CMOS and MEMS Based Microsystems for Manipulation and Detection of Magnetic Beads for Biomedical Applications

RÉSUMÉ Les micro et nano billes magnétiques dédiées à l'étiquetage des bio-particules attirent de plus en plus d'intérêt dans de nombreuses applications environnementales et sanitaires, tels que l'analyse de gènes, le transport des médicaments, la purification et l'immunologie. Les dimensions réduites et la haute sensibilité des billes magnétiques rendent leurs manipulations à haute précision possibles. Leur simplicité de suivi dans le milieu biologique et leur biocompatibilité permettent d’effectuer des détections rapides et à haute sensibilité pour des applications in vivo et in vitro. L'utilisation traditionnelle des billes magnétiques prend place dans un laboratoire se servant du matériel encombrant et dispendieux. Avec le développement de la technologie de microfabrication, des billes magnétiques peuvent être traitées dans un microsystème, plus précisément, dans une structure laboratoire sur puce (LoC). La combinaison microfluidique et microélectronique offre des possibilités d’autoévaluation, ce qui peut augmenter l'efficacité du travail. Cette thèse est orientée vers de nouvelles approches pour la manipulation et la détection de bio-particules se servant de la technologie de microsystèmes basées sur des structures microelectroniques et microfluidiques et en utilisant des marqueurs de billes magnétiques. Basé sur un réseau de microbobines à la fois comme une source de champ magnétique et un capteur inductif, le microsystème proposé est réalisé grâce à l'efficacité de fabrication de structures CMOS-MEMS, ainsi que des circuits intégrés dédiés CMOS de haute performance afin d'obtenir un rendement élevé de manipulation et de détection de billes magnétiques. Plusieurs défis ont été analysés dans la mise en œuvre de ces microsystèmes et des solutions correspondantes fournies. Plus précisément, la conception et la mise en œuvre d'une plate-forme contrôlée en température en format portable sont d'abord présentées, dans un effort réalisé pour résoudre la question de la chaleur par effet Joule lors de l'application du réseau de microbobines comme une source de champ magnétique dédié à la manipulation de billes magnétiques. Une plateforme similaire à cette dernière a été améliorée pour effectuer une analyse magnétique immunologique, en ajoutant des circuits de détection par des billes magnétiques. De plus, des IgG et anti-IgG de souris ont été utilisés dans des expériences pour vérifier les performances de détection de la plateforme de microsystème proposé.----------ABSTRACT Magnetic micro/nano beads as labels of bio-particles have been attracting more and more interest in many environmental and health applications, such as gene and drug delivery, purification, and immunoassay. The miniature size and high sensitivity of magnetic bead allow accurate manipulation, whereas its high distinguishability from biological background and biocompatibility make fast and high sensitivity detection possible for in vitro and in vivo applications. Traditional employment of magnetic beads is done in laboratory environment with the assist of bulky and expensive equipment. Thanks to the development of microfabrication technology, magnetic beads therefore can be handled on a microsystem, more specifically, a Lab-on-Chip (LoC). The combination of microfluidics with microelectronics offers the possibility of automatic analyses, which can liberate the labor and increase the efficiency.This thesis focuses on new approaches for bio-particles manipulation and detection on microelectronic/microfluidic hybrid microsystems using magnetic beads as labels. Based on planar microcoil array as both magnetic field source and the front-end inductive sensor, the proposed microsystems can take advantage of the massive producible CMOS/MEMS fabrication process, as well as the customized high performance CMOS circuits, to achieve a high efficient magnetic beads manipulation and a quantitative detection. Several challenges in implementing such microsystems are analyzed and corresponding solutions are provided. Specifically, the design and implementation of a temperature controllable LoC platform in portable format is firstly presented, for the sake of resolving the Joule heat issue when applying microcoil array as magnetic field source in magnetic beads manipulation. The similar platform is then improved to be used for magnetic immunoassay, by adding magnetic beads sensing circuits. Mouse IgG and anti-mouse IgG are employed in experiments to verify the detection performance of the proposed microsystem platform. Additionally, a fully integrated silicon substrate MEMS chip which integrates both microfluidic channel and microcoil array on a single chip is designed and fabricated following the Finite Element Analysis (FEA) simulation results and tested using bio-particles attached magnetic beads. This monolithic chip has the potential to be applied for in vivo applications

