801 research outputs found

    Beam scanning by liquid-crystal biasing in a modified SIW structure

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    A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium

    Visualization and manipulation of repair and regeneration in biological systems using light

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    Tissue repair after an injury is a fundamental process in biomedicine. It can involve regeneration, which uses new growth to restore tissue function. The interest in repair and regeneration is motivated by the desire to treat injuries and diseases and has attracted researchers for centuries. In the last decades, it evolved in the field of regenerative medicine, which has the ultimate goal of providing strategies for regenerating human cells, tissues, or even organs, for instance, via engineering principles. Already since the first experiments on regeneration by Abraham Trembley, novel findings in biomedicine, repair, and regeneration have been enabled or accompanied by research in optics, for example, on the development of novel microscopy techniques. Nowadays, novel optical techniques are advancing, which allow to understand the role of single cells in tissue repair processes. Moreover, repair processes within cells can be visualized and manipulated. Ultimately, optics can provide enabling techniques for regenerative therapies. This habilitation thesis aims to present several of these advances. On a single cell level, femtosecond laser nanosurgery was used to target specific intracellular structures during concurrent imaging in vitro. The relation of femtosecond laser nanosurgery to the cell state and cellular staining was investigated. Manipulation of single Z-discs in cardiomyocytes using a femtosecond oscillator laser system was accomplished, which allows to better elucidate the role of a single Z-disc in cardiomyocyte function. In particular, measurements on cell survival, (calcium-) homeostasis, and morphology yielded only minor deviations from control cells after single Z-disc ablation. A reduction in force generation was elucidated via traction force microscopy and gene expression level changes, for instance, an upregulation of -actinin were examined. Additionally, light-based systems to influence single cells in their alignment or to trigger single cells, for example, to activate other cells via optogenetics were applied. On the tissue scale, imaging via confocal microscopy or multiphoton microscopy has been applied for various contexts of regenerative approaches. Furthermore, a fiber-based imaging approach, which could later be used for longitudinal imaging in vivo and builds upon a fluorescence microscope system and an imaging fiber bundle in combination with reconstruction via a neural network, was developed. As another imaging strategy, an abdominal imaging window served to image the mouse liver in vivo via multiphoton microscopy in successive imaging sessions. Manipulation in tissue was applied in colonoids, which resemble the structure of the colon on an in vitro scale, and revealed different cell dynamics dependent on the location of the damage. In particular, activation of the Wnt signaling pathway after crypt damage was observed. Cell ablation via a femtosecond laser amplifier system during concurrent two-photon microscopy was also established during in vivo liver imaging to study micro-regenerative processes. Furthermore, laser-based delivery processes with novel materials or in the context of genome editing using CRISPR/Cas9 technology were investigated as enabling technologies for regenerative medicine. In conclusion, this thesis addresses the question of how optics can help to illuminate future directions in research on tissue repair and regeneration, as well as, regenerative therapies by addressing (longitudinal) imaging in a complex environment, sophisticated cell-manipulation strategies, and the application of novel materials for laser-based delivery

    Microfluidic systems based on electroactive polymers technology

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    Dielectric elastomer actuators (DEAs) have been widely investigated for more than 30 years. Lately, several fabrication methods have successfully allowed the creation of very thin elastomer and electrode layers. The development of attractive applications, in which DEAs offer advantages over conventional technologies, is thus necessary for the advance of the technology. In this work, new biocompatible microfluidic devices based on DEAs are developed. In the first part of this thesis, several prototypes of peristaltic pumps of single layer dielectric elastomer actuators are designed, manufactured and characterized. Although these prototypes were not able to produce fluid flow, novel insights into the capabilities of Electroactive Polymer technology were gained. In the second part of this work, a pumping micromixer as a novel application of dielectric elastomer stacked actuators is manufactured. The pumping micromixer is based on peristaltic movements, which gently act as a mixer and a pump for microfluidics. Experimental data show a maximal flow rate of 21.5 µL/min at 10 Hz. Image analysis at the outlet proves a 50/50 mixing when all actuators are functioning at the same pace and voltage. The performance of the pumping micromixer is further studied with the Finite Element Method, using the COMSOL Multiphysics® software. Simulations demonstrate the versatility of the pumping characteristics of such a microdevice, from very few µL/min to mL/min, and from a very low pressure in the range of Pa to hundreds of kPa, by only changing the duty cycle, phase shift and actuation frequency

