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  • 51.
    Johansson, Sebastian
    et al.
    Stockholms Universitet.
    Juhos, Szilveszter
    Stockholms Universitet.
    Redin, David
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Ahmadian, Afshin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Käller, Max
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Comprehensive haplotyping of the HLA gene family using nanopore sequencingManuscript (preprint) (Other academic)
    Abstract [en]

    The HLA gene family is the most polymorphic loci in the human genome; it encodes for the major histocompatibility complexes (MHC) which mediates the immune response in terms of cellular interactions with antigens. Compatibility between HLA alleles is thus of great medical interest for recipients of allogeneic transplantations. Traditional serological techniques to evaluate compatibility are now being replaced by more accurate DNA sequencing-based methods. However, short read sequencing data typically result in collapsed sequences representing a mixture of variants from native haplotypes. In addition, most previous studies have been limited to a few highly polymorphic exons of various HLA genes. Here we present haplotype-resolved full-length sequencing of the six most clinically relevant MHC Class I and Class II genes, to characterize the haplotypes of eight reference individuals, using a single MinION flow cell. The results show that full-length sequencing of single molecules enables haplotypes to be resolved to the highest degree of accuracy (four-field resolution). In this study, a majority of the alleles were classified with four-field resolution and could be verified through previously published genotyping studies. These results support the notion that nanopore sequencing could be a viable solution for highly accurate clinical evaluation of histocompatibility.

    Download full text (pdf)
    ONT-HLA_incl.SI
  • 52.
    Johansson, Staffan B.
    et al.
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Eklund, Anders
    Malm, Jan
    Stemme, Göran
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Roxhed, Niclas
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    A MEMS-based passive hydrocephalus shunt for body position controlled intracranial pressure regulation2014In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 16, no 4, p. 529-536Article in journal (Refereed)
    Abstract [en]

    This paper reports a novel micro electro mechanical system (MEMS) valve with posture controlled flow characteristics for improved treatment of hydrocephalus, a disease that is characterized by elevated pressure in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord. In contrast to conventional differential pressure CSF valves, the CSF valve presented here features a third port which utilizes hydrostatic pressure from a pressure compensating catheter to adapt CSF drainage to optimized levels irrespective of body position. Prototypes have been fabricated using standard MEMS manufacturing processes and the experimental evaluation successfully showed that the flow rate was adjustable with a varying hydrostatic pressure on the third port. Measured data showed that flow rate was at near ideal values at laying body position and that the flow rate can be adjusted to optimal values at standing body position by selecting an appropriate length of the pressure compensating catheter. This is the first pressure balanced CSF valve intended for body position controlled CSF pressure regulation.

  • 53.
    Jonas, Hansson
    et al.
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Yasuga, Hiroki
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Haraldsson, Tommy
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    van der Wijngaart, Wouter
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Synthetic microfluidic paper: high surface area and high porosity polymer micropillar arrays2016In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 16, no 2, p. 298-304Article in journal (Refereed)
    Abstract [en]

    We introduce Synthetic Microfluidic Paper, a novel porous material for microfluidic applications that consists of an OSTE polymer that is photostructured in a well-controlled geometry of slanted and interlocked micropillars. We demonstrate the distinct benefits of Synthetic Microfluidic Paper over other porous microfluidic materials, such as nitrocellulose, traditional paper and straight micropillar arrays: in contrast to straight micropillar arrays, the geometry of Synthetic Microfluidic Paper was miniaturized without suffering capillary collapse during manufacturing and fluidic operation, resulting in a six-fold increased internal surface area and a three-fold increased porous fraction. Compared to commercial nitrocellulose materials for capillary assays, Synthetic Microfluidic Paper shows a wider range of capillary pumping speed and four times lower device-to-device variation. Compared to the surfaces of the other porous microfluidic materials that are modified by adsorption, Synthetic Microfluidic Paper contains free thiol groups and has been shown to be suitable for covalent surface chemistry, demonstrated here for increasing the material hydrophilicity. These results illustrate the potential of Synthetic Microfluidic Paper as a porous microfluidic material with improved performance characteristics, especially for bioassay applications such as diagnostic tests.

    Download full text (pdf)
    Hansson_2016_Synthetic-microfluidic-paper.pdf
  • 54.
    Jönsson, Håkan
    et al.
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Samuels, Michael L.
    Brouzes, Eric R.
    Medkova, Martina
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Link, Darren R.
    Andersson-Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Detection and Analysis of Low-Abundance Cell-Surface Biomarkers Using Enzymatic Amplification in Microfluidic Droplets2009In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 48, no 14, p. 2518-2521Article in journal (Refereed)
    Abstract [en]

    Finding the few: Cell-surface proteins are useful disease biomarkers, but current high-throughput methods are limited to detecting cells expressing more than several hundred proteins. Enzymatic amplification in microfluidic droplets (see picture) is a high-throughput method for detection and analysis of cell-surface biomarkers expressed at very low levels on individual human cells. Droplet optical labels allow concurrent analysis of several samples.

  • 55. Kane, Bridget
    et al.
    Groth, Kristina
    KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID. Karolinska University Hospital, Sweden.
    Multidisciplinary Work Practices: A Comparison of Three Major European Hospitals2014Conference paper (Refereed)
    Abstract [en]

    This paper reviews the practices of multidisciplinary teamwork (MDT) for cancer care in three large teaching hospitals in separate jurisdictions. Ethnographic observations provide the main source of data, which are verified though interviews, and in some cases by surveys and analysis of video recordings. We demonstrate how MDT practices develop among different groups, and in different jurisdictions. Common practices are identified and differences explained. Work practice analysis is an integral part of our research, and this study provides insights into medical teamwork and decision-making.

  • 56. Katona, Borbala
    et al.
    Ibrahim, Ahmed
    Sundberg, Mårten
    Williams, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Antibody Validation Strategy for Nuclear Receptors.2019In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1966, p. 79-99Article in journal (Refereed)
    Abstract [en]

    Antibodies are invaluable biological tools that we can use to detect the presence, location, or alteration of nuclear receptors. However, antibodies frequently cross-react with other proteins and their performance can vary from batch to batch, from application to application and from lab to lab. When each lot of antibody is not thoroughly validated for each assay, each sample type, and each lab and user, antibody-based assays can lead to flawed interpretations and reproducibility problems. In this chapter, we describe a scheme for thorough antibody validation, suitable for nuclear receptors. The method is based on using highly characterized positive and negative controls assembled into a validation tissue microarray (TMA). Through correlation of immunohistochemical staining (IHC) and mRNA levels over multiple tissues, use of current public databases, and assessment of binding to intended and nonintended targets using western blotting (WB), immunoprecipitation (IP), and mass spectrometry (MS), we describe a path for thoroughly validation of antibodies.

  • 57.
    Kazemzadeh, Amin
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Lapins, Noa
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Banerjee, Indradumna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Akhtar, Ahmad Saleem
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Russom, Aman
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mobile-LabDisc for Point-of-Care DiagnosticsManuscript (preprint) (Other academic)
    Abstract [en]

    At resource limited settings, point of care devices require a very low-cost, robust and easy to use platform that is preferably capable of automating and multiplexing intricate bioassays. We report on a mobile lab-disc platform that is specifically designed to meet the needs at resource- limited settings. It uses a smartphone as an electrical power source and a disposable, rigid and portable casing made of cardboard that securely accommodate the entire lab-disc system rotor, lightning and wiring and other accessories. The mobile lab-disc is light, less-expensive and functional at places where the electrical power infrastructure is not available. We show that the electrical energy stored in most mobile phones can be used for spinning a lab-Disc at up to 5500 rpm, a speed sufficient for most of the required functional steps in a bioassay including ELISA. We develop individual components of the mobile lab-disc system by experimentally conducting colorimetric assays using HRP and sandwich immunoassay. Finally, the full potential of the mobile lab-disc for integrating and multiplexing bioassays is demonstrated by measuring the hematocrit level in whole blood. The mobile phone-operated process integrates sample preparation i.e., blood-plasma separation, imaging and image analysis. The total cost of our prototype system for the tests, excluding the phone is ~$5, assuming that a lab-disc unit is worth $1.

