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<p>Cyklosporin A (CsA) är en cyklisk polypeptid med molekylvikten är 1202.6 Da. Substansen har svampursprung (<em>Tolypocladium inflatum Gams)</em> och starka immunhämmande egenskaper. CsA används därför som immunsuppressivt läkemedel för att förhindra avstötning av transplanterade organ och benmärg, samt vid behandling av graft-versus-host-disease (transplantat-mot-värd-sjukdom). CsA har ett snävt terapeutiskt fönster, vilket betyder att skillnaden mellan effektivitet och toxicitet är liten. Biverkningarna av substansen är många och en del av dem allvarliga, såsom nedsatt njurfunktion och ökad risk för utvecklande av diabetes och maligna sjukdomar som exempelvis lymfom. Den inter- och intraindividuella variabiliteten i farmakokinetik och farmakodynamik är dessutom stor. Det är därför ytterst viktigt att följa behandlingen med koncentrationsbestämningar av CsA i helblod.</p><p>Det finns ett flertal olika analysmetoder för CsA tillgängliga, såsom immunoassays, vätskekromatografi (HPLC) och vätskekromatografi-tandem-massspektrometri (LC-MS/MS). Avdelningen för klinisk kemi vid Centralsjukhuset i Karlstad har sedan många år använt en radioimmunoassay, CYCLO-Trac SP^®, från DiaSorin för att bestämma CsA i helblod. Laboratoriets önskan är att ersätta denna metod, vilken använder radioaktiva isotoper, med en snabbare och mer selektiv LC-MS/MS-metod. </p><p>I detta arbete har en LC-MS/MS-metod för analys av cyklosporin A i helblod utvecklats och validerats. Metoden har snabb provupparbetning och kromatografi och använder positiv elektrospray som joniseringsteknik. Två procedurer för proteinfällning utvärderades som provupparbetningsförfarande under metodutvecklingen och två olika internstandarder testades; CsA analogen cyklosporin D och isotopmärkt CsA (d₁₂-CsA). </p><p>Efter den fullständiga valideringen infördes metoden i rutinarbetet 2009-11-01. Resultat från både LC-MS/MS och den radioimmunologiska metoden lämnas ut parallellt under minst fem månader.</p> / <p>Cyclosporine A (CsA) is a cyclic undecapolypeptide of fungal origin (<em>Tolypocladium inflatum Gams</em>). It has a molecular weight of 1202.6 Da and is used as an immunouppressive drug to prevent rejection of transplanted organs and bone marrow, and for the treatment of graft-versus-host disease. CsA exhibits a narrow therapeutic range between efficacy and toxicity. There are many side effects exerted by the drug and some of them are serious, such as renal dysfunction and increased risk of developing diabetes and malignant diseases such as lymphoma. In addition, the inter-individual and intra-individual pharmacokinetic and pharmacodynamic variability is large. Constant monitoring of the CsA-concentration is therefore mandatory. </p><p>There are several analytical methods available for the determination of CsA, such as immunoassays, liquid chromatography (HPLC) and tandem mass spectrometry (LC-MS/MS). The department of Clinical Chemistry at the Central Hospital in Karlstad has for many years used a radioimmunoassay, the CYCLO-Trac SP^® from DiaSorin, for CsA-determinations. The laboratory wants to replace this method, which uses radioactive isotopes, with a faster and more selective LC-MS/MS method. </p><p>In this work a LC-MS/MS method, utilizing positive electrospray, with a fast sample preparation and chromatography for the determination of CsA in whole blood has been developed and validated. Two protein precipitation procedures were evaluated for sample preparation during the method development and two different internal standards were tested; the CsA analog cyclosporine D (CsD) and an isotope labelled CsA (d₁₂-CsA). The LC-MS/MS assay was fully validated and implemented in the routine work at the laboratory on November 1 2009. Results from both the CYCLO-Trac SP^® method and the LC-MS/MS assay will be reported for at least five months.</p>

Two-dimensionally (2D) braided tubular composites have been utilized in a wide range of applications including medical equipment such as braided stents and catheters. Catheters are long flexible tubes used in catheterization procedures, such as angiography and ablations. In this thesis, angiographic catheters were specifically targeted; which are referred as catheters for the remaining of the document. Catheters are typically used with guidewires which provide structural support to the often low rigidity catheters. In some catheterization procedures, it may be beneficial to use a 2D braided catheter for increased control and maneuverability in the body. The 2D braided catheter, if designed properly, may provide all the required rigidities for a successful procedure and decrease the dependency to the guidewire compared to conventional catheters. Hence, use of 2D braided catheters may decrease the procedure time, may provide superior control of the device due to its design, and may also decrease the inherent patient discomfort. A thorough understanding of 2D braided composites is of absolute necessity considering the delicate use of medical equipment, such as catheters, in the human body. The aim of this PhD thesis is to address the shortcomings of the available models in the literature by developing an analytical model geometrically consistent with small braided tubular structures and provide all the necessary tools possible to design a target specific braided catheter. An analytical model that accounts for the effect of diameter of a braided tubular product on the elastic properties, needed for catheter design, was developed. Parametric studies were conducted to highlight the effects of the change in radius on elastic properties of braided composites. Case studies that underline the important geometrical parameters that affect predictions were conducted and findings discussed. Effect of increased undulation length on elastic properties of braided composites was also investigated. The findings were compared to experimental work using three different fiber/matrix system composites. As predicted by the model, a decrease in the properties was observed experimentally; however, this decrease was found to be more important than predicted. Possible reasons for this behavior are discussed in the view of composite materials and geometrical factors. The experimental findings of the open-mesh composites were also used to further validate a regression based model available in the literature. Lower linearity limit values for the regression based model were calculated for longitudinal elastic and shear moduli predictions.