    Analysis, Design and Fabrication of Micromixers, Volume II

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    Micromixers are an important component in micrototal analysis systems and lab-on-a-chip platforms which are widely used for sample preparation and analysis, drug delivery, and biological and chemical synthesis. The Special Issue "Analysis, Design and Fabrication of Micromixers II" published in Micromachines covers new mechanisms, numerical and/or experimental mixing analysis, design, and fabrication of various micromixers. This reprint includes an editorial, two review papers, and eleven research papers reporting on five active and six passive micromixers. Three of the active micromixers have electrokinetic driving force, but the other two are activated by mechanical mechanism and acoustic streaming. Three studies employs non-Newtonian working fluids, one of which deals with nano-non-Newtonian fluids. Most of the cases investigated micromixer design

    Electronic Devices for the Combination of Electrically Controlled Drug Release, Electrostimulation, and Optogenetic Stimulation for Nerve Tissue Regeneration

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    [ES] La capacidad de las células madre para proliferar formando distintas células especializadas les otorga la potencialidad de servir de base para terapias efectivas para patologías cuyo tratamiento era inimaginable hasta hace apenas dos décadas. Sin embargo, esta capacidad se encuentra mediada por estímulos fisiológicos, químicos, y eléctricos, específicos y complejos, que dificultan su traslación a la rutina clínica. Por ello, las células madre representan un campo de estudio en el que se invierten amplios esfuerzos por parte de la comunidad científica. En el ámbito de la regeneración nerviosa, para modular su desarrollo y diferenciación el tratamiento farmacológico, la electroestimulación, y la estimulación optogenética son técnicas que están consiguiendo prometedores resultados. Es por ello por lo que en la presente tesis se ha desarrollado un conjunto de sistemas electrónicos para permitir la aplicación combinada de estas técnicas in vitro, con perspectiva a su aplicación in vivo. Hemos diseñado una novedosa tecnología para la liberación eléctricamente controlada de fármacos. Esta tecnología está basada en nanopartículas de sílice mesoporosa y puertas moleculares de bipiridina-heparina. Las puertas moleculares son electroquímicamente reactivas, y encierran los fármacos en el interior de las nanopartículas, liberándolos ante un estímulo eléctrico. Hemos caracterizado esta tecnología, y la hemos validado mediante la liberación controlada de rodamina en cultivos celulares de HeLa. Para la combinación de liberación controlada de fármacos y electroestimulación hemos desarrollado dispositivos que permiten aplicar los estímulos eléctricos de forma configurable desde una interfaz gráfica de usuario. Además, hemos diseñado un módulo de expansión que permite multiplexar las señales eléctricas a diferentes cultivos celulares. Además, hemos diseñado un dispositivo de estimulación optogenética. Este tipo de estimulación consiste en la modificación genética de las células para que sean sensibles a la radiación lumínica de determinada longitud de onda. En el ámbito de la regeneración de tejido mediante células precursoras neurales, es de interés poder inducir ondas de calcio, favoreciendo su diferenciación en neuronas y la formación de circuitos sinápticos. El dispositivo diseñado permite obtener imágenes en tiempo real mediante microscopía confocal de las respuestas transitorias de las células al ser irradiadas. El dispositivo se ha validado irradiando neuronas modificadas con luz pulsada de 100 ms. También hemos diseñado un dispositivo electrónico complementario de medida de irradiancia con el doble fin de permitir la calibración del equipo de irradiancia y medir la irradiancia en tiempo real durante los experimentos in vitro. Los resultados del uso de los bioactuadores en procesos complejos y dinámicos, como la regeneración de tejido nervioso, son limitados en lazo abierto. Uno de los principales aspectos analizados es el desarrollo de biosensores que permitiesen la cuantización de ciertas biomoléculas para ajustar la estimulación suministrada en tiempo