  • 58.
    Kothapalli, Satya V.V.N.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Janerot Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Investigation of Polymer-Shelled Microbubble Motions in AcoustophoresisManuscript (preprint) (Other academic)
    Abstract [en]

    The objective of this paper is to explore the trajectory motion of microsize (typically smaller than a redblood cell) encapsulated polymer-shelled gas bubbles propelled by radiation force in an acousticstanding-wave field and to compare the corresponding movements of solid polymer microbeads. Theexperimental setup consists of a microfluidic chip coupled to a piezoelectric crystal (PZT) with aresonance frequency of about 2.8 MHz. The microfluidic channel consists of a rectangular chamberwith a width, w, corresponding to one wavelength of the ultrasound standing wave. It creates one fullwave ultrasound of a standing-wave pattern with two pressure nodes at4w and43w and threeantinodes at 0,2w , and w. The peak-to-peak amplitude of the electrical potential over the PZT wasvaried between 1 and 10 volts. From Gor’kov’s potential equation, the acoustic contrast factor, Φ, forthe polymer-shelled microbubbles was calculated to about -60.7. Experimental results demonstratethat the polymer-shelled microbubbles are translated and accumulated at the pressure antinode planes.This trajectory motion of polymer-shelled microbubbles toward the pressure antinode plane is similarto what has been described for other acoustic contrast particles with a negative Φ. First, primaryradiation forces dragged the polymer-shelled microbubbles into proximity with each other at thepressure antinode planes. Then, secondary radiation forces caused them to aggregate at different spotsalong the channel. The relocation time for polymer-shelled microbubbles was 40 times shorter thanthat for polymer microbeads, and in contrast to polymer microbeads, the polymer-shelledmicrobubbles were actuated even at driving voltages (proportional to radiation forces) as low as 1 volt.In short, the polymer-shelled microbubbles demonstrate the behavior attributed to the negativeacoustic contrast factor particles and thus can be trapped at the antinode plane and thereby seperatedfrom solid particles, such as cells. This phenomenon could be utilized in exploring future applications,such as bioassay, bioaffinity, and cell interaction studies in vitro in a well-controlled environment.

  • 59.
    Langer, Krzysztof
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jönsson, Håkan
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Rapid production and recovery of cell spheroids by automated droplet microfluidics2019Manuscript (preprint) (Other academic)
    Abstract [en]

    Droplet microfluidics enables high throughput cell processing, analysis and screening by miniaturizing the reaction vessels to nano- or pico-liter water-in oil droplets, but like many other microfluidic formats, droplet microfluidics have not been interfaced with or automated by laboratory robotics. Here we demonstrate automation of droplet microfluidics based on an inexpensive liquid handling robot for the automated production of human scaffold-free cell spheroids, using pipette actuation and interfacing the pipetting tip with a droplet generating microfluidic chip. In this chip we produce highly mono-disperse 290μm droplets with diameter CV of 1.7%. By encapsulating cells in these droplets, we produce cell spheroids in droplets and recover them to standard formats at a throughput of 85000 spheroids per microfluidic circuit per hour. The viability of the cells in spheroids remains high after recovery only decreased by 4% starting from 96% after 16 hours incubation in nanoliter droplets. Scaffold-free cell spheroids and 3D tissue constructs recapitulate many aspects of functional human tissue more accurately than 2D or single cell cultures, but assembly methods for spheroids, e.g. hanging drop micro-plates, has had limited throughput. The increased throughput and decreased cost of our method enables spheroid production at the scale needed for lead discovery drug screening and approaches the cost where these micro tissues could be used as building blocks for organ scale regenerative medicine.

  • 60. Li, F.
    et al.
    Zhu, H.
    Wu, S.
    Gao, Q.
    Hu, Z.
    Xu, J.
    Xu, G.
    He, Sailing
    KTH, School of Electrical Engineering (EES), Electromagnetic Engineering. South China Normal University (SCNU).
    Effect of frequent degree of deceiving on the prefrontal cortical response to deception: A functional near-infrared spectroscopy (fNIRS) study2015Conference paper (Refereed)
    Abstract [en]

    Functional near-infrared spectroscopy (fNIRS) is an emerging brain-imaging technique which has been used to various areas. Previous studies have indicated that frequent deceiving would make deceiving easier. In this study, fNIRS was used to explore the effect of frequent degree of deceiving on the prefrontal cortical response to deception. Self-related questions were used in the experiment. The results showed different patterns of neural activation between non-frequent deceiving and frequent deceiving. In Channel 11 (in the left prefrontal cortex), non-frequent deceiving led to a greater neural activation than telling the truth, while this pattern did not appear in frequent deceiving. Our finding suggested that fNIRS has ability to detect deception under different situations.

  • 61.
    Li, Peng
    et al.
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Laudato, Marco
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics.
    Mihaescu, Mihai
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics.
    Time-Dependent Fluid-Structure Interaction Simulations of a Simplified Human Soft Palate2023In: Bioengineering, E-ISSN 2306-5354, Vol. 10, no 11, article id 1313Article in journal (Refereed)
    Abstract [en]

    Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep-related disorder. It is characterized by recurrent partial or total collapse of pharyngeal upper airway accompanied by induced vibrations of the soft tissues (e.g., soft palate). The knowledge of the tissue behavior subject to a particular airflow is relevant for realistic clinic applications. However, in-vivo measurements are usually impractical. The goal of the present study is to develop a 3D fluid-structure interaction model for the human uvulopalatal system relevant to OSA based on simplified geometries under physiological conditions. Numerical simulations are performed to assess the influence of the different breathing conditions on the vibrational dynamics of the flexible structure. Meanwhile, the fluid patterns are investigated for the coupled fluid-structure system as well. Increasing the respiratory flow rate is shown to induce larger structural deformation. Vortex shedding induced resonance is not observed due to the large discrepancy between the flow oscillatory frequency and the natural frequency of the structure. The large deformation for symmetric breathing case under intensive respiration is mainly because of the positive feedback from the pressure differences on the top and the bottom surfaces of the structure.

  • 62.
    Lindroos, Robert
    KTH, School of Computer Science and Communication (CSC).
    A simplied Medium SpinyNeuron-model with retained intrinsic characteristics and plateau properties2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This master thesis studies how a morphological reduction aects theperformance of a biophysically detailed model of a medium spiny neuron. Themorphological reduction is done using a MATLAB toolbox developed forautomatic 3-dimensional morphological reduction. Two versions of the toolboxare developed in which dierent criteria are used during the merge. Theevaluation of the two toolboxes shows that keeping the absolute distance to thesoma of the branching points and the surface area of the dendrites gives a moreaccurate result than if these criteria are not used. These criteria are implementedin Toolbox 2. In total 8 models with dierent maximal compartment length arethen constructed using Toolbox 2. The number of compartments in the resultingmodels range from 1/2 to 1/10 of the compartments in the original model. Furtherthe performance of the reduced models are evaluated against the original model.The results of this evaluation shows that an increasing compartment length givesa decrease in consistency with the response of the original model. However theresponse of all models are largely similar to the original model.