An Optofluidic Lens Biochip and an x-ray Readable Blood Pressure Microsensor: Versatile Tools for in vitro and in vivo Diagnostics.

Three different microfabricated devices were presented for use in vivo and in vitro diagnostic biomedical applications: an optofluidic-lens biochip, a hand held digital imaging system and an x-ray readable blood pressure sensor for monitoring restenosis. An optofluidic biochip–termed the ‘Microfluidic-based Oil-Immersion Lens’ (mOIL) biochip were designed, fabricated and test for high-resolution imaging of various biological samples. The biochip consists of an array of high refractive index (n = 1.77) sapphire ball lenses sitting on top of an oil-filled microfluidic network of microchambers. The combination of the high optical quality lenses with the immersion oil results in a numerical aperture (NA) of 1.2 which is comparable to the high NA of oil immersion microscope objectives. The biochip can be used as an add-on-module to a stereoscope to improve the resolution from 10 microns down to 0.7 microns. It also has a scalable field of view (FOV) as the total FOV increases linearly with the number of lenses in the biochip (each lens has ~200 microns FOV). By combining the mOIL biochip with a CMOS sensor, a LED light source in 3D printed housing, a compact (40 grams, 4cmx4cmx4cm) high resolution (~0.4 microns) hand held imaging system was developed. The applicability of this system was demonstrated by counting red and white blood cells and imaging fluorescently labelled cells. In blood smear samples, blood cells, sickle cells, and malaria-infected cells were easily identified. To monitor restenosis, an x-ray readable implantable blood pressure sensor was developed. The sensor is based on the use of an x-ray absorbing liquid contained in a microchamber. The microchamber has a flexible membrane that is exposed to blood pressure. When the membrane deflects, the liquid moves into the microfluidic-gauge. The length of the microfluidic-gauge can be measured and consequently the applied pressure exerted on the diaphragm can be calculated. The prototype sensor has dimensions of 1x0.6x10mm and adequate resolution (19mmHg) to detect restenosis in coronary artery stents from a standard chest x-ray. Further improvements of our prototype will open up the possibility of measuring pressure drop in a coronary artery stent in a non-invasively manner.PhDMacromolecular Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111384/1/toning_1.pd

Microfluidic Overhauser DNP chip for signal-enhanced compact NMR

Nuclear magnetic resonance at low field strength is an insensitive spectroscopic technique, precluding portable applications with small sample volumes, such as needed for biomarker detection in body fluids. Here we report a compact double resonant chip stack system that implements in situ dynamic nuclear polarisation of a 130 nL sample volume, achieving signal enhancements of up to − 60 w.r.t. the thermal equilibrium level at a microwave power level of 0.5 W. This work overcomes instrumental barriers to the use of NMR detection for point-of-care applications

