Within the field of neuroprosthetics the possibility to use implanted electrodes for communication with the nervous system is explored. Much effort is put into the material aspects of the electrode implant to increase charge injection capacity, suppress foreign body response and build micro sized electrode arrays allowing close contact with neurons. Conducting polymers, in particular poly(3,4-ethylene dioxythiophene) (PEDOT), have been suggested as materials highly interesting for such neural communication electrodes. The possibility to tailor the material both mechanically and biochemically to suit specific applications, is a substantial benefit with polymers when compared to metals. PEDOT also have hybrid charge transfer properties, including both electronic and ionic conduction, which allow for highly efficient charge injection.   Part of this thesis describes a method of tailoring PEDOT through exchanging the counter ion used in electropolymerisation process. Commonly used surfactants can thereby be excluded and instead, different biomolecules can be incorporated into the polymer. The electrochemical characteristics of the polymer film depend on the ion. PEDOT electropolymerised with heparin was here determined to have the most advantageous properties. In vitro methods were applied to confirm non-cytotoxicity of the formed PEDOT:biomolecular composites. In addition, biocompatibility was affirmed for PEDOT:heparin by evaluation of inflammatory response and neuron density when implanted in rodent cortex.   One advantage with PEDOT often stated, is its high stability compared to other conducting polymers. A battery of tests simulating the biological environment was therefore applied to investigate this stability, and especially the influence of the incorporated heparin. These tests showed that there was a decline in the electroactivity of PEDOT over time. This also applied in phosphate buffered saline at body temperature and in the absence of other stressors. The time course of degradation also differed depending on whether the counter ion was the surfactant polystyrene sulphonate or heparin, with a slightly better stability for the former.   One possibility with PEDOT, often overlooked for biological applications, is the use of its semi conducting properties in order to include logic functions in the implant. This thesis presents the concept of using PEDOT electrochemical transistors to construct textile electrode arrays with in-built multiplexing. Using the electrolyte mediated interaction between adjacent PEDOT coated fibres to switch the polymer coat between conducting and non conducting states, then transistor function can be included in the conducting textile. Analogue circuit simulations based on experimentally found transistor characteristics proved the feasibility of these textile arrays. Developments of better polymer coatings, electrolytes and encapsulation techniques for this technology, were also identified to be essential steps in order to make these devices truly useful.   In summary, this work shows the potential of PEDOT to improve neural interfaces in several ways. Some weaknesses of the polymer and the polymer electronics are presented and this, together with the epidemiological data, should point in the direction for future studies within this field. / QC 20100623

Left ventricular (LV) volumes and ejection fraction (EF) are important predictors of cardiac morbidity and mortality. LV volumes provide valuable prognostic information which isparticularly useful in the selection of therapy or determination of the optimal time for surgery. Two-dimensional (2D) echocardiography is the most widely used non-invasive method forassessment of cardiac function, 2D echocardiography has however several limitations inmeasuring LV volumes and EF since the formulas for quantifications are based on geometricalassumptions. Three-dimensional (3D) echocardiography has been available for almost twodecades, although the use of this modality has not gained wide spread acceptance. 3D echocardiography can overcome the above mentioned limitation in LV volume and EF evaluation since it is not based on geometrical assumption. 3D echocardiography has been shownin several studies to be more accurate and reproducible with low inter- and intraobservervariability in comparison to 2D echocardiography regarding the measurements of LV volumesand EF. The overall aim of the thesis was to evaluate the feasibility and accuracy of 3D echocardiography based-methods in the clinical context. In Study I the feasibility of 3D echocardiography was investigated for determination of LV volumes and EF using parasternal, apical and subcostal approaches. The study demonstrated that the apical 3D echocardiography view offers superior visualization. Study II tested the possibility of creating flow-volume loops to differentiate patients with valvular abnormalities from normal subjects. There were significant differences in the pattern from flow-volume loops clearly separating the groups. In Study III