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    fulltext
  • 63.
    Luis, Israel
    et al.
    KTH, School of Engineering Sciences (SCI).
    Afschrift, Maarten
    Department of Movement Sciences, KU Leuven, Leuven, Belgium.
    De Groote, Friedl
    Department of Movement Sciences, KU Leuven, Leuven, Belgium.
    Gutierrez-Farewik, Elena
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics. Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Evaluation of musculoskeletal models, scaling methods, and performance criteria for estimating muscle excitations and fiber lengths across walking speeds2022In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 10Article in journal (Refereed)
    Abstract [en]

    Muscle-driven simulations have been widely adopted to study muscle-tendon behavior; several generic musculoskeletal models have been developed, and their biofidelity improved based on available experimental data and computational feasibility. It is, however, not clear which, if any, of these models accurately estimate muscle-tendon dynamics over a range of walking speeds. In addition, the interaction between model selection, performance criteria to solve muscle redundancy, and approaches for scaling muscle-tendon properties remain unclear. This study aims to compare estimated muscle excitations and muscle fiber lengths, qualitatively and quantitatively, from several model combinations to experimental observations. We tested three generic models proposed by Hamner et al., Rajagopal et al., and Lai-Arnold et al. in combination with performance criteria based on minimization of muscle effort to the power of 2, 3, 5, and 10, and four approaches to scale the muscle-tendon unit properties of maximum isometric force, optimal fiber length, and tendon slack length. We collected motion analysis and electromyography data in eight able-bodied subjects walking at seven speeds and compared agreement between estimated/modelled muscle excitations and observed muscle excitations from electromyography and computed normalized fiber lengths to values reported in the literature. We found that best agreement in on/off timing in vastus lateralis, vastus medialis, tibialis anterior, gastrocnemius lateralis, gastrocnemius medialis, and soleus was estimated with minimum squared muscle effort than to higher exponents, regardless of model and scaling approach. Also, minimum squared or cubed muscle effort with only a subset of muscle-tendon unit scaling approaches produced the best time-series agreement and best estimates of the increment of muscle excitation magnitude across walking speeds. There were discrepancies in estimated fiber lengths and muscle excitations among the models, with the largest discrepancy in the Hamner et al. model. The model proposed by Lai-Arnold et al. best estimated muscle excitation estimates overall, but failed to estimate realistic muscle fiber lengths, which were better estimated with the model proposed by Rajagopal et al. No single model combination estimated the most accurate muscle excitations for all muscles; commonly observed disagreements include onset delay, underestimated co-activation, and failure to estimate muscle excitation increments across walking speeds.

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    fulltext
  • 64.
    Lundin, Sverker
    KTH, School of Biotechnology (BIO), Gene Technology.
    Methods to Prepare DNA for Efficient Massive Sequencing2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Massive sequencing has transformed the field of genome biology due to the continuous introduction and evolution of new methods. In recent years, the technologies available to read through genomes have undergone an unprecedented rate of development in terms of cost-reduction. Generating sequence data has essentially ceased to be a bottleneck for analyzing genomes instead to be replaced by limitations in sample preparation and data analysis. In this work, new strategies are presented to increase both the throughput of library generation prior to sequencing, and the informational content of libraries to aid post-sequencing data processing. The protocols developed aim to enable new possibilities for genome research concerning project scale and sequence complexity.

    The first two papers that underpin this thesis deal with scaling library production by means of automation. Automated library preparation is first described for the 454 sequencing system based on a generic solid-phase polyethylene-glycol precipitation protocol for automated DNA handling. This was one of the first descriptions of automated sample handling for producing next generation sequencing libraries, and substantially improved sample throughput. Building on these results, the use of a double precipitation strategy to replace the manual agarose gel excision step for Illumina sequencing is presented. This protocol considerably improved the scalability of library construction for Illumina sequencing. The third and fourth papers present advanced strategies for library tagging in order to multiplex the information available in each library. First, a dual tagging strategy for massive sequencing is described in which two sets of tags are added to a library to trace back the origins of up to 4992 amplicons using 122 tags. The tagging strategy takes advantage of the previously automated pipeline and was used for the simultaneous sequencing of 3700 amplicons. Following that, an enzymatic protocol was developed to degrade long range PCR-amplicons and forming triple-tagged libraries containing information of sample origin, clonal origin and local positioning for the short-read sequences. Through tagging, this protocol makes it possible to analyze a longer continuous sequence region than would be possible based on the read length of the sequencing system alone. The fifth study investigates commonly used enzymes for constructing libraries for massive sequencing. We analyze restriction enzymes capable of digesting unknown sequences located some distance from their recognition sequence. Some of these enzymes have previously been extensively used for massive nucleic acid analysis. In this first high throughput study of such enzymes, we investigated their restriction specificity in terms of the distance from the recognition site and their sequence dependence. The phenomenon of slippage is characterized and shown to vary significantly between enzymes. The results obtained should favor future protocol development and enzymatic understanding.

    Through these papers, this work aspire to aid the development of methods for massive sequencing in terms of scale, quality and knowledge; thereby contributing to the general applicability of the new paradigm of sequencing instruments.

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    fulltext
  • 65.
    Maksuti, Elira
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Bjällmark, Anna
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institute, Sweden .
    Broomé, Michael
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institute, Sweden .
    Modelling the heart with the atrioventricular plane as a piston unit2015In: Medical Engineering and Physics, ISSN 1350-4533, E-ISSN 1873-4030, Vol. 37, no 1, p. 87-92Article in journal (Refereed)
    Abstract [en]

    Medical imaging and clinical studies have proven that the heart pumps by means of minor outer volume changes and back-and-forth longitudinal movements in the atrioventricular (AV) region. The magnitude of AV-plane displacement has also shown to be a reliable index for diagnosis of heart failure. Despite this, AV-plane displacement is usually omitted from cardiovascular modelling. We present a lumped-parameter cardiac model in which the heart is described as a displacement pump with the AV plane functioning as a piston unit (AV piston). This unit is constructed of different upper and lower areas analogous with the difference in the atrial and ventricular cross-sections. The model output reproduces normal physiology, with a left ventricular pressure in the range of 8-130 mmHg, an atrial pressure of approximatly 9 mmHg, and an arterial pressure change between 75 mmHg and 130 mmHg. In addition, the model reproduces the direction of the main systolic and diastolic movements of the AV piston with realistic velocity magnitude (similar to 10 cm/s). Moreover, changes in the simulated systolic ventricular-contraction force influence diastolic filling, emphasizing the coupling between cardiac systolic and diastolic functions. The agreement between the simulation and normal physiology highlights the importance of myocardial longitudinal movements and of atrioventricular interactions in cardiac pumping.

  • 66.
    Martorella, Molly
    et al.
    New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA.
    Kasela, Silva
    New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA.
    Garcia-Flores, Renee
    New York Genome Center, New York, NY, USA; Department of Computer Science, Columbia University, New York, NY, USA; Undergraduate Program On Genomic Sciences, National Autonomous University of Mexico, Cuernavaca, Morelos, Mexico.
    Gokden, Alper
    New York Genome Center, New York, NY, USA.
    Castel, Stephane E.
    New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA.
    Lappalainen, Tuuli
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA;.
    Evaluation of noninvasive biospecimens for transcriptome studies2023In: BMC Genomics, E-ISSN 1471-2164, Vol. 24, no 1, article id 790Article in journal (Refereed)
    Abstract [en]

    Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are limited to investigating cell types found in blood. Noninvasive tissues may improve disease-relevant discovery by enabling more complex longitudinal study designs, by capturing different and potentially more applicable cell types, and by increasing sample sizes due to reduced collection costs and possible higher enrollment from vulnerable populations. Here, we develop methods for sampling noninvasive biospecimens, investigate their performance across commercial and in-house library preparations, characterize their biology, and assess the feasibility of using noninvasive tissues in a multitude of transcriptomic applications. We collected buccal swabs, hair follicles, saliva, and urine cell pellets from 19 individuals over three to four timepoints, for a total of 300 unique biological samples, which we then prepared with replicates across three library preparations, for a final tally of 472 transcriptomes. Of the four tissues we studied, we found hair follicles and urine cell pellets to be most promising due to the consistency of sample quality, the cell types and expression profiles we observed, and their performance in disease-relevant applications. This is the first study to thoroughly delineate biological and technical features of noninvasive samples and demonstrate their use in a wide array of transcriptomic and clinical analyses. We anticipate future use of these biospecimens will facilitate discovery and development of clinical applications.

