80 research outputs found

    Optogenetics in striated muscle: defibrillation of the heart and direct stimulation of skeletal muscles with light

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    Optogenetic depolarization of cells using the non-selective cation channel Channelrhodopsin-2 (ChR2) enables precise control over the membrane potential of cells within a specific area of intact organs. Furthermore, the selective overexpression of light-gated proteins allows cell type-specific and pain-free stimulation which could be of great benefit for future scientific and therapeutic approaches. In my thesis, I explored two potential applications of optogenetic methods in striated muscle: optogenetic defibrillation to terminate ventricular arrhythmia in intact mouse hearts and direct optogenetic stimulation of skeletal muscles. These new approaches could lead in the future to the development of optogenetic defibrillators and laryngeal pacemakers. Most experiments were performed with explanted hearts, isolated skeletal fibers and muscles or larynges from transgenic ChR2 expressing mice. To add translational perspectives, we also explored optogenetic defibrillation and intralaryngeal muscles stimulation after ChR2 gene transfer to wild type mice using adeno-associated virus (AAV). Optogenetic defibrillation by epicardial illumination was highly efficient in terminating ventricular arrhythmia in transgenic hearts and the success rate of optogenetic defibrillation was depending on the pulse duration, the size of illumination and the light intensity. Importantly, we were also able to terminate ventricular arrhythmia in non-transgenic hearts even one year after AAV mediated gene transfer. The potential applicability of optogenetic defibrillation in the human heart was assessed in experimentally-calibrated computer simulations of a patient’s heart with infarct-related ventricular tachycardia. Because optogenetic stimulation would be in principle pain-free in patients, the proof for its feasibility could lay the foundation for the development of a new treatment option for patients at high risk for ventricular arrhythmia. Direct optogenetic stimulation of skeletal muscle was first proven in isolated Flexor digitorum brevis fibers and in intact soleus muscles, which could both be stimulated using brief light pulses. The force of light-induced single twitches could be precisely controlled by varying the pulse duration and light intensity. Optogenetic stimulation was most efficient with 10 ms long pulses at a repetition rate of 40 Hz reaching ~84% of the maximum force generated by electrical stimulation with 100 Hz. Recurrent nerve paralysis is a severe complication of neck surgery, malignant processes or central neurological diseases and results in a fixed paramedian position of the vocal cords as well as life-threatening dyspnea in the case of bilateral paralysis. Current treatment options consist only of destructive surgery. Unfortunately the use of local electrical stimulation to restore laryngeal function faces severe technical limitations. Therefore I sought to explore direct optogenetic stimulation of intralaryngeal muscles in explanted larynges from ChR2 transgenic mice. Specific illumination of the individual intralaryngeal muscle groups led to an opening or closing of the vocal cords depending on the site of illumination. This proves the sufficient spatial resolution of light for selective stimulation of the intralaryngeal muscles groups. In addition, we were able to induce opening of the vocal cords in wild type mice after AAV-based gene transfer of ChR2 with light. Thus optogenetic stimulation could become a new treatment option for patients suffering from bilateral laryngeal paralysis. In conclusion, optogenetic stimulation can overcome the severe limitations of electrical stimulation of the heart and skeletal muscles. The new technologies, I have developed and characterized in this thesis, allow for the design of completely new stimulation patterns to address open questions in muscle physiology. Furthermore, optogenetic stimulation of striated muscles could become a new treatment option for patients enabling selective and pain-free stimulation with few side effects

    Novel magnetic resonance antennas and applications

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    This dissertation describes novel magnetic resonance imaging (MRI) surface antennas and arrays, and their applications at both 3 and 7 Tesla. While the first half of this work describes flexible lightweight antenna arrays, the other half focuses on the use of solid ceramic high-permittivity materials as a substantial part of the antenna. NWOLUMC / Geneeskund

    Atlas of sensations - on sensibilities in a computational design practice

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    The driving force behind the body of work of SPAN is defined by the application of advanced computational design methodologies. This dissertation can be understood as a cartography (in the best tradition of an atlas) of the work of the practice from its founding year 2003 until 2017 - a period profoundly shaped by the progress made in technological advances. These technological means allow SPAN to discuss architectural project through a series of different lenses such as conceptualization, planning, fabrication to the maintenance of the designed objects, through the use of emerging technical opportunities wither this be the interrogation of novel geometries (Blocks, Ore, Barcelona Recursion), computational methods of rationalization (Expo Façade) or advanced methods of fabrication (Robots, as for example in Plato's Columns). In a parallel move between the necessities and desires of the practice and the ambitious studios and seminars in academia, novel toolsets and design concepts are developed to address contemporary architectural problems. These areas can be understood as different territories of interrogation, forming a landscape of opportunities, or as we describe it internally in our office: a design ecology. The interrogation of these distinct territories, and the unique way in which SPAN assembles those various elements to something larger than its parts, is what constitutes part of SPAN's contribution to the discipline. Apart from projects and visual work, SPAN´s contribution to discourse started early with papers to conferences such as IASS (International Association for Shell and Spatial Structures) in 2007, Design Modeling Symposium in 2008, and ACADIA (Association for Computer Aided Design in Architecture) in 2008, which included ideas such as the application of tissue engineering in architecture, aspects of artifact and affect, fabrication, and considerations on architectural details in complex curved geometries. Within the Atlas of Sensations, a second ecology is defined by the contribution to the paradigm shift in the discourse from the continuous to the hyper-articulated surface, which contains an additional level of information. A surface, which describes architectural properties through the deep pochés, folds, joints, niches, and arches it generates.  The question is: How does this shift in the conception of architecture affect the qualities of the design, and by extension the context these objects construct? To further investigate this question the work focuses on one part of the practice's design ecology: design sensibilities. In order to interrogate this question, the presented work observes these moments in SPAN's practice through the lens of geometrical properties. Ultimately resulting in thoughts on Postdigital design ecologies that discuss aspects of design agency in our contemporary age

    CFD study of hydrodynamic signal perception by fish using the lateral line system

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    Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution February 2009The lateral line system on fish has been found to aid in schooling behavior, courtship communication, active and passive hydrodynamic imaging, and prey detection. The most widely used artificial prey stimulus has been the vibrating sphere, which some fish are able to detect even when the signal velocities to its lateral line are orders of magnitude smaller than background current velocities. It is not clear how the fish are able to extract this signal. This thesis uses a series of computational fluid dynamic (CFD) simulations, matched with recent experiments, to quantify the effects of 3D fish body parts on the received dipole signals, and to determine signal detection abilities of the lateral line system in background flow conditions. An approximation is developed for the dipole induced, oscillatory, boundary layer velocity profile over the surface of a fish. An analytic solution is developed for the case when the surface is a wall, and is accurate at points of maximal surface tangential velocity. Results indicate that the flow outside a thin viscous layer remains potential in nature, and that body parts, such as fins, do not significantly affect the received dipole signal in still water conditions. In addition, the canal lateral line system of the sculpin is shown to be over 100 times more sensitive than the superficial lateral line system to high frequency dipole stimuli. Analytical models were developed for the Mottled Sculpin canal and superficial neuromast motions, in response to hydrodynamic signals. When the background flow was laminar, the neuromast motions induced by the stimulus signal at threshold had a spectral peak larger than spectral peaks resulting from the background flow induced motions. When the turbulence level increased, the resulting induced neuromast motions had dominant low frequency oscillations. For fish using the signal encoding mechanisms of phase-locking or spike rate increasing, signal masking should occur
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