E-plane parallel coupled resonators for waveguide bandpass filter applications

High skirt selectivity and extended out-of-band rejection is a major challenge for the successful progress of in-line microwave filters. This thesis presents novel filter realizations with improved performance, compatible with the standard single thin all-metal insert in a split-block housing and therefore maintaining the low-cost fabrication characteristics. In addition, significant filter performance improvement is achieved. The synthesis procedure implemented for the filter concept consists of a few steps. Some preliminary steps are a rigorous characterization of a double-ridge coaxial waveguide, and the modelling of an equivalent circuit model for the parallel coupled ridge waveguide devised in the filter concept. From these elements, a full wave electromagnetic analysis shows that parallel-coupled asymmetric ridge waveguides produce strongly dispersive coupling which introduces a transmission zero. Later on this property is extended to parallel-coupled asymmetric ridge waveguide resonators, where it is demonstrated that it is possible to independently control the coupling coefficient and the frequency of the transmission zero. This allows the realization of pseudo-elliptic narrowband in-line bandpass filters in E-plane technology. A general synthesis procedure for high order filters is outlined and numerical and experimental results are presented for validation. The elements employed for the synthesis procedure of the bandpass prototypes are also applied to investigate structures suitable for different applications. In particular, stopband and dual stopband filters are presented with numerical and experimental results. Finally, the study of a microwave chemical/biochemical sensing device for the characterization and detection of cells in chemical substances and cells in solution in micro-litre volumes is also reported.Engineering and Physical Sciences Research Council(EPSRC

An Exploration of Paul Bowles\u27 Piano-Solo Pieces

This research paper provides a general overview of the piano-solo literature by the American composer Paul Frederic Bowles (1910-1999). Thanks to recent contributions, this repertoire is now available in recordings and musical scores as it has never been before.;This paper is divided into two sections. The first covers the biography of Paul Bowles and his musical achievements as a composer, along with his research into the folk music of Morocco and his literary writings as a music critic for the journal Modern Music and for The New Herald Tribune. The second part is about Bowles\u27 piano-solo output, divided thematically into pieces with similar forms and structures.;For Bowles\u27 solo piano music, theoretical analysis and a review of existing literature help to reveal style traits; these include his preference for short character pieces, in which Bowles employs neoclassical elements, such as melodies with classical harmonies that display bitonal and pandiatonal tendencies, along with ostinato patterns and Alberti-bass accompaniments. Bowles\u27 music often displays ternary or free structures, with motivic development techniques through which themes or passages are derived from previous motives. Jazz and folk idioms are also an important aspect of Bowles\u27 piano music, particularly in his dancelike pieces, many of which display a Latin-American flavor

Wireless colorimetric readout to enable resource-limited point-of-care

Patientennahe Diagnostik in Entwicklungsländer birgt spezielle Herausforderungen, die ihren Erfolg bisher begrenzen. Diese Arbeit widmet sich daher der Entwicklung eines in seiner Herstellung skalierbaren und vielseitig einsetzbaren funkbasierten Auslesegerätes für Laborteststreifen. Durch die Kombination einer wachsenden Auswahl an papierbasierten Teststreifendiagnostiken mit gedruckter Elektronik und unter Berücksichtigung des diagnostischen Alltags im südlichen Afrika wurde ein Gerät entwickelt, das Teststreifen zuverlässig ausliest und die Daten per Funk an eine Datenbank übertragen kann. Die Technik basiert auf RFID-Tags (radio frequency identification devices), welche auf verschiedene flexible Substrate gedruckt wurden, um die technische Umsetzbarkeit und Funktionalität zu evaluieren. Um den Preis für die geplante Anwendung niedrig zu halten, wurden unter anderem Papier und Karton als Substrate genutzt. Das Ergebnis dieser Studie sind passive RFID-Tags auf unterschiedlichen, meist günstigen Substraten, die über eine Distanz von über 75 mm betrieben und ausgelesen werden können. Basierend auf der über RFID bereitgestellten Energie und Datenübertragung wurde eine Ausleseeinheit für Standardpapierstreifentests entwickelt und integriert. Durch das Auslesen verschiedener Teststreifen wurde das Gerät evaluiert und in seiner Aussagekraft mit einer scanner-basierten Aufnahme und anschließender Bildanalyse (ImageJ), einem kommerziellen Auslesegerät sowie einer manuellen Auslesung mit Hilfe von Farbtabellen verglichen. Das Gerät kann die Streifen zuverlässig auslesen und die Daten über die RFID-Schnittstelle übertragen. Die funkbasierte Ausleseeinheit ist mit verschiedenen kommerziellen Teststreifen sowohl im biodiagnostischen (lateral flow tests) wie auch im chemischen Bereich (pH-Wert) kompatibel. Die modulare Lösung erlaubt ein breites Einsatzgebiet und führt dadurch zu reduzierten Trainingszeiten der Anwender und einer zuverlässigen Handhabung. Die vorgestellte Lösung ist äußerst kostengünstig und bedarf keiner Wartung, wodurch sie sich sehr gut für den Einsatz in abgelegenen Feldkrankenhäusern eignet. Es wurde ein skalierbarer Prototyp entwickelt, der auf konventionellen Herstellungsverfahren der Verpackungsindustrie aufbaut. Aktuell handelt es sich noch um einen bogenbasierten Prozess, der sich aber prinzipiell auch auf Rolle-zu-Rolle Maschinen übertragen lässt. Bei der Entwicklung des Geräts spielte die Möglichkeit der lokalen Herstellung in den Einsatzländern eine große Rolle. Diese hätte neben der Generierung von Arbeitsplätzen auch den Vorteil einer einfacheren Verteilung der Geräte in ländliche Regionen, in denen sie den größten Nutzen für die Diagnostik erzielen würden