  • 67.
    Muhammad, Arif
    KTH, School of Technology and Health (STH).
    Iterative Reconstruction for Quantitative Material Decomposition in Dual-Energy CT2010Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    It is of clinical interest to decompose a three material mixture into its constituted substances using dual-energy CT. In radiation therapy, for example material decomposition can be used to determine tissue properties for the calculation of dose in treatment planning. Due to use of polychromatic spectrum in CT, beam hardening artifacts prevent to achieve fully satisfactory results. Here an iterative reconstruction algorithm proposed by A. Malusek, M. Magnusson, M.Sandborg, and G. Alm Carlsson in 2008 is implemented to achieve this goal. The iterative algorithm can be implemented with both single- and dual-energy CT. The material decomposition process is based on mass conservation and volume conservation assumptions. The implementation and evaluation of iterative reconstruction algorithm is done by using simulation studies of analyzing mixtures of water, protein and adipose tissue. The results demonstrated that beam hardening artifacts are effectively removed and accurate estimation of mass fractions of each base material can be achieved with the proposed method. We also compared our novel iterative reconstruction algorithm to the commonly used water pre-correction method. Experimental results show that our novel iterative algorithm is more accurate.

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  • 68. Occhiuzzi, C.
    et al.
    Ajovalasit, A.
    Sabatino, M. A.
    Dispenza, Clelia
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. Univ Palermo, Italy; CNR, Palermo, Italy.
    Marrocco, G.
    RFID epidermal sensor including hydrogel membranes for wound monitoring and healing2015In: 2015 IEEE International Conference on RFID, RFID 2015, IEEE conference proceedings, 2015, p. 182-188Conference paper (Refereed)
    Abstract [en]

    This contribution experimentally demonstrates for the first time the feasibility of joint application of passive UHF RFID technology and hydrogel membranes to fabricate smart plasters able to gather and remotely transmit information on the conditions of human skin. In particular, this intelligent plaster is sensitive to temperature and fluid uptake/release and could open interesting scenarios in wound healing monitoring and drug delivery.

  • 69.
    Ohlander, Anna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bose, Indranil
    Njenda, Duncan
    Zelenin, Sergey
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Neogi, Ujjwal
    Kutter, Christoph
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lab-on-foil based portable microPCR for point-of-care nucleic acid testing of HIV-1Manuscript (preprint) (Other academic)
  • 70.
    Ohlander, Anna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zelenin, Sergey
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Huygens, Flavia
    Kutter, Christoph
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Staphylococcus Aureus subtyping and detection of MRSA on a microfluidic lab-on-Foil deviceManuscript (preprint) (Other academic)
  • 71. Pateraki, Irini
    et al.
    Andersen-Ranberg, Johan
    Jensen, Niels Bjerg
    Wubshet, Sileshi Gizachew
    Heskes, Allison Maree
    Forman, Victor
    Hallström, Björn M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hamberger, Britta
    Motawia, Mohammed Saddik
    Olsen, Carl Erik
    Staerk, Dan
    Hansen, Jorgen
    Moller, Birger Lindberg
    Hamberger, Bjorn
    Total biosynthesis of the cyclic AMP booster for skolin from Coleus forskohlii2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23001Article in journal (Refereed)
    Abstract [en]

    Forskolin is a unique structurally complex labdane-type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source, the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here, we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane-type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L.

  • 72.
    Peolsson, Michael
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brodin, Lars-Ake
    KTH, School of Technology and Health (STH), Medical Engineering.
    Peolsson, Anneli
    Tissue motion pattern of ventral neck muscles investigated by tissue velocity ultrasonography imaging2010In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 109, no 5, p. 899-908Article in journal (Refereed)
    Abstract [en]

    We designed this experimental study to investigate tissue motions and thus infer the recruitment pattern of the ventral neck muscles [sternocleidomastoid (SCM), longus capitis (Lca), and longus colli (Lco)] at the C4-C5 level in healthy volunteers during isometric manual resistance of the head in flexion in a seated position. This exercise is used in the physiotherapeutic treatment of neck pain and is assumed to activate the deep ventral muscles, but the assumption has not been clearly evaluated. Neck flexors of 16 healthy volunteers (mean age 24 years, SD 3.7) were measured using ultrasonography with strain and strain rate (SR) tissue velocity imaging (TVI) during isometric contraction of flexor muscles. TVI involves using Doppler imaging to study tissue dynamics. All three muscles showed a deformation compared to rest. Except for the initial contraction phase, Lco exhibited a lower strain than Lca and SCM but was the only muscle with a significant change in SR between the phases. When the beginning of the contraction phase was analysed, Lco was the first to be deformed among most volunteers, followed by Lca and then SCM. The exercise investigated seems to be useful as a "stabilizing" exercise for Lco. Our suggestion is that in further research, Lco and Lca should be investigated as separate muscles. TVI could be used to study tissue motions and thus serve as an indicator of muscle patterning between the neck flexors, with the possibility of separating Lco and Lca.

  • 73.
    Pereira da Silva Neves, Marta Maria
    et al.
    Inst Politecn Porto, Inst Super Engn Porto, REQUIMTE LAQV, P-4200072 Porto, Portugal..
    Martín-Yerga, Daniel
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemical Engineering, Applied Electrochemistry.
    Advanced Nanoscale Approaches to Single-(Bio)entity Sensing and Imaging2018In: Biosensors, ISSN 2079-6374, Vol. 8, no 4, article id 100Article, review/survey (Refereed)
    Abstract [en]

    Individual (bio)chemical entities could show a very heterogeneous behaviour under the same conditions that could be relevant in many biological processes of significance in the life sciences. Conventional detection approaches are only able to detect the average response of an ensemble of entities and assume that all entities are identical. From this perspective, important information about the heterogeneities or rare (stochastic) events happening in individual entities would remain unseen. Some nanoscale tools present interesting physicochemical properties that enable the possibility to detect systems at the single-entity level, acquiring richer information than conventional methods. In this review, we introduce the foundations and the latest advances of several nanoscale approaches to sensing and imaging individual (bio)entities using nanoprobes, nanopores, nanoimpacts, nanoplasmonics and nanomachines. Several (bio)entities such as cells, proteins, nucleic acids, vesicles and viruses are specifically considered. These nanoscale approaches provide a wide and complete toolbox for the study of many biological systems at the single-entity level.

