and in samples with inactive branching enzyme (BE) IIb. Single nucleotide polymorphisms (SNPs) in the gene coding for SSIIa have been associated with lowered gelatinisation temperature. On the other hand, non-functionality of BEIIb changes the amylopectin structure such that gelatinisation temperature is increased. The novel feature of the lnP(N) plot is found when either or both SSIIa and BEIIb are non-functional. Waxy rice starch has hot-water-soluble (HWS) and insoluble (HWI) components. It has been confirmed that the soluble polysaccharides are structurally different from phytoglycogen, and are similar to amylopectin. Structural differences between the two fractions, which can account for their differences in solubility, were determined. At the level of the chain length distribution, the HWI fraction contained long chains not found in the HWS fraction. Considerable amounts of sucrose and glucose were found in the HWS fraction. At another level of structure, the degree of branching of the HWS components was higher than in the HWI fraction. On the other hand, the whole molecules of the HWS fraction were smaller than those of the HWI fraction. These structural differences between the two fractions potentially affected their physical behaviour, particularly solubility. The amount of leached material appears to be a property of the method, as varying cooking conditions changed the amount of HWS components. This amount reaches equilibrium at certain conditions, indicating the limited amount of the HWS material. On the other hand, the HWI component contains molecules that are insoluble in water, rather than molecules that solubilise slowly. Given the stability of the HWS fraction in solution, the ratio of the HWS fraction to the HWI fraction could potentially be used in measuring quality if the amount of the HWS fraction is variety-specific. However, the quantity of the HWS fraction appears to be a feature of the starch, rather than of the variety. Nevertheless, the fact that the soluble fraction is structurally and thermodynamically different from the insoluble fraction could presumably be grounds to classify the soluble component as a group of molecules distinct from amylopectin.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.

This work examines the chemical and physical effects of a material treatment process on the biopolymers PEEK, POM-h, POM-c, PTFE and UHMWPE. The polymers are analyzed physically and chemically using atomic force microscopy, profilometry, scanning electron microscopy, optical microscopy, contact angle measurement, FT infra-red spectroscopy and energy dispersive X-ray spectrometry. PEEK is found to be the most suitable polymer and FT Infra-red spectroscopy an informative analytic tool.

Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-04-13T17:46:55Z No. of bitstreams: 1 MÁRCIA CRISTINA DE MORAES REIS RIBEIRO - DISSERTAÇÃO PPG-CEMat 2014..pdf: 1739612 bytes, checksum: 483de315f077aaf3a1be5bb9bddc6639 (MD5) / Made available in DSpace on 2018-04-13T17:46:55Z (GMT). No. of bitstreams: 1 MÁRCIA CRISTINA DE MORAES REIS RIBEIRO - DISSERTAÇÃO PPG-CEMat 2014..pdf: 1739612 bytes, checksum: 483de315f077aaf3a1be5bb9bddc6639 (MD5) Previous issue date: 2014-07-16 / O polietileno de ultra alto peso molecular (PEUAPM) é um polímero com excelentes propriedades físicas e mecânicas tendo como mais notáveis a sua inércia química, a lubricidade, resistência impacto e resistência a abrasão. Exibe um papel relevante no sucesso na Artroplastia Total de Joelho (ATJ) e Artroplastia Total de Quadril (ATQ). A Artroplastia se caracteriza pela substituição da articulação natural por uma articulação artificial. As articulações artificiais são formadas por um conjunto de componentes, sendo fabricados de matéria prima metálica ou cerâmica e um componente, normalmente feito em PEUAPM, que é interposto entre componentes metálicos. Alguns fatores contribuem para um maior desgaste do componente de polietileno. Os componentes fabricados em polietileno PEUAPM não possuem fotoestabilizadores. E em inspeções realizadas em fabricantes e distribuidores destes produtos foi observado que durante seu processamento fabril e comercialização eles não são adequadamente protegidos da iluminação direta. As características consideradas importantes para o desempenho in vitro destes dispositivos estão definidas em normas técnicas, mas muitas destas normas somente recomendam determinados requisitos considerados importantes do ponto de vista técnico. Atualmente a área de materiais de uso em saúde trabalha em regulamentos que visam instituir os requisitos mínimos para registro de implantes ortopédicos. Desta forma, este trabalho propôs avaliar as possíveis alterações de componentes fabricados em polietileno de ultra alto peso molecular utilizados em procedimentos cirúrgicos de artroplastia e joelho e quadril, exposto a radiação ultravioleta. O trabalho foi dividido em 4 grupos: grupo 1 (material não exposto a UV); grupo 2 (material exposto a UV por 1h); grupo 3 (material exposto a UV por 24h) e grupo 4 (material exposto a UV por 48h). Todas as amostras foram caracterizadas por Difração de Raio X (DRX), Espectroscopia de Absorção de Infravermelho por Transformada de Fourier (FTIR), Microscopia Ótica (MO), Microscopia Eletrônica de Varredura (MEV) com mapeamento por EDS e Microscopia de Força Atômica (AFM) com o intuito de avaliar as possíveis degradações do PEUAPM submetidos a radiação UV. Os resultados demonstraram que a exposição do polímero a radiação UV em todos os tempos testados neste trabalho promoveu alterações nas amostras, pois foi observado, principalmente, nos ensaios de DRX e EDS que ocorreu respectivamente, um discreto aumento da cristalinidade do material e diminuição no percentual de oxigênio. Desta forma, pode-se concluir que o aumento da cristalinidade pode, pela ação da radiação UV, afetar nas propriedades do material contribuindo para o aumento do desgaste e diminuição do tempo de vida útil do implante. / The polyethylene, ultra high molecular weight (UHMWPE) is a polymer with excellent physical and mechanical properties with the most notable its chemical inertness, lubricity, impact resistance and abrasion resistance. Displays a relevant role in the successful Total Knee Arthroplasty (TKA) and Total Hip Arthroplasty (THA). The arthroplasty is characterized by replacement of the natural joint with an artificial joint. Artificial joints are formed by a set of components, being manufactured from metal or ceramic raw material and a component normally done in UHMWPE, which is interposed between the metal components. Some factors contribute to increased wear of the polyethylene component. Components manufactured in polyethylene UHMWPE not have photostabilizers. And inspections on manufacturers and distributors of these products was observed that during its industrial processing and marketing they are not adequately protected from direct light. Characteristics considered important for the in vitro performance of these devices are set in technical standards, but many of these standards only recommend certain requirements considered important from a technical standpoint. Currently the area of materials for use in healthcare working on regulations that seek to establish the minimum requirements for registration of orthopedic implants. Thus, this study aimed to evaluate the possible changes of components manufactured in polyethylene, ultra high molecular weight used in surgical procedures and knee arthroplasty and hip, exposed to ultraviolet radiation. The work was divided into 4 groups: group 1 (material not exposed to UV); group 2 (material exposed to UV for 1 h); group 3 (material exposed to UV for 24 h) and group 4 (material exposed to UV for 48 h). All samples were characterized by X-Ray Diffraction (XRD), Absorption Spectroscopy Fourier Transform Infrared (FTIR), optical microscopy (OM), scanning electron microscopy (SEM) with EDS mapping and Atomic Force Microscopy (AFM) in order to evaluate the possible degradation of UHMWPE subjected to UV radiation. The results showed that exposure of the polymer to UV radiation at all times tested in this study modified the samples, it was observed mainly in the experimental XRD and EDS which occurred respectively a slight increase in crystallinity and decrease in the percentage oxygen. Thus, it can be concluded that the increase in crystallinity can by the action of UV radiation, affect the material properties contributing to increased wear and reduced useful life of the implant.