real. Por ejemplo, la segregación de serotonina es una respuesta identificada en la elongación de células precursoras neurales, pero hay otras biomoléculas de interés para la implementación de un control en lazo cerrado. Entre las tecnologías en el estado del arte, los biosensores basados en transistores de efecto de campo (FET) funcionalizados con aptámeros son realmente prometedores para esta aplicación. Sin embargo, esta tecnología no permitía la medición simultánea de más de una biomolécula objetivo en un volumen reducido debido a las interferencias entre los distintos FETs, cuyos terminales se encuentran inmersos en la solución. Por ello, hemos desarrollado instrumentación electrónica capaz de medir simultáneamente varios de estos biosensores, y la hemos validado mediante la medición simultánea de pH y la detección preliminar de serotonina y glutamato.[CA] La capacitat de les cèl·lules mare per a proliferar formant diferents cèl·lules especialitzades els atorga la potencialitat de servir de base per a teràpies efectives per a patologies el tractament de les quals era inimaginable fins fa a penes dues dècades. No obstant això, aquesta capacitat es troba mediada per estímuls fisiològics, químics, i elèctrics, específics i complexos, que dificulten la seua translació a la rutina clínica. Per això, les cèl·lules mare representen un camp d'estudi en el qual s'inverteixen amplis esforços per part de la comunitat científica. En l'àmbit de la regeneració nerviosa, per a modular el seu desenvolupament i diferenciació el tractament farmacològic, l'electroestimulació, i l'estimulació optogenética són tècniques que estan aconseguint prometedors resultats. És per això que en la present tesi s'ha desenvolupat un conjunt de sistemes electrònics per a permetre l'aplicació combinada d'aquestes tècniques in vitro, amb perspectiva a la seua aplicació in vivo. Hem dissenyat una nova tecnologia per a l'alliberament elèctricament controlat de fàrmacs. Aquesta tecnologia està basada en nanopartícules de sílice mesoporosa i portes moleculars de bipiridina-heparina. Les portes moleculars són electroquímicament reactives, i tanquen els fàrmacs a l'interior de les nanopartícules, alliberant-los davant un estímul elèctric. Hem caracteritzat aquesta tecnologia, i l'hem validada mitjançant l'alliberament controlat de rodamina en cultius cel·lulars de HeLa. Per a la combinació d'alliberament controlat de fàrmacs i electroestimulació hem desenvolupat dispositius que permeten aplicar els estímuls elèctrics de manera configurable des d'una interfície gràfica d'usuari. A més, hem dissenyat un mòdul d'expansió que permet multiplexar els senyals elèctrics a diferents cultius cel·lulars. A més, hem dissenyat un dispositiu d'estimulació optogenètica. Aquest tipus d'estimulació consisteix en la modificació genètica de les cèl·lules perquè siguen sensibles a la radiació lumínica de determinada longitud d'ona. En l'àmbit de la regeneració de teixit mitjançant cèl·lules precursores neurals, és d'interés poder induir ones de calci, afavorint la seua diferenciació en neurones i la formació de circuits sinàptics. El dispositiu dissenyat permet obtindré imatges en temps real mitjançant microscòpia confocal de les respostes transitòries de les cèl·lules en ser irradiades. El dispositiu s'ha validat irradiant neurones modificades amb llum polsada de 100 ms. També hem dissenyat un dispositiu electrònic complementari de mesura d'irradiància amb el doble fi de permetre el calibratge de l'equip d'irradiància i mesurar la irradiància en temps real durant els experiments in vitro. Els resultats de l'ús dels bioactuadors en processos complexos i dinàmics, com la regeneració de teixit nerviós, són limitats en llaç obert. Un dels principals aspectes analitzats és el desenvolupament de biosensors que permeteren la quantització de certes biomolècules per a ajustar l'estimulació subministrada en temps real. Per exemple, la segregació de serotonina és una resposta identificada amb l'elongació de les cèl·lules precursores neurals, però hi ha altres biomolècules d'interés per a la implementació d'un control en llaç tancat. Entre les tecnologies en l'estat de l'art, els biosensors basats en transistors d'efecte de camp (FET) funcionalitzats amb aptàmers són realment prometedors per a aquesta aplicació. No obstant això, aquesta tecnologia no permetia el mesurament simultani de més d'una biomolècula objectiu en un volum reduït a causa de les interferències entre els diferents FETs, els terminals dels quals es troben immersos en la solució. Per això, hem desenvolupat instrumentació electrònica capaç de mesurar simultàniament diversos d'aquests biosensors i els hem validat amb mesurament simultani del pH i la detecció preliminar de serotonina i glutamat.