  • 74. Picone, P.
    et al.
    Ditta, L. A.
    Sabatino, M. A.
    Militello, V.
    San Biagio, P. L.
    Di Giacinto, M. L.
    Cristaldi, L.
    Nuzzo, D.
    Dispenza, Clelia
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. University of Palermo, Italy.
    Giacomazza, D.
    Di Carlo, M.
    Ionizing radiation-engineered nanogels as insulin nanocarriers for the development of a new strategy for the treatment of Alzheimer’s disease2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 80, p. 179-194Article in journal (Refereed)
    Abstract [en]

    A growing body of evidence shows the protective role of insulin in Alzheimer’s disease (AD). A nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for Alzheimer’s Disease (AD), is designed and synthetized. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation is chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility and hemocompatibility of the naked carrier is demonstrated. The insulin conjugated to the NG (NG-In) is protected by protease degradation and able to bind to insulin receptor (IR), as demonstrated by immunofluorescence measurements showing colocalization of NG-InFITC with IR. Moreover, after binding to the receptor, NG-In is able to trigger insulin signaling via AKT activation. Neuroprotection of NG-In against dysfunction induced by amyloid β (Aβ), a peptide mainly involved in AD, is verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier (BBB) is demonstrated. All together these results indicate that the synthesized NG-In is a suitable vehicle system for insulin deliver in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases.

  • 75.
    Pirozzi, Ileana
    et al.
    Department of Bioengineering Stanford University Palo Alto 94301 USA.
    Kight, Ali
    Department of Bioengineering Stanford University Palo Alto 94301 USA.
    Han, Amy Kyungwon
    Department of Mechanical Engineering Seoul National University Seoul 08826 South Korea.
    Cutkosky, Mark R.
    Department of Mechanical Engineering Stanford University Palo Alto 94301 USA.
    Dual, Seraina A.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Circulatory Support: Artificial Muscles for the Future of Cardiovascular Assist Devices2023In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, article id 2210713Article in journal (Refereed)
    Abstract [en]

    Artificial muscles enable the design of soft implantable devices which are poised to transform the way we mechanically support the heart today. Heart failure is a prevalent and deadly disease, which is treated with the implantation of rotary blood pumps as the only alternative to heart transplantation. The clinically used mechanical devices are associated with severe adverse events, which are reflected here in a comprehensive list of critical requirements for soft active devices of the future: low power, no blood contact, pulsatile support, physiological responsiveness, high cycle life, and less-invasive implantation. In this review, we investigate and critically evaluate prior art in artificial muscles for their applicability in the short and long term. We highlight the main challenges regarding the effectiveness, controllability, and implantability of recently proposed actuators and explore future perspectives for attachment, physiological responsiveness, durability, and biodegradability as well as equitable design considerations.

  • 76. Polzer, Stanislav
    et al.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Markert, Bernd
    Bursa, Jiri
    Skacel, Pavel
    Impact of poroelasticity of intraluminal thrombus on wall stress of abdominal aortic aneurysms2012In: Biomedical engineering online, E-ISSN 1475-925X, Vol. 11, p. 62-Article in journal (Refereed)
    Abstract [en]

    Background: The predictions of stress fields in Abdominal Aortic Aneurysm (AAA) depend on constitutive descriptions of the aneurysm wall and the Intra-luminal Thrombus (ILT). ILT is a porous diluted structure (biphasic solid-fluid material) and its impact on AAA biomechanics is controversially discussed in the literature. Specifically, pressure measurements showed that the ILT cannot protect the wall from the arterial pressure, while other (numerical and experimental) studies showed that at the same time it reduces the stress in the wall. Method: To explore this phenomenon further a poroelastic description of the ILT was integrated in Finite Element (FE) Models of the AAA. The AAA model was loaded by a pressure step and a cyclic pressure wave and their transition into wall tension was investigated. To this end ILT's permeability was varied within a microstructurally motivated range. Results: The two-phase model verified that the ILT transmits the entire mean arterial pressure to the wall while, at the same time, it significantly reduces the stress in the wall. The predicted mean stress in the AAA wall was insensitive to the permeability of the ILT and coincided with the results of AAA models using a single-phase ILT description. Conclusion: At steady state, the biphasic ILT behaves like a single-phase material in an AAA model. Consequently, computational efficient FE single-phase models, as they have been exclusively used in the past, accurately predict the wall stress in AAA models.

  • 77.
    Rinne, Sara S.
    et al.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Yin, Wen
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Mestre Borras, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Abouzayed, Ayman
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75237 Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.;Uppsala Univ, Dept Immunol Genet & Pathol, S-75237 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75237 Uppsala, Sweden..
    Gräslund, Torbjörn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules2022In: Biomedicines, E-ISSN 2227-9059, Vol. 10, no 6, article id 1293Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K-D 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 +/- 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.

  • 78.
    Roxhed, Niclas
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    A Fully Integrated Microneedle-based Transdermal Drug Delivery System2007Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. However, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. By using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulins or vaccines. These microneedles only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors of the lower skin. Thus, microneedle insertions are perceived as painless.

    The thesis presents research in the field of microneedle-based drug delivery with the specific aim of investigating a microneedle-based transdermal patch concept. To enable controllable drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system includes a small active dispenser mechanism. The dispenser is based on a novel thermal actuator consisting of highly expandable microspheres. When actuated, the microspheres expand into a liquid reservoir and, subsequently, dispense stored liquid through outlet holes.

    The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching. The needles are organized in arrays situated on a chip. To allow active delivery, the microneedles are hollow with the needle bore-opening located on the side of the needle. This way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further requirement to achieve microneedle insertion into skin by hand.

    The thesis presents fabrication and evaluation of both the microneedle structure and the transdermal patch as such. Issues such as penetration reliability, liquid delivery into the skin and microneedle packaging are discussed. The microneedle patch was also tested and studied in vivo for insulin delivery. Results show that intradermal administration with microneedles give rise to similar insulin concentration as standard subcutaneous delivery with the same dose rate.

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  • 79. Schmidt, Thomas
    et al.
    Balzani, Daniel
    Schriefl, Andreas J.
    Holzapfel, Gerhard A.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Material Modeling Of The Damage Behavior Of Arterial Tissues2013In: Biomedizinische Technik (Berlin. Zeitschrift), ISSN 1862-278X, E-ISSN 0013-5585, Vol. 58, no (Suppl. 1)Article in journal (Refereed)
    Abstract [en]

    In this contribution we present a damage model for collagenous soft tissues such as arterial walls, which takes into account the statistical distributions of microscopic parameters. This approach extends the constitutive framework proposed in [1] by specific damage functions arising from microscopical considerations. In detail, statistical distributions of proteoglycan (PG) orientations, fibril length parameters and ultimate proteoglycan stretch can be considered, cf. [2]. The influence of each distributed quantity on the damage behavior is investigated by adjusting the model to uniaxial experimental data of a human carotid artery. Furthermore, the proposed model is implemented into a finite element framework and used within a numerical example in order to show its applicability to inhomogeneous boundary-value problems.

  • 80. Schriefl, Andreas J.
    et al.
    Schmidt, Thomas
    Balzani, Daniel
    Holzapfel, Gerhard A.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Determination Of Mechanical And Microstructural Tissue Quantities For Modeling Damage In Arterial Tissues2013In: Biomedizinische Technik (Berlin. Zeitschrift), ISSN 1862-278X, E-ISSN 0013-5585, Vol. 58, no (Suppl. 1)Article in journal (Refereed)
    Abstract [en]

    The overstretching of arterial walls as it occurs, e.g., during balloon angioplasty, results in a stress-softening of the collagenous wall which is believed to arise from microscopic tissue damage. To model such damage we use a macroscopic, fiber-reinforced constitutive framework including a characterization of the individual tissue components. We employed traditional and novel experimental investigations to determine and quantify the required mechanical and microstructural tissue parameters for the constitutive model. Herein we present some of our experimental approaches and the resulting preliminary findings.