the visual estimation, “eyeballing” of EF was evaluated with two- and tri-plane echocardiography in comparison to quantitative 3D echocardiography. The study confirmed that an experienced echocardiographer can, with a high level of agreement estimate EF both with two- and tri-plane echocardiography. Study IV exposed the high accuracy of stroke volume and cardiac output determination using a3D biplane technique by planimetrically tracing the left ventricular outflow tract and indicating that an assumption of circular left ventricular outflow tract is not reliable. In Study V, two 3D echocardiography modalities, single-beat and four-beat ECG-gated 3D echocardiography were evaluated in patients having sinus rhythm and atrial fibrillation. Thesingle-beat technique showed significantly lower inter-and intraobserver variability in LV volumes and EF measurements in patients having atrial fibrillation in comparison to four-beat ECG-gated acquisition due to absence of stitching artifact. All studies demonstrated good results suggesting 3D echocardiography to be a feasible andaccurate method in daily clinical settings. / degree of Medical DoctorQC 20100629

In cardiovascular medicine, the assessment of blood flow is fundamental to the understanding and detection of disease. Many pharmaceutical, interventional, and surgical treatments impact the flow. The primary purpose of the cardiovascular system is to drive, control and maintain blood flow to all parts of the body. In the normal cardiovascular system, fluid transport is maintained at high efficiency and the blood flow is essentially laminar. Disturbed and turbulent blood flow, on the other hand, appears to be present in many cardiovascular diseases and may contribute to their initiation and progression. Despite strong indications of an important interrelationship between flow and cardiovascular disease, medical imaging has lacked a non-invasive tool for the in vivo assessment of disturbed and turbulent flow. As a result, the extent and role of turbulence in the blood flow of humans have not yet been fully investigated. Magnetic resonance imaging (MRI) is a versatile tool for the non-invasive assessment of flow and has several important clinical and research applications, but might not yet have reached its full potential. Conventional MRI techniques for the assessment of flow are based on measurements of the mean velocity within an image voxel. The mean velocity corresponds to the first raw moment of the distribution of velocities within a voxel. An MRI framework for the quantification of any moment (mean, standard deviation, skew, etc.) of arbitrary velocity distributions is presented in this thesis. Disturbed and turbulent flows are characterized by velocity fluctuations that are superimposed on the mean velocity. The intensity of these velocity fluctuations can be quantified by their standard deviation, which is a commonly used measure of turbulence intensity. This thesis focuses on the development of a novel MRI method for the quantification of turbulence intensity. This method is mathematically derived and experimentally validated. Limitations and sources of error are investigated and guidelines for adequate application of MRI measurements of turbulence intensity are outlined. Furthermore, the method is adapted to the quantification of turbulence intensity in the pulsatile blood flow of humans and applied to a wide range of cardiovascular diseases. In these applications, elevated turbulence intensity was consistently detected in regions where highly disturbed flow was anticipated, and the effects of potential sources of errors were small. Diseased heart valves are often replaced with prosthetic heart valves, which, in spite of improved benefits and durability, continue to fall short of matching native flow patterns. In an in vitro setting, MRI was used to visualize and quantify turbulence intensity in the flow downstream from four common designs of prosthetic heart valves. Marked differences in the extent and degree of turbulence intensity were detected between the different valves. Mitral valve regurgitation is a common valve lesion associated with progressive left atrial and left ventricular remodelling, which may often require surgical correction to avoid irreversible ventricular dysfunction. The spatiotemporal dynamics of flow disturbances in mitral regurgitation were assessed based on measurements of flow patterns and turbulence intensity in a group of patients with significant regurgitation arising from similar valve lesions. Peak turbulence intensity occurred at the same time in all patients and the total turbulence intensity in the left atrium appeared closely related to the severity of regurgitation. MRI quantification of turbulence intensity has the potential to become a valuable tool in investigating the extent, timing and role of disturbed blood flow in the human cardiovascular system, as well as in the assessment of the effects of different therapeutic options in patients with vascular or valvular disorders.