O objetivo da presente tese foi avaliar os efeitos da heparina de baixo peso molecular (HBPM) na perda óssea alveolar em ratos Wistar. Para a melhor compreensão e entendimento dos efeitos da HBPM se elaborou um único artigo com 40 ratos machos da linhagem Wistar de 60 dias de nascidos, os quais foram dívidos em 4 grupos experimentais previamente randomizados: Grupo Controle (C), Grupos Doença Periodontal (DP), Grupo Heparina (Hp) e Grupo Heparina+Doença Periodontal (Hp+DP) com um período experimental de 60 dias. Um animal foi perdido no período de aclimação, dois animais foram perdidos na primeira de três coletas sanguíneas pré-programadas e um rato foi perdido na colocação da ligadura. Os resultados observados foram analisados são perda óssea alveolar induzida onde houve diferença significava entre os grupos (C) e (DP), entre o grupo (C) e (Hp+DP), entre o grupo (DP) e (Hp) e o grupo (Hp) e (Hp+DP). Foi avaliado perda óssea alveolar não induzida onde não existiu diferença entre os grupos. Foi avaliado o peso do início ao final do período experimental. Foram avaliados o consumo de ração e agua onde não houve diferença significativa entre os grupos. Foram avaliados o número de megacariócitos nos fémures, onde também não existiram diferenças estatísticas. Foram avaliados números de adipócitos no timo, não havendo diferença significativa entre os grupos. Foram avaliados as plaquetas e desvio padrão onde não existiu diferença significativa entre os grupos. Foram avaliados os leucócitos e desvio padrão onde não houve diferença significativa entre os grupos. Posteriormente foi avaliado a porcentagem de linfócitos onde se achou diferença estatisticamente significativa na segunda coleta sanguínea entre o grupo (C) e grupo (Hp+DP) e grupo (Hp) e grupo (Hp+DP). Foi assim que as conclusões deste trabalho foram que o presente estudo mostrou que a HBPM não foi capaz de produzir perda óssea alveolar nos ratos Wistar, mas foi capaz de aumentar a quantidade de leucócitos e linfócitos, indicando a presença de um processo inflamatório. / In order to better understand and understand the effects of (LMWH), a single article was elaborated with 40 male rats of the 60 day old Wistar line, which were divided into four previously randomized experimental groups: Control Group (C), Groups Periodontal Disease (PD), Heparin Group (Hp) and Heparin Group + Periodontal Disease (Hp + PD) with an experimental period of 60 days. One animal was lost in the acclimation period, two animals were lost in the first of three preprogrammed blood collections and one mouse was lost in the ligation placement. The observed results were analyzed for induced alveolar bone loss where there was significant difference between groups (C) and (PD), between group (C) and (Hp + PD), between (PD) and (Hp) group and Group (Hp) and (Hp + PD). Uninduced alveolar bone loss was assessed where there was no difference between the groups. The weight of the onset at the end of the experimental period was evaluated. The ration and water consumption were evaluated where there was no significant difference between the groups. The number of megakaryocytes in the femurs was evaluated, in which there were also no statistical differences. Adipocyte numbers were evaluated in the thymus, with no significant difference between the groups. Platelets and standard deviation were evaluated where there was no significant difference between the groups. Leukocytes and standard deviation were evaluated where there was no significant difference between the groups. Later, the percentage of lymphocytes where a statistically significant difference was found in the second blood collection between group (C) and group (Hp + PD) and group (Hp) and group (Hp + PD) was evaluated. Thus the conclusions of this study were that the present study showed that LMWH was not able to produce alveolar bone loss in Wistar rats, but was able to increase the amount of leukocytes and lymphocytes, indicating the presence of a process inflammatory.