NANOELECTRONIC DEVICES FOR SENSITIVE DETECTION OF BIOMARKERS IN HEALTHCARE MONITORING

In recent years, biosensors have seen an exponential rise of their applications in a number of fields including the field of health care monitoring, particularly in point-of-care diagnostics. With the contemporary rise of nanotechnology, these biosensors have experienced an ever-growing inclusion of nano scale electronic devices or nanoelectronic devices to exploit the plethora of advantages of nanoelectronics. The performances of these nanoelectronic devices, however, largely depend on the nanomaterials used. Especially, carbon-based nanomaterials such as carbon nanotubes (CNTs) and graphene have proven to be superior candidates compared to others because of their multitude of electronic and mechanical properties suitable for biosensing. In particular, graphene-based FET (GFET) that combines the favorable material properties of graphene as well as the device properties of field-effect transistor have demonstrated its potential in biosensing with high sensitivity and signal-to-noise ratio (SNR). Though GFETs have been applied for sensitive detection of a number of analytes, there are still areas for further development in a number of ways—application of the platform for sensing new biomarkers, developing an integrated microfluidics platform, etc. in order to improve the sensing performances as well as applicability in real-world setting. Therefore, in this seminar, I will discuss the current states and challenges of the GFET-based sensing and present my work to further advance this platform. Moreover, development of a flexible GFET biosensor compatible with wearable platform will also be discussed. To provide the biosensors with the required selectivity, DNA-based aptamers with specific affinity towards the target analyte are used. However, conventional techniques for functionalization of aptamers suffer from several challenges including low throughput, poor control, and long turnaround time. To address these challenges, I will present my efforts on the development of new strategies to address these challenges both on CNT and graphene-based platforms

MatriGrid® based biological morphologies: tools for 3D cell culturing

Recent trends in 3D cell culturing has placed organotypic tissue models at another level. Now, not only is the microenvironment at the cynosure of this research, but rather, microscopic geometrical parameters are also decisive for mimicking a tissue model. Over the years, technologies such as micromachining, 3D printing, and hydrogels are making the foundation of this field. However, mimicking the topography of a particular tissue-relevant substrate can be achieved relatively simply with so-called template or morphology transfer techniques. Over the last 15 years, in one such research venture, we have been investigating a micro thermoforming technique as a facile tool for generating bioinspired topographies. We call them MatriGrid ® s. In this research account, we summarize our learning outcome from this technique in terms of the influence of 3D micro morphologies on different cell cultures that we have tested in our laboratory. An integral part of this research is the evolution of unavoidable aspects such as possible label-free sensing and fluidic automatization. The development in the research field is also documented in this account