In orthopaedic practice, fractures are usually stabilised with metal screws or rods. This is done in order to keep the fracture parts in place during the rather slow healing process. The healing time can potentially be reduced by local- or systemic treatment with different bone promoting drugs. In later years, lithium, otherwise used to treat bipolar disease, has shown promise to be such a drug.   The aim of this master thesis was to find a way to coat metal bone screws with lithium and to characterise the coating. The coating was to be designed in such a way that it could release lithium to the surrounding bone tissue.   Lithium chloride was incorporated into a titanate sol-gel and attached to silicon wafers and stainless steel screws by dip coating. Wafers were used for initial in vitro studies of how lithium changed coating characteristics. This was studied using ellipsometry, AFM and SEM. Lithium is most probably physisorbed and not incorporated into the network building up the sol-gel. Coating structure is changed as more lithium is incorporated. For large amounts of lithium, the nanoparticles normally formed when curing the sol-gel are inhibited. One effect of this is reduced bioactivity, seen as a reduced ability for calcium phosphate crystals to nucleate on the coating when immersed in simulated body fluid. Lithium release was investigated using AAS. Lithium is released from the coating, showing a burst effect. By changing the number of coating layers used, the release profile can be partly altered. The coating was also applied to screws, showing good attachment, and the lithium release profile was similar to the one seen from wafers. Finally, a screw model was used in rats to assess the effect of local lithium treatment from screws and systemic lithium treatment on fracture healing. In the model, a screw was inserted in tibia, mimicking a fracture. When the bone around the screw was healed, a pullout test was performed, giving information about the strength of the bone surrounding the screw. No significant difference could be found for either local- or systemic lithium treatment compared to control. However, when evaluating the strength of intact bone in a similar way, a positive effect of systemic lithium treatment could be seen. Therefore, it is still likely that lithium has a positive effect on bone and further studies are needed to fully evaluate its role in fracture healing. / Vid behandling av benbrott stabiliseras vanligtvis frakturen internt med metallskruvar och metallstavar. Detta görs för att hålla brottbitarna på plats under den relativt långsamma läkprocessen. Det är möjligt att minska tiden för frakturläkning genom att lokalt eller systemiskt behandla med olika läkemedel som främjar bentillväxt. På senare år har det presenterats bevis för att litium, som annars används som psykofarmaka, fungerar som ett sådant läkemedel.   Syftet med detta examensarbete var att hitta en metod för att fästa litium på benimplantat. Litium skulle fästas på ett sådant sätt att frisläppning till omgivande vävnad blev möjlig.   Litiumklorid inkorporerades i en titanat-solgel och lager av detta lades på kiselytor och rostfria skruvar genom s.k. ”dip-coating”. Kiselytorna användes för initiala in vitro-studier av hur litium ändrade beläggningens egenskaper. Litium sitter antagligen fast på ytan av det tredimensionella nätverk som utgör solgelen, istället för att sitta inbundet i nätverket. Lagerstrukturen ändras ju mer litium som inkorporeras och vid stora mängder skapas inte de nanopartiklar som vanligtvis finns i en solgel-baserad beläggning. En följd av detta är reducerad bioaktivitet för beläggningen, dvs. en minskad förmåga för kalciumfosfatkristaller att bildas på ytan. Litium frisläpps från beläggningen, dock sker denna frisläppning snabbt. Genom att belägga ytan med flera lager av solgel kan frisläppningskinetiken delvis ändras. Solgelen kunde också med god vidhäftning appliceras på skruvar och frisläppningskinetiken från en skruv är liknande den från en kiselyta. Slutligen användes en skruvmodell i råtta för att undersöka vilken effekt lokal respektive systemisk litiumbehandling har på frakturläkning. I modellen efterliknas ett benbrott genom att en skruv sätts in i skenbenet.  När benvävnaden runt skruven har läkt görs ett utdragstest på skruven vilket ger information om benets styrka. Ingen signifikant skillnad i skruvens utdragskraft kunde ses mellan de båda försöksgrupperna och kontrollgruppen. Däremot hade gruppen som fick systemisk litiumbehandling fått starkare ben totalt, vilket indikerar att litium har effekt på intakt ben. På grund av dessa resultat finns det fortfarande skäl att tro att litium har en positiv påverkan på ben, varför dess effekt på frakturläkning bör undersökas ytterligare.