[EN] The stem cells' ability to proliferate to form different specialized cells gives them the potential to serve as the basis for effective therapies for pathologies whose treatment was unimaginable until just two decades ago. However, this capacity is mediated by specific and complex physiological, chemical, and electrical stimuli that complicate their translation to clinical routine. For this reason, stem cells represent a field of study in which the scientific community is investing a great deal of effort. In the field of nerve regeneration, to modulate their development and differentiation, pharmacological treatment, electrostimulation, and optogenetic stimulation are techniques that are achieving promising results. For this reason, we have developed a set of electronic systems to allow the combined application of these techniques in vitro, with a view to their application in vivo. We have designed a novel technology for the electrically controlled release of drugs. This technology is based on mesoporous silica nanoparticles and bipyridine-heparin molecular gates. The molecular gates are electrochemically reactive and entrap the drugs inside the nanoparticles, releasing them upon electrical stimulus. We have characterized this technology and validated it by controlled release of rhodamine in HeLa cell cultures. For combining electrostimulation and controlled drug release we have developed devices that allow applying the different electrical stimuli in a configurable way from a graphical user interface. In addition, we have designed an expansion module that allows multiplexing electrical signals to different cell cultures. In addition, we have designed an optogenetic stimulation device. This type of stimulation consists of genetically modifying cells to make them sensitive to light radiation of a specific wavelength. In tissue regeneration using neural precursor cells, it is interesting to be able to induce calcium waves, favoring the cell differentiation into neurons and the formation of synaptic circuits. The designed device enable the obtention of real-time images through confocal microscopy of the transient responses of cells upon irradiation. The device has been validated by irradiating modified neurons with 100 ms pulsed light stimulation. We have also designed a complementary electronic irradiance measurement device to allow calibration of the irradiator equipment and measuring irradiance in real time during in vitro experiments. The results of using bioactuators in complex and dynamic processes, such as nerve tissue regeneration, are limited in an open loop. One of the main aspects analyzed is the development of biosensors that would allow quantifying of specific biomolecules to adjust the stimulation provided in real time. For instance, serotonin secretion is an identified response of neural precursor cells elongation, among other biomolecules of interest for the implementation of a closed-loop control. Among the state-of-the-art technologies, biosensors based on field effect transistors (FETs) functionalized with aptamers are promising for this application. However, this technology did not allow the simultaneous measurement of more than one target biomolecule in a small volume due to interferences between the different FETs, whose terminals are immersed in the solution. This is why we have developed electronic instrumentation capable of simultaneously measuring several of these biosensors, and we have validated it with the simultaneous pH measurement and the preliminary detection of serotonin and glutamate.Monreal Trigo, J. (2023). Electronic Devices for the Combination of Electrically Controlled Drug Release, Electrostimulation, and Optogenetic Stimulation for Nerve Tissue Regeneration [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/19384