Prototypenentwicklung eines oberflächen-integrierten Mikrosensor Systems für 3D Traktionskraftmessungen durch DHM/DIC

In times of a rapid development and growing market in robotics, high-tech protheses and the personalization of medicine, biomimicking natural materials like artificial tissue are of central interest within research and industry. To fully understand the structure-function relations within living systems, comprehensive knowledge about the smallest living block, the cell, and its biomechanics are a central topic in world-wide research. However, there is so far no comprehensive technique established that can measure 3D cell forces simultaneously and quantitatively. In this project, a novel surface-integrated mechano-optical microsensor system has therefore been conceptualized, prototyped and tested, which allows for the record of pico- to micronewton traction forces in three dimensions simultaneously. First, adequate microsensor elements were designed via topology optimization and linear static finite element analysis. These designs were fabricated by micromachining processes of biocompatible thin films of nickel-titanium and amorphous silicon. Furthermore, a plasma etching process was developed to fabricate polydimethylsiloxane sensor elements. For accurate and quantitative traction force measurements, AFM cantilever based calibrations of the out-of-plane and in-plane sensor element spring constants were established. For the first time, a diamagnetic levitation force calibrator was used as an adequate pre-calibration method for the sensor elements with a high accuracy of 1 %. For the cost-efficient, simple, compact, variable and sensitive mechano-optical readout, a setting was conceptualized and tested based on the combination of digital holography and digital image correlation. To control cell adhesion, a high-throughput micro-nano structuring method was developed based on the fusion of ink-jet printing with the established method of diblock-copolymer micelle nanolithography.In Zeiten schneller Entwicklung und wachsender Märkte in der Robotik, der high-tech Prothetik und der personalisierten Medizin ist die Biomimetik natürlicher Materialien wie beispielsweise künstliche Haut von zentralem Interesse in Forschung und Industrie. Um die Struktur-Funktions-Beziehungen in lebenden Systemen umfassend zu verstehen ist die umfangreiche Wissenserweiterung hinsichtlich des kleinsten lebenden Bausteins, der Zelle, und seiner Biomechanik Gegenstand weltweiter Forschungsprojekte. Dennoch gab es bis jetzt keine Methode, die 3D Zellkräfte simultan und quantitativ messen kann. In diesem Projekt wurde ein neuartiges, oberflächen-integriertes, mechano-optisches Mikrosensorsystem konzeptioniert, prototypisiert und getestet, das die Messung piko-bis mikronewton kleiner Zugkräfte gleichzeitig in alle drei Dimensionen ermöglicht. Die Sensorelemente wurden mittels Topologieoptimierung und linear statischer Finite Elementanalyse konzipiert. Diese Designs wurden in Mikromaterialbearbeitungsprozessen aus biokompatiblen Nickel-Titan und amorphen Silizium-Dünnschschichten hergestellt. Desweiteren wurde ein Prozess entwickelt, um Polydimethylsiloxan basierte Sensorelemente herzustellen. Für genaue, quantitative Zugkraftmessungen wurden AFM-Cantilever basierte Kalibrierungen der axialen und lateralen Sensorelement-Federkonsten etabliert. Zum ersten Mal wurde dabei ein diamagnetischer Levitationskraftkalibrator mit einer Genauigkeit von 1% als geeignete Kalibrierungsmethode für die Sensorelemente genutzt. Für eine günstige, einfache, kompakte, variable und im Nanometerbereich empfindliche mechano-optische Datenauslesung wurde ein Aufbau konzeptioniert und getestet, in dem digitale Holographie und digitale Bildkorrelation kombiniert werden. Zur Zell-Adhäsionskontrolle wurde eine Hochdurchsatz-Mikro-Nanostrukturierungsmethode entwickelt, die auf der Kombination von Ink-Jet Drucken mit der etablierten Methode der Diblock-Copolymer Mizellen Nanolithographie basiert