The number of monoclonal antibodies approved for therapeutic use has increased rapidlyover the last decade. As a consequence, precise and robust kinetic characterization techniquesare crucial in order to select the best suitable candidates. A kinetic characterization methodwas developed in Gyrolab with automated sample transfers. The characterization wasperformed in solution in a mixing CD, containing an integrated nanoliter mixing chamberwith affinity binding columns. Association rate constants were determined for four anti-TSHantibodies with values ranging from 3x105 M-1s-1 to 10x105 M-1s-1. The antibodies wereranked according to kass. Reproducibility

Optical coherence tomography is an imaging modality with an outstanding resolution. During the project, a time domain OCT system based on a Michelson fibre interferometer was implemented and put into operation. A super-luminescent diode with a centre wavelength of 1295nm and a bandwidth of 45nm was selected as light source and a linear variable delay line as reference. Basic tests were made on phantoms constructed of filter foils and on gel-like agar slices with optical properties similar to human tissue. It was shown that the achievable resolution was at least 36um and can be increased. The system can easily be enhanced to create two-dimensional images. / Optische Kohärenztomographie ist ein bildgebendes Verfahren mit einer hervorragenden räumlichen Auflösung. Im Laufe des Projekts wurde ein OCT-System basierend auf einem faseroptischen Michelson-Interferometer implementiert und in Betrieb genommen. Als Lichtquelle wurde eine Superlumineszenzdiode mit einer Mittenwellenlänge von 1295nm und einer Bandbreite von 45nm gewählt. Eine variable optische Verzögerungsleitung diente als Referenz. Erste Messungen an Filterfolien und gelähnlichen Agarphantomen, die die optischen Eigenschaften von menschlichem Gewebe nachbildeten, lieferten eine räumliche Auflösung von mindestens 36um. Durch die modulare Bauweise ist das System leicht für zweidimensionale Aufnahmen erweiterbar.

Direct Volume Rendering (DVR) is a visualization technique that has proved to be a very powerful tool in many scientific visualization applications. Diagnostic medical imaging is one domain where DVR could provide clear benefits in terms of unprecedented possibilities for analysis of complex cases and highly efficient work flow for certain routine examinations. The full potential of DVR in the clinical environment has not been reached, however, primarily due to limitations in conventional DVR methods and tools. This thesis presents methods addressing four major challenges for DVR in clinical use. The foundation of all methods is to incorporate the domain knowledge of the medical professional in the technical solutions. The first challenge is the very large data sets routinely produced in medical imaging today. To this end a multiresolution DVR pipeline is proposed, which dynamically prioritizes data according to the actual impact in the rendered image to be reviewed. Using this prioritization the system can reduce the data requirements throughout the pipeline and provide high performance and visual quality in any environment. Another problem addressed is how to achieve simple yet powerful interactive tissue classification in DVR. The methods presented define additional attributes that effectively captures readily available medical knowledge. The task of tissue detection is also important to solve in order to improve efficiency and consistency of diagnostic image review. Histogram-based techniques that exploit spatial relations in the data to achieve accurate and robust tissue detection are presented in this thesis. The final challenge is uncertainty visualization, which is very pertinent in clinical work for patient safety reasons. An animation method has been developed that automatically conveys feasible alternative renderings. The basis of this method is a probabilistic interpretation of the visualization parameters. Several clinically relevant evaluations of the developed techniques have been performed demonstrating their usefulness. Although there is a clear focus on DVR and medical imaging, most of the methods provide similar benefits also for other visualization techniques and application domains.