    Nanostructured biosensors with DNA-based receptors for real-time detection of small analytes

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    In zahlreichen lebenswichtigen Bereichen haben sich Biosensoren als unverzichtbare Messgeräte erwiesen. Der Nachweis von spezifischen Molekülen im Körper für eine frühzeitige Krankheitserkennung erfordert empfindliche und zugleich zuverlässige Messmethoden. Ein rasantes Fortschreiten im Bereich der Nanotechnologie führt dabei zur Entwicklung von Materialien mit neuen Eigenschaften, und damit verbunden, auch zu innovativen Anwendungsmöglichkeiten im Bereich der Biosensorik. Das Zusammenspiel von Nanotechnologie und Sensortechnik gewährleistet die Konstruktion von Sensoren mit empfindlicheren Nachweisgrenzen und kürzeren Reaktionszeiten. Die Option zur Integration und Miniaturisierung stellen daher einen erfolgreichen Einsatz in direkter Patientennähe in Aussicht, sodass Nanobiosensoren die Brücke zwischen Laborddiagnostik und Standardanwendungen schließen können. Die folgende Arbeit widmet sich der Anwendung von nanostrukturierten Biosensoren für einen empfindlichen und markierungsfreien Nachweis von Zielmolekülen. Ein Hauptaugenmerk liegt dabei auf der kontinuierlichen Messung von Biomarkern mit kompakten Auslesesystemen, die eine direkte Signalmeldung und somit eine Detektion in Echtzeit ermöglichen. Dies erfordert zunächst die sorgfältige Funktionalisierung von Sensoroberflächen mit geeigneten DNA-basierten Rezeptoren. Infolgedessen werden beispielhaft verschiedene Sensorsysteme, Analyten und Charakterisierungsmethoden vorgestellt sowie universelle Strategien für die erfolgreiche Konfiguration von Nanobiosensorplattformen präsentiert. Das erste Anwendungsbeispiel widmet sich einem plasmonischen Biosensor, bei dem vertikal ausgerichtete Gold-Nanoantennen Signale mittels sog. lokalisierter Oberflächenplasmonenresonanz (LSPR) erzeugen. Mit dem Sensor konnte erfolgreich die Immobilisierung, das nachträgliche Blocken sowie die anschließende Hybridisierung von DNA nachgewiesen werden. Mithilfe des LSPR-Sensors wurden gleichzeitig grundlegende Hybridisierungsmechanismen auf nanostrukturierten und planaren Oberflächen verglichen und damit verbunden die einzigartigen optischen Eigenschaften metallischer Nanostrukturen betont. In einem zweiten Anwendungsbeispiel misst ein elektrischer Biosensor kontinuierlich die Konzentration des Stressmarkers Cortisol im menschlichen Speichel. Der direkte, markierungsfreie Nachweis von Cortisol mit Silizium-Nanodraht basierten Feldeffekttransistoren (SiNW FET) wurde anhand zugrunde liegender Ladungsverteilungen innerhalb des entstandenen Rezeptor-Analyte-Komplexes bewertet, sodass ein Nachweis des Analyten innerhalb der sog. Debye-Länge ermöglicht wird. Die erfolgreiche Strategie zur Oberflächenfunktionalisierung im Zusammenspiel mit dem Einsatz von SiNW FETs auf einem tragbaren Messgerät wurde anhand des Cortisolnachweises im Speichel belegt. Ein übereinstimmender Vergleich der gemessenen Corisolkonzentrationen mit Werten, die mit einer kommerziellen Alternative ermittelt wurden, verdeutlichen das Potential der entwickelten Plattform. Zusammenfassend veranschaulichen beide vorgestellten Nanobiosensor-Plattformen die vielseitige und vorteilhafte Leistungsfähigkeit der Systeme für einen kontinuierlichen Nachweis von Biomarkern in Echtzeit und vorzugsweise in Patientennähe.:Kurzfassung I Abstract III Abbreviations and symbols V Content VII 1 Introduction 1 1.1 Scope of the thesis 4 1.2 References 6 2 Fundamentals 9 2.1 Biosensors 9 2.2 Influence of nanotechnology on sensor development 10 2.3 Biorecognition elements 12 2.3.1 Biorecognition element: DNA 13 2.3.2 Aptamers 14 2.3.3 Immobilization of receptors 15 2.4 Transducer systems 17 2.4.1 Optical biosensors - surface plasmon resonance 17 2.4.2 Electric Biosensors – Field-effect transistors (FETs) 21 2.5 Metal oxide semiconductor field-effect transistor - MOSFET 21 2.6 Summary 26 2.7 References 27 3 Materials and methods 33 3.1 Plasmonic biosensors based on vertically aligned gold nanoantennas 33 3.1.1 Materials 33 3.1.2 Manufacturing of nanoantenna arrays 