  • 81. Selimovic, A.
    et al.
    Penrose, J.
    Bogunovic, H.
    Villa-Uriol, M. -C
    Holzapfel, Gerhard A.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.). Graz University of Technology, Austria .
    Ventikos, Y.
    Watton, P. N.
    A computational framework to explore the role of pulsatile haemodynamics on cerebral aneurysm development for patient-specific arterial geometries2010In: 6th World Congress of Biomechanics (WCB 2010). August 1-6, 2010 Singapore: In Conjunction with 14th International Conference on Biomedical Engineering (ICBME) and 5th Asia Pacific Conference on Biomechanics (APBiomech, Springer Berlin/Heidelberg, 2010, p. 759-762Conference paper (Refereed)
    Abstract [en]

    A patient-specific cerebral aneurysm case was identified from clinical imaging data, and then segmented to create a geometrical representation of the aneurysm and surrounding vasculature. Using ANSYS ICEM CFD, the geometry was manipulated to remove the aneurysm and replace it with a short (initially cylindrical) section, which reconnected to the upstream and downstream arterial sections so that the surface gradients were continuous. This section is modelled using a realistic constitutive model of the arterial wall and is the location where the computational model of the aneurysm evolves. The aneurysm evolution FEA model is combined with detailed 3D haemodynamic solutions using ANSYS CFX. A rigid-wall approach is adopted to solve the flow, to derive the haemodynamic stimuli that act on the endothelial cell layer of the tissue. Additionally, the geometry of the aneurysm is obtained at systolic and diastolic pressures (using a quasi-static approach) to obtain the cyclic stretch experienced by the cells within the arterial wall. This is the first patient-specific model of cerebral aneurysm evolution to explicitly link growth and remodelling of arterial tissue to the local mechanical environment. It will provide the basis for investigating the role and importance of various mechanical stimuli on the progression of the disease and will yield improved understanding of the aetiology of cerebral aneurysm formation.

  • 82.
    Shahgaldi, Kambiz
    KTH, School of Technology and Health (STH), Medical Engineering.
    Assessment of Left Ventricular Function and Hemodynamics Using Three-dimensional Echocardiography2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    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.

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  • 83. Sommer, G.
    et al.
    Schwarz, M.
    Kutschera, M.
    Kresnik, R.
    Regitnig, P.
    Schriefl, A. J.
    Wolinski, H.
    Kohlwein, S. D.
    Holzapfel, Gerhard A.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Biomechanical Properties Of The Human Ventricular Myocardium2013In: Biomedizinische Technik (Berlin. Zeitschrift), ISSN 1862-278X, E-ISSN 0013-5585, Vol. 58, no (Suppl. 1)Article in journal (Refereed)
    Abstract [en]

    In the multidisciplinary field of heart research it is of utmost importance, for the description of phenomena such as mechano-electric feedback or heart wall thickening, to accurately identify the biomechanical properties of the myocardium. Hence, this study aims at determining biaxial tensile and triaxial shear properties of the passive human myocardium. This novel combination of biaxial and shear testing, together with the investigation of the myocardial microstructure, yields new innovative and essential information of the material properties to fulfil the short term goals of constructing realistic myocardial models. Through such modeling efforts, capable to capture the biomechanical behaviour of the heart, it is possible to improve some methods of medical treatment, and hence the quality of life for people suffering from heart diseases - at least as a long-term goal.

  • 84.
    Stevens, Raoul
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Solid Mechanics (Div.).
    Grytsan, Andrii
    Biasetti, Jacopo
    Roy, Joy
    Liljeqvist, Moritz Lindquist
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Biomechanical changes during abdominal aortic aneurysm growth2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187421Article in journal (Refereed)
    Abstract [en]

    The biomechanics-based Abdominal Aortic Aneurysm (AAA) rupture risk assessment has gained considerable scientific and clinical momentum. However, such studies have mainly focused on information at a single time point, and little is known about how AAA properties change over time. Consequently, the present study explored how geometry, wall stress-related and blood flow-related biomechanical properties change during AAA expansion. Four patients with a total of 23 Computed Tomography-Angiography (CT-A) scans at different time points were analyzed. At each time point, patient-specific properties were extracted from (i) the reconstructed geometry, (ii) the computed wall stress at Mean Arterial Pressure (MAP), and (iii) the computed blood flow velocity at standardized inflow and outflow conditions. Testing correlations between these parameters identified several nonintuitive dependencies. Most interestingly, the Peak Wall Rupture Index (PWRI) and the maximum Wall Shear Stress (WSS) independently predicted AAA volume growth. Similarly, Intra-luminal Thrombus (ILT) volume growth depended on both the maximum WSS and the ILT volume itself. In addition, ILT volume, ILT volume growth, and maximum ILT layer thickness correlated with PWRI as well as AAA volume growth. Consequently, a large ILT volume as well as fast increase of ILT volume over time may be a risk factor for AAA rupture. However, tailored clinical studies would be required to test this hypothesis and to clarify whether monitoring ILT development has any clinical benefit.

  • 85.
    Ternström, Sten
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Speech, Music and Hearing, TMH.
    Update 3.1 to FonaDyn: A system for real-time analysis of the electroglottogram, over the voice range2024In: SoftwareX, E-ISSN 2352-7110, Vol. 26Article in journal (Refereed)
    Abstract [en]

    The human voice is notoriously variable, and conventional measurement paradigms are weak in terms of providing evidence for effects of treatment and/or training of voices. New methods are needed that can take into account the variability of metrics and types of phonation across the voice range. The “voice map” is a generalization of the Voice Range Profile (a.k.a. the phonetogram), with the potential to be used in many ways, for teaching, training, therapy and research. FonaDyn is intended as a proof-of concept workbench for education and research on phonation, and for exploring and validating the analysis paradigm of voice-mapping. Version 3.1 of the FonaDyn system adds many new functions, including listening from maps; displaying multiple maps and difference maps to track effects of voice interventions; smoothing/interpolation of voice maps; clustering not only of EGG shapes but also of acoustic and EGG metrics into phonation types; extended multichannel acquisition;24-bit recording with optional max 140 dB SPL; a built-in SPL calibration and signal diagnostics tool; EGG noise suppression; more Matlab integration; script control; the acoustic metrics Spectrum Balance, Cepstral Peak Prominence and Harmonic Richness Factor (of the EGG); and better window layout control. Stability and usability are further improved. Apple M-series processors are now supported natively.

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  • 86.
    Trossbach, Martin
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    de Lucas Sanz, Marta
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Seashore-Ludlow, Brinton
    Jönsson, Håkan
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    A Portable, Negative-Pressure Actuated, Dynamically Tunable Microfluidic Droplet Generator2022In: Micromachines, E-ISSN 2072-666X, Vol. 13, no 11, p. 1823-1823Article in journal (Refereed)
    Abstract [en]

    Droplet microfluidics utilize a monodisperse water-in-oil emulsion, with an expanding toolbox offering a wide variety of operations on a range of droplet sizes at high throughput. However, translation of these capabilities into applications for non-expert laboratories to fully harness the inherent potential of microscale manipulations is woefully trailing behind. One major obstacle is that droplet microfluidic setups often rely on custom fabricated devices, costly liquid actuators, and are not easily set up and operated by non-specialists. This impedes wider adoption of droplet technologies in, e.g., the life sciences. Here, we demonstrate an easy-to-use minimal droplet production setup with a small footprint, built exclusively from inexpensive commercially sourced parts, powered and controlled by a laptop. We characterize the components of the system and demonstrate production of droplets ranging in volume from 3 to 21 nL in a single microfluidic device. Furthermore, we describe the dynamic tuning of droplet composition. Finally, we demonstrate the production of droplet-templated cell spheroids from primary cells, where the mobility and simplicity of the setup enables its use within a biosafety cabinet. Taken together, we believe this minimal droplet setup is ideal to drive broad adoption of droplet microfluidics technology.