Background Spinal pain is one of humanity’s most frequent complaints with high costs for the individual and society, and is commonly related to spinal disorders. There are many origins behind these disorders e.g., trauma, disc hernia or of other organic origins. However, for many of the disorders, the origin is not known. Thus, more knowledge is needed about how pain affects the neck and neural function in pain affected regions. The purpose of this dissertation was to improve the medical examination of patients suffering from chronic whiplash-associated disorders or other pain related neck-disorders. Methods A new assessment tool for objective movement analysis was developed. In addition, basic aspects of proprioceptive information transmission, which can be of relevance for muscular tension and pain, are investigated by studying the coding of populations of different types of sensory afferents by using a new spike sorting method. Both experiments in animal models and humans were studied to accomplish the goals of this dissertation. Four cats where were studied in acute animal experiments. Mixed ensembles of afferents were recorded from L7-S1 dorsal root filaments when mechanical stimulating the innervated muscle. A real-time spike sorting method was developed to sort units in a multi-unit recording. The quantification of population coding was performed using a method based on principal component analysis. In the human studies, 3D neck movement data were collected from 59 subjects with whiplash-associated disorders (WAD) and 56 control subjects. Neck movement patterns were identified by processing movement data into parameters describing the rotation of the head for each subject. Classification of neck movement patterns was performed using a neural network using processed collected data as input. Finally, the effect of marker position error on the estimated rotation of the head was evaluated by computer simulations. Results Animal experiments showed that mixed ensembles of different types of afferents discriminated better between different muscle stimuli than ensembles of single types of these afferents. All kinds of ensembles showed an increase in discriminative ability with increased ensemble size. It is hypothesized that the main reason for the greater discriminative ability might be the variation in sensitivity tuning among the individual afferents of the mixed ensemble will be larger than that for ensembles of only one type of afferent. In the human studies, the neural networks had a predictivity of 0.89, a sensitivity of 0.90 and a specificity of 0.88 when discriminating between control and WAD subjects. Also, a systematic error along the radial axis of the rigid body added to a single marker had no affect on the estimated rotation of the head. Conclusion The developed spike sorting method, using neural networks, was suitable for sorting a multiunit recording into single units when performing neurophysiological experiments. Also, it was shown that neck movement analysis combined with a neural network could build the basis of a decision support system for classifying suspected WAD or other pain related neck-disorders.

Filtering is a fundamental operation in image science in general and in medical image science in particular. The most central applications are image enhancement, registration, segmentation and feature extraction. Even though these applications involve non-linear processing a majority of the methodologies available rely on initial estimates using linear filters. Linear filtering is a well established cornerstone of signal processing, which is reflected by the overwhelming amount of literature on finite impulse response filters and their design. Standard techniques for multidimensional filtering are computationally intense. This leads to either a long computation time or a performance loss caused by approximations made in order to increase the computational efficiency. This dissertation presents a framework for realization of efficient multidimensional filters. A weighted least squares design criterion ensures preservation of the performance and the two techniques called filter networks and sub-filter sequences significantly reduce the computational demand. A filter network is a realization of a set of filters, which are decomposed into a structure of sparse sub-filters each with a low number of coefficients. Sparsity is here a key property to reduce the number of floating point operations required for filtering. Also, the network structure is important for efficiency, since it determines how the sub-filters contribute to several output nodes, allowing reduction or elimination of redundant computations. Filter networks, which is the main contribution of this dissertation, has many potential applications. The primary target of the research presented here has been local structure analysis and image enhancement. A filter network realization for local structure analysis in 3D shows a computational gain, in terms of multiplications required, which can exceed a factor 70 compared to standard convolution. For comparison, this filter network requires approximately the same amount of multiplications per signal sample as a single 2D filter. These results are purely algorithmic and are not in conflict with the use of hardware acceleration techniques such as parallel processing or graphics processing units (GPU). To get a flavor of the computation time required, a prototype implementation which makes use of filter networks carries out image enhancement in 3D, involving the computation of 16 filter responses, at an approximate speed of 1MVoxel/s on a standard PC.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 6 uppsatser.