34 3.1.3 Surface modification and characterization 35 3.1.4 Measurement setup for detection of analytes 38 3.2 SiNW FET-based real-time monitoring of cortisol 40 3.2.1 Materials 40 3.2.2 Manufacturing of silicon nanowire field effect transistors (SiNW FETs) 42 3.2.3 Integration of SiNW FETs into a portable platform 42 3.2.4 Biomodification and characterization of electronic biosensors SiNW FETs 42 3.2.5 Electric characterization of FETs 47 3.3 References 50 4 Plasmonic DNA biosensor based on vertical arrays of gold nanoantennas 51 4.1 Introduction - Optical biosensors operating by means of LSPR 53 4.2 Biosensing with vertically aligned gold nanoantennas 56 4.2.1 Sensor fabrication, characterization, and integration 56 4.2.2 Integration of microfluidics 58 4.2.3 Immobilization of probe DNA and backfilling 58 4.2.4 Hybridization of complementary DNA strands 62 4.2.5 Surface coverage and hybridization efficiency of DNA 69 4.2.6 Refractive index sensing 72 4.2.7 Backfilling and blocking 73 4.3 Summary 75 4.4 References 77 5 Label-free detection of salivary cortisol with SiNW FETs 83 5.1 Introduction 85 5.2 Design, integration, and performance of SiNW FETs into a portable platform 89 5.2.1 Structure and electrical characteristics of honeycomb SiNW FETs 89 5.2.2 Integration of SiNW FET into a portable measuring unit 91 5.2.3 Performance of SiNW FET arrays 93 5.3 Detection of biomolecules with SiNW FETs 102 5.3.1 General considerations for biodetection with FETs 102 5.3.2 Sensing aptamers with FETs 103 5.3.3 Biodetection of the analyte cortisol with SiNW FETs 104 5.3.4 Detection of cortisol with SiNW FETs 112 5.4 Summary 119 5.5 References 121 6 Summary and outlook 131 6.1 Summary 131 6.2 Perspectives – toward multiplexed biosensing applications 134 6.3 References 137 Appendix i A.1 Protocols i A.1.1 Functionalization of gold antennas with thiolated DNA i A.1.2 Functionalization of SiO2 with TESPSA and amino-modified receptors i A.1.3 Functionalization with APTES and carboxyl-modified receptors ii A.1.4 Preparation of microfluidic channels via soft lithography ii A.2 Predicted secondary structures iv A.2.1 Secondary structures of 100base pair target without probe-strands iv A.2.2 Secondary structures of 100base pair target with 25 base pair probe-strand x Versicherung xvii Acknowledgments xix List of publications xxi Peer-reviewed publications xxi Publications in preparation xxi Selected international conferences xxii Curriculum Vitae xxiiiBiosensors have proven to be indispensable in numerous vital areas. For example, detecting the presence and concentration of specific biomarkers requires sensitive and reliable measurement methods. Rapid developments in the field of nanotechnology lead to nanomaterials with new properties and associated innovative applications. Thus, nanotechnology has a far-reaching impact on biosensors' development, e.g., delivery of biosensing devices with greater sensitivity, shorter response times, and precise but cost-effective sensor platforms. In addition, nanobiosensors hold high potential for integration and miniaturization and can operate directly at the point of care - serving as a bridge between diagnostics and routine tests. This work focuses on applying nanostructured biosensors for the sensitive and label-free detection of analytes. A distinct aim is the continuous monitoring of biomarkers with compact read-out systems to provide direct, valuable feedback in real-time. The first step in achieving this goal is the adequate functionalization of nanostructured sensor surfaces with suitable receptors to detect analytes of interest. Due to their thermal and chemical stability with the possibility for customizable functionalization, DNA-based receptors are selected. Thereupon, universal strategies for confining nanobiosensor platforms are presented using different sensor systems, analytes, and characterization methods. As a first application, a plasmonic biosensor based on vertically aligned gold nanoantennas tracked the immobilization, blocking, and subsequent hybridization of DNA by means of localized surface plasmon resonance (LSPR). At the same time, the