Spectroscopic imaging is a vital tool for studying heterogeneous samples such as bacteria and tissue. Its ability to acquire spatially resolved information allows for identification and classification of the various constituents within a sample. Spectroscopic imagers quickly acquire thousands to tens of thousands of spectra per measurement. These data are often arranged in the form of a 3-dimensional (3D) data cube which contains two spatial dimensions and one spectral dimension. This large amount of data is beneficial for gaining a thorough understanding about the distributions of chemical information. If too little information is measured, important chemical behavior may be overlooked. Statistical analysis algorithms (chemometrics) are required to determine the relevant spectroscopic information within a data cube. Applying chemometrics to such large volumes of data presents computational difficulties regarding computer memory and processing speed. To overcome these burdens, wavelet transform compression is applied prior to chemometric evaluation to accelerate computations and reduce data storage requirements. To optimize compression by enhancing acceleration and reducing approximation errors, different wavelets, or „hybrid wavelets‟, can be applied to the different dimensions of a 3D data set. Determining which combination of wavelets will yield the most compression and best data representation is difficult since many possibilities exist. A compression method is presented that automatically determines the optimum wavelet combinations for a given data set. Principal component analysis (PCA) is used to demonstrate the capabilities of this new procedure, but the compression routine is advantageous for many chemometric techniques. Although linear algorithms like PCA work well in many situations, they are not well-adapted for explaining nonlinear relationships. Kernel principal component analysis (KPCA) has recently been developed to overcome the limitations of linear algorithms. However, when applied to spectroscopic imaging, KPCA calculations require multiple gigabytes of RAM just for holding the data. Therefore, routine use of the algorithm is often prohibited on personal computers. To circumvent such situations, a wavelet compression algorithm is presented that avoids ever having to hold all data in memory at any point during the calculations. The goal is to enable the application of KPCA to large imaging data sets of heterogeneous samples.

Raman spectroscopy is normally a non-destructive, highly selective technique that has become an ubiquitous tool for analytical chemists. One of the primary limitations of Raman spectroscopy, however, is the relatively low cross-section of the technique. With signal enhancements relative to normal Raman scattering as high as 1011, the ultra-trace detection of adsorbates down to the single molecule level has been achieved with SERS. Despite the dramatic improvement in the sensitivity and the high selectivity afforded by the SERS method, the acceptance of SERS as a general analytical tool has been hindered by a lack of stability and reproducibility in the substrates. This lack of stability has been particularly troublesome because unstable substrates exhibit reduced shelf lives as well as a reduced ability to monitor processes that occur under non-ideal conditions such as high temperature or harsh chemical environments. In this thesis, two different works are reported that address the two major hurdles facing the SERS field in the development of a stable and reproducible SERS substrate. First, the development of a SERS-active substrate that exhibits improved temporal and thermal stability and is capable of in-situ high temperature measurement of analytes adsorbed on the surface is presented. The substrates are prepared by depositing an ultra-thin layer of alumina by Atomic Layer Deposition (ALD) onto silver island films grown by thermal evaporation. We demonstrate the application of alumina-coated substrates to the measurement of the dehydration of trace amounts of calcium nitrate tetrahydrate as a function of temperature. As a development of the above mentioned work, the combination of a silver/gold layered architecture obtained by thermal evaporation with an ultra-thin alumina overlayer to generate a re-usable SERS substrate that is simple, relatively inexpensive and stable is reported. The relative thicknesses of the silver and gold and the alumina overlayer was optimized to deliver the maximum SERS enhancement and optimal stability when the substrate was subjected to high temperature. Utilizing the method of thermal desorption of the analyte, the substrate surface is regenerated and able to be reused multiple times with little reduction in SERS activity. Second, in the development of a reproducible SERS substrate, the application of monodisperse silver nanocube colloidal substrate in microfluidic SERS is demonstrated. In static SERS experiments, one often has to search for “hot spots”, which are positions of a drastically increased SERS signal compared to the rest of the probe volume, in an inhomogeneous solution. To overcome this problem and prevent the decomposition and or fragmentation of SERS substrate and analyte, respectively, the implementation of flow cell is a promising way. At the beginning analyte, colloidal solution and aggregation agent were brought into a mixing chamber, where they were thoroughly mixed before being directed to a sample cell for detection. With this method, a relatively high amount of sample volume is necessary. In addition to the advantages listed above, efforts have been made to reduce the required amount of the sample solution by the design of low-cost poly (dimethylsiloxane) chips via soft lithography technique. The sample solution is passively pumped through the microfluidic channel, where an optical detection window is implemented for acquisition of a SERS spectrum.