  • 87.
    Törne, Karin
    et al.
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF. St Jude Medical Systems AB, Sweden.
    Larsson, Mariann
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Norlin, Anna
    Weissenrieder, Jonas
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Degradation of zinc in saline solutions, plasma, and whole blood2016In: Journal of Biomedical Materials Research. Part B - Applied biomaterials, ISSN 1552-4973, E-ISSN 1552-4981, Vol. 104, no 6, p. 1141-1151Article in journal (Refereed)
    Abstract [en]

    The initial degradation of zinc has been investigated through exposures to simulated and real body fluids of increasing complexity: phosphate buffered saline (PBS), Ringer's saline solution, human plasma, and whole blood. Real body fluids were used to close the electrolyte gap between simulated and in vivo environment. Polarization of zinc in whole blood show a passive response not present in other electrolytes. The analysis shows a decrease in corrosion rate with time for plasma and whole blood and an increase for PBS and Ringer's. During exposure to plasma and whole blood a bi-layered corrosion product with poor adherence was formed over a uniformly corroding surface. The corrosion products comprise a mixture of inorganic material and biomolecules. Samples degrading in PBS were prone to localized corrosion and formed thick porous corrosion products of primarily zinc phosphates while in Ringer's solution a gel like layer of zinc carbonate was formed over an interface with shallow pits. The use of whole blood or plasma as electrolytes for short term in vitro evaluation of potential biodegradable metals may provide an improved understanding of the behavior in vivo, while Ringer's solution is preferred over PBS for long term degradation studies of zinc.

  • 88.
    Valastyán, Iván
    KTH, School of Technology and Health (STH), Medical Engineering.
    Software Solutions for Nuclear Imaging Systems in Cardiology, Small Animal Research and Education2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The sensitivity for observing physiological processes makes nuclear imaging an important tool in medical diagnostics. Different types of nuclear imaging modalities, with emphasis on the software components and image reconstructions, are presented in this thesis:  the Cardiotom for myocardial heart studies at the Karolinska University Hospital, the small animal Positron Emission Tomograph (PET) scanners for research and the SPECT, PET, spiral CT and Cardiotom demonstrators for the Royal Institute of Technology medical imaging laboratory.

    A modular and unified software platform has been developed for data representation, acquisition, visualization, reconstruction and presentation of the programs of the imaging devices mentioned above. The high performance 3D ML-EM and OS-EM iterative image reconstruction methods are implemented both on Cardiotom and miniPET scanners.

    As a result, the in-slice resolution of the first two prototypes of the Cardiotom today is the same as the formerly used filtered back-projection, however the in-depth resolution is considerably increased. Another improvement due to the new software is the shorter time that is required for data acquisition and image reconstruction. The new electronics with the newly developed software ensure images for medical diagnosis within 10 minutes from the start ofthe examination. The first system from the standardized production of the Cardiotom cameras is in the test phase.

    The performance parameters (sensitivity, spatial and energy resolution, coincidence time resolution) of the full ring mini PET camera are comparable to other small animal PETsystems.

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  • 89.
    Valastyán, Iván
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Bone, D.
    Brodin, L.-A.
    Elmqvist, H.
    Lagerlöf, J.
    Kerek, Andras
    KTH, School of Technology and Health (STH), Medical Engineering.
    Molnar, J.
    Novak, D.
    Validation of an iterative reconstruction for a mobile tomographic gamma camera system - The Cardiotom2007In: Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, ISSN 0168-9002, E-ISSN 1872-9576, Vol. 580, no 2, p. 1097-1100Article in journal (Refereed)
    Abstract [en]

    The Cardiotom is a mobile gamma camera that uses ectomography, an alternative method of acquisition to SPECT. It is designed for early diagnosis of myocardial and cerebral infarctions in the emergency room. Ectomography is a limited view angle method, using a rotating slant hole collimator and a stationary camera head, to acquire projection images. The aim of this work was to validate a fully 3D ML-EM iterative reconstruction algorithm for the Cardiotom. Validation measurements were performed with Tc-99m point sources. Resolution in the reconstructed volume was determined in X, Y. and Z directions from the point spread functions. The results were compared with the values for the formerly used filtered back projection (FBP). The new reconstruction algorithm provides greatly improved depth resolution with respect to the FBP method previously implemented on the Cardiotom. Furthermore, for clinical examinations, images can be available for interpretation within 15 min of the injection, therefore, valuable information can be obtained without delaying treatment of the patient. (c) 2007 Elsevier B.V. All rights reserved.

  • 90.
    Valastyán, Iván
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Bonec, D.
    Kerek, Andras
    KTH, School of Technology and Health (STH), Medical Engineering.
    Molnár, J.
    Novák, D.
    Unified software platform for nuclear medical image representation visualization and reconstructionIn: Journal of InstrumentsArticle in journal (Other academic)
  • 91.
    Valastyán, Iván
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering.
    Elmqvist, Håkan
    KTH, School of Technology and Health (STH), Medical Engineering.
    Kerek, Andras
    KTH, School of Technology and Health (STH), Medical Engineering.
    Molnar, J.
    Novak, D.
    Ribbe, T.
    Gated tomographic imaging in ectomography using a dynamic heart phantom2007In: Nuclear Science Symposium Conference Record, 2007. NSS '07. IEEE, IEEE , 2007, p. 3414-3417Conference paper (Refereed)
    Abstract [en]

    A new computer controlled dynamic heart phantom and the connection of an ECG unit to a tomographic gamma camera system, developed for ectomographic imaging, is presented. The phantom is used for validation of the camera. Measurements were performed to test the phantom as well as to study the feasibility of gated imaging in ectomography. The camera is intended for early diagnosis of myocardial and cerebral infarctions.

  • 92.
    Valastyán, Iván
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Imrek, J.
    Hegyesi, G.
    Molnar, J.
    Novak, D.
    Bone, D.
    Kerek, Andras
    KTH, School of Technology and Health (STH), Medical Engineering.
    Data acquisition and image reconstruction systems from the MiniPET scanners to the CARDIOTOM camera2007In: Nuclear Physics Methods And Accelerators In Biology And Medicine / [ed] Granja, C; Leroy, C; Stekl, I, American Institute of Physics (AIP), 2007, Vol. 958, p. 282-283Chapter in book (Refereed)
    Abstract [en]

    Nuclear imaging devices play an important role in medical diagnosis as well as drug research. The first and second generation data acquisition systems and the image reconstruction library developed provide a unified hardware and software platform for the miniPET-I, miniPET-II small animal PET scanners and for the CARDIOTOM(TM).

  • 93.
    Vastesson, Alexander
    et al.
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Guo, Maoxiang
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Haraldsson, Tommy
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    van der Wijngaart, Wouter
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems. KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.
    Polymer Nanoliter Well Arrays for Liquid Storage and Rapid On-demand Electrochemical Release2018In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 267, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Polymer microfluidic systems are of increasing importance in several applications in biomedicine and biosensing. The integrated encapsulation, storage, and controlled release of small amounts of liquid in such systems remains an unresolved technical challenge. Here, we report two methods for the room-temperature and adhesive-free sealing of 1–330 nanoliter volumes of liquid in off-stoichiometry thiol-ene polymer well arrays by spontaneous bonding to 200 nm thin gold films. Sealed well arrays were stored for more than one month in a liquid environment with <10% liquid loss, and for more than one week in air with minimal loss. We demonstrated that controlling the electrical potential and polarity over encapsulated wells allowed for selecting one of two well opening mechanisms: slow anodic electrochemical etching, or rapid electrolytic gas pressure-induced bursting of the gold film. The results may find potential applications in diagnostic testing, in vivo drug delivery, or in spatio-temporal release of chemical compounds in biological assays.