LSPR sensor was used to evaluate fundamental hybridization mechanisms on nanostructured and planar surfaces, emphasizing the unique optical properties of metallic nanostructures. In a second application, an electric sensor based on silicon nanowire field-effect transistors (SiNW FET) monitored the level of the stress marker cortisol in human saliva. Based on evaluating the underlying charge distributions within the resulting receptor-analyte complex of molecules, the detection of cortisol within the Debye length is facilitated. Thus, direct, label-free detection of cortisol in human saliva using SiNW FET was successfully applied to the developed platform and compared to cortisol levels obtained using a commercial alternative. In summary, both presented platforms indicate a highly versatile and beneficial performance of nanobiosensors for continuous detection of biomarkers in real-time and preferably point-of-care (POC).:Kurzfassung I Abstract III Abbreviations and symbols V Content VII 1 Introduction 1 1.1 Scope of the thesis 4 1.2 References 6 2 Fundamentals 9 2.1 Biosensors 9 2.2 Influence of nanotechnology on sensor development 10 2.3 Biorecognition elements 12 2.3.1 Biorecognition element: DNA 13 2.3.2 Aptamers 14 2.3.3 Immobilization of receptors 15 2.4 Transducer systems 17 2.4.1 Optical biosensors - surface plasmon resonance 17 2.4.2 Electric Biosensors – Field-effect transistors (FETs) 21 2.5 Metal oxide semiconductor field-effect transistor - MOSFET 21 2.6 Summary 26 2.7 References 27 3 Materials and methods 33 3.1 Plasmonic biosensors based on vertically aligned gold nanoantennas 33 3.1.1 Materials 33 3.1.2 Manufacturing of nanoantenna arrays 34 3.1.3 Surface modification and characterization 35 3.1.4 Measurement setup for detection of analytes 38 3.2 SiNW FET-based real-time monitoring of cortisol 40 3.2.1 Materials 40 3.2.2 Manufacturing of silicon nanowire field effect transistors (SiNW FETs) 42 3.2.3 Integration of SiNW FETs into a portable platform 42 3.2.4 Biomodification and characterization of electronic biosensors SiNW FETs 42 3.2.5 Electric characterization of FETs 47 3.3 References 50 4 Plasmonic DNA biosensor based on vertical arrays of gold nanoantennas 51 4.1 Introduction - Optical biosensors operating by means of LSPR 53 4.2 Biosensing with vertically aligned gold nanoantennas 56 4.2.1 Sensor fabrication, characterization, and integration 56 4.2.2 Integration of microfluidics 58 4.2.3 Immobilization of probe DNA and backfilling 58 4.2.4 Hybridization of complementary DNA strands 62 4.2.5 Surface coverage and hybridization efficiency of DNA 69 4.2.6 Refractive index sensing 72 4.2.7 Backfilling and blocking 73 4.3 Summary 75 4.4 References 77 5 Label-free detection of salivary cortisol with SiNW FETs 83 5.1 Introduction 85 5.2 Design, integration, and performance of SiNW FETs into a portable platform 89 5.2.1 Structure and electrical characteristics of honeycomb SiNW FETs 89 5.2.2 Integration of SiNW FET into a portable measuring unit 91 5.2.3 Performance of SiNW FET arrays 93 5.3 Detection of biomolecules with SiNW FETs 102 5.3.1 General considerations for biodetection with FETs 102 5.3.2 Sensing aptamers with FETs 103 5.3.3 Biodetection of the analyte cortisol with SiNW FETs 104 5.3.4 Detection of cortisol with SiNW FETs 112 5.4 Summary 119 5.5 References 121 6 Summary and outlook 131 6.1 Summary 131 6.2 Perspectives – toward multiplexed biosensing applications 134 6.3 References 137 Appendix i A.1 Protocols i A.1.1 Functionalization of gold antennas with thiolated DNA i A.1.2 Functionalization of SiO2 with TESPSA and amino-modified receptors i A.1.3 Functionalization with APTES and carboxyl-modified receptors ii A.1.4 Preparation of microfluidic channels via soft lithography ii A.2 Predicted secondary structures iv A.2.1 Secondary structures of 100base pair target without probe-strands iv A.2.2 Secondary structures of 100base pair target with 25 base pair probe-strand x Versicherung xvii Acknowledgments xix List of publications xxi Peer-reviewed publications xxi Publications in preparation xxi Selected international conferences xxii Curriculum Vitae xxii

    Medical devices with embedded electronics: design and development methodology for start-ups

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    358 p.El sector de la biotecnología demanda innovación constante para hacer frente a los retos del sector sanitario. Hechos como la reciente pandemia COVID-19, el envejecimiento de la población, el aumento de las tasas de dependencia o la necesidad de promover la asistencia sanitaria personalizada tanto en entorno hospitalario como domiciliario, ponen de manifiesto la necesidad de desarrollar dispositivos médicos de monitorización y diagnostico cada vez más sofisticados, fiables y conectados de forma rápida y eficaz. En este escenario, los sistemas embebidos se han convertido en tecnología clave para el diseño de soluciones innovadoras de bajo coste y de forma rápida. Conscientes de la oportunidad que existe en el sector, cada vez son más las denominadas "biotech start-ups" las que se embarcan en el negocio de los dispositivos médicos. Pese a tener grandes ideas y soluciones técnicas, muchas terminan fracasando por desconocimiento del sector sanitario y de los requisitos regulatorios que se deben cumplir. La gran cantidad de requisitos técnicos y regulatorios hace que sea necesario disponer de una metodología procedimental para ejecutar dichos desarrollos. Por ello, esta tesis define y valida una metodología para el diseño y desarrollo de dispositivos médicos embebidos

    1-D broadside-radiating leaky-wave antenna based on a numerically synthesized impedance surface

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    A newly-developed deterministic numerical technique for the automated design of metasurface antennas is applied here for the first time to the design of a 1-D printed Leaky-Wave Antenna (LWA) for broadside radiation. The surface impedance synthesis process does not require any a priori knowledge on the impedance pattern, and starts from a mask constraint on the desired far-field and practical bounds on the unit cell impedance values. The designed reactance surface for broadside radiation exhibits a non conventional patterning; this highlights the merit of using an automated design process for a design well known to be challenging for analytical methods. The antenna is physically implemented with an array of metal strips with varying gap widths and simulation results show very good agreement with the predicted performance
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