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    fulltext
  • 94.
    Veses-Garcia, Marta
    et al.
    Karolinska Inst, Swedish Med Nanosci Ctr, Dept Neurosci, Stockholm, Sweden..
    Antypas, Haris
    Karolinska Inst, Swedish Med Nanosci Ctr, Dept Neurosci, Stockholm, Sweden..
    Loffler, Susanne
    Karolinska Inst, Swedish Med Nanosci Ctr, Dept Neurosci, Stockholm, Sweden..
    Brauner, Annelie
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Div Clin Microbiol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Svahn Andersson, Helene
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Swedish Med Nanosci Ctr, Dept Neurosci, Stockholm, Sweden..
    Rapid Phenotypic Antibiotic Susceptibility Testing of Uropathogens Using Optical Signal Analysis on the Nanowell Slide2018In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 9, article id 1530Article in journal (Refereed)
    Abstract [en]

    Achieving fast antimicrobial susceptibility results is a primary goal in the fight against antimicrobial resistance. Standard antibiotic susceptibility testing (AST) takes, however, at least a day from patient sample to susceptibility profile. Here, we developed and clinically validated a rapid phenotypic AST based on a miniaturized nanotiter plate, the nanowell slide, that holds 672 wells in a 500 nl format for bacterial cultivation. The multitude of nanowells allows multiplexing with a panel of six antibiotics relevant for urinary tract infections. Inclusion of seven concentrations per antibiotic plus technical replicates enabled us to determine a precise minimum inhibitory concentration for 70 clinical uropathogenic Escherichia coil isolates. By combining optical recordings of bacterial growth with an algorithm for optical signal analysis, we calculated T-lag, the point of transition from lag to exponential phase, in each nanoculture. Algorithm-assisted analysis determined antibiotic susceptibility as early as 3 h 40 min. In comparison to standard disk diffusion assays, the nanowell AST showed a total categorical agreement of 97.9% with 2.6% major errors and 0% very major errors for all isolate-antibiotic combination tested. Taking advantage of the optical compatibility of the nanowell slide, we performed microscopy to illustrate its potential in defining susceptibility profiles based on bacterial morphotyping. The excellent clinical performance of the nanowell AST, combined with a short detection time, morphotyping, and the very low consumption of reagents clearly show the advantage of this phenotypic AST as a diagnostic tool in a clinical setting.

  • 95.
    von Hofsten, Olof
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Bertilson, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Lindblom, M.
    Holmberg, Anders
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Vogt, Ulrich
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Compact Zernike phase contrast x-ray microscopy using a single-element optic2008In: Optics Letters, ISSN 0146-9592, E-ISSN 1539-4794, Vol. 33, no 9, p. 932-934Article in journal (Refereed)
    Abstract [en]

    We demonstrate Zernike phase contrast in a compact soft x-ray microscope using a single-element optic. The optic is a combined imaging zone plate and a Zernike phase plate and does not require any additional alignment or components. Contrast is increased and inversed in an image of a test object using the Zernike zone plate. This type of optic may be implemented into any existing x-ray microscope where phase contrast is of interest.

  • 96.
    Weibull, Emilie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Miniaturised Microwell-based Cell Assays2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cell heterogeneity in genetically identical cell populations is becoming a well-known and important phenomenon in cell biology. Current methods commonly utilise population-based analysis founded on averaged result. Hence there is a need for high-throughput cell assays on the single-cell level. By using miniaturised devices it is possible to enhance spatial and temporal control of the individual cells, increase the potential throughput and minimise the needed sample and reagent volume while enabling a wide range of biological applications.

    This thesis is based on the results generated with a miniaturised microwell slide for cell assays. The microwell slide’s high-throughput compartmentalised configuration enables several hundred isolated experiments to be run simultaneously. The bottom of the wells is made out of a thin glass slide, which supports high-resolution imaging. The slide has a standardised format and its’ compatibility with conventional instruments is used extensively throughout the thesis. The presented papers all contribute to the development of the microwell slide by adding technical value or increasing the number of potential applications. For example, the slide was success-fully implemented as a chip-to-world output format for single microfluidic droplets in Paper I, by interfacing two miniaturised systems with fluorescence-activated cell sorting. In Paper II and III, microfluidic channels were integrated to increase spatial and temporal control of the added samples and reagents. In Paper II an automated stepwise concentration gradient generator was developed delivering a drug gradient to adherent mammalian cells in designated wells. In Paper III fluidic-imposed shear stress on endothelial cells was studied. In Paper IV, the slide was functionalised by coating the surfaces of the wells with several antibiotics at a defined concentration range. The coated slide was used for multiplex antibiotic susceptibility testing of bacterial pathogens, using an algorithm-based identification of the point defining lag to exponential phase transition. It successfully determined the pathogens susceptibility profile in 3-5 hours. Finally, in Paper V, a method to retrieve bacteria colonies with a desired phenotype from the wells for downstream genetic analysis was developed. In summary, the presented work has furthered the development of miniaturised high-throughput tools for various cell heterogeneity assays.

  • 97.
    Weibull, Emilie
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ohashi, Toshiro
    A microfluidic device towards shear stress analysis on clonal expanded endothelial cells2013Manuscript (preprint) (Other academic)
  • 98.
    Weibull, Emilie
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Antipas, Haris
    Richter-Dahlfors, Agneta
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dynamic optical screening of single-bacterium and retrieval of the subsequent liquid colony for genetic analysis2014Manuscript (preprint) (Other academic)
  • 99.
    Weibull, Emilie
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Antypas, Haris
    Kjäll, Peter
    Brauner, Annelie
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Richter-Dahlfors, Agneta
    Bacterial nano-scale cultures for rapid multiplexed antibiotic susceptibility testing2013Manuscript (preprint) (Other academic)
  • 100.
    Weibull, Emilie
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Matsui, S.
    Sakai, M.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ohashi, T.
    Microfluidic device for generating a stepwise concentration gradient on a microwell slide for cell analysis2013In: Biomicrofluidics, E-ISSN 1932-1058, Vol. 7, no 6, p. 064115-Article in journal (Refereed)
    Abstract [en]

    Understanding biomolecular gradients and their role in biological processes is essential for fully comprehending the underlying mechanisms of cells in living tissue. Conventional in vitro gradient-generating methods are unpredictable and difficult to characterize, owing to temporal and spatial fluctuations. The field of microfluidics enables complex user-defined gradients to be generated based on a detailed understanding of fluidic behavior at the μm-scale. By using microfluidic gradients created by flow, it is possible to develop rapid and dynamic stepwise concentration gradients. However, cells exposed to stepwise gradients can be perturbed by signals from neighboring cells exposed to another concentration. Hence, there is a need for a device that generates a stepwise gradient at discrete and isolated locations. Here, we present a microfluidic device for generating a stepwise concentration gradient, which utilizes a microwell slide’s pre-defined compartmentalized structure to physically separate different reagent concentrations. The gradient was generated due to flow resistance in the microchannel configuration of the device, which was designed using hydraulic analogy and theoretically verified by computational fluidic dynamics simulations. The device had two reagent channels and two dilutant channels, leading to eight chambers, each containing 4 microwells. A dose-dependency assay was performed using bovine aortic endothelial cells treated with saponin. High reproducibility between experiments was confirmed by evaluating the number of living cells in a live-dead assay. Our device generates a fully mixed fluid profile using a simple microchannel configuration and could be used in various gradient studies, e.g., screening for cytostatics or antibiotics.

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