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

Characterization of Flexible RF Microcoil Dedicated to Surface Mri

In Magnetic Resonance Imaging (MRI), to achieve sufficient Signal to Noise Ratio (SNR), the electrical performance of the RF coil is critical. We developed a device (microcoil) based on the original concept of monolithic resonator. This paper presents the used fabrication process based on micromoulding. The dielectric substrates are flexible thin films of polymer, which allow the microcoil to be form fitted to none-plane surface. Electrical characterizations of the RF coils are first performed and results are compared to the attempted values. Proton MRI of a saline phantom using a flexible RF coil of 15 mm in diameter is performed. When the coil is conformed to the phantom surface, a SNR gain up to 2 is achieved as compared to identical but planar RF coil. Finally, the flexible coil is used in vivo to perform MRI with high spatial resolution on a mouse using a small animal dedicated scanner operating at in a 2.35 T.Comment: Submitted on behalf of TIMA Editions (http://irevues.inist.fr/tima-editions

Polymer NdFeB Hard Magnetic Scanner for Biomedical Scanning Applications

Micromirror scanners are the most significant of the micro-optical actuator elements with applications in portable digital displays, automotive head-up displays, barcode scanners, optical switches and scanning optical devices in the health care arena for external scanning diagnostics and in vivo scanning diagnostics. Recent development in microscanning technology has seen a shift from conventional electrostatic actuation to electromagnetic actuation mechanisms with major advantages in the ability to produce large scan angles with low voltages, remote actuation, the absence of the pull-in failure mode and the acceptable electrical safety compared to their electrostatic counterparts. Although attempts have been made to employ silicon substrate based MEMS deposition techniques for magnetic materials, the quality and performance of the magnets are poor compared to commercial magnets. In this project, we have developed novel low-cost single and dual-axis polymer hard magnetic micromirror scanners with large scan angles and low power consumption by employing the hybrid fabrication technique of squeegee coating to combine the flexibility of polydimethylsiloxane (PDMS) and the superior magnetic performance of fine particle isotropic NdFeB micropowders. PCB coils produce the Lorentz force required to actuate the mirror for scanning applications. The problem of high surface roughness, low radius of curvature and the magnetic field interaction between the gimbal frame and the mirror have been solved by a part PDMS-part composite fabrication process. Optimum magnetic, electrical and time dependent parameters have been characterized for the high performance operating conditions of the micromirror scanner. The experimental results have been demonstrated to verify the large scan angle actuation of the micromirror scanners at low power consumption

A CMOS-Based Lab-on-Chip Array for Combined Magnetic Manipulation and Opto-Chemical Sensing

Accepted versio

Single chip dynamic nuclear polarization microsystem

The integration on a single chip of the sensitivity-relevant electronics of nuclear magnetic resonance (NMR) and electron spin resonance (ESR) spectrometers is a promising approach to improve the limit of detection, especially for samples in the nanoliter and subnanoliter range. Here we demonstrate the co-integration on a single silicon chip of the front-end electronics of an NMR and an ESR detector. The excitation/detection planar spiral microcoils of the NMR and ESR detectors are concentric and interrogate the same sample volume. This combination of sensors allows to perform dynamic nuclear polarization (DNP) experiments using a single-chip integrated microsystem having an area of about 2 mm$^2$. In particular, we report $^1$H DNP-enhanced NMR experiments on liquid samples having a volume of about 1 nL performed at 10.7 GHz(ESR)/16 MHz(NMR). NMR enhancements as large as 50 are achieved on TEMPOL/H$_{2}$O solutions at room temperature. The use of state-of-the-art submicrometer integrated circuit technologies should allow the future extension of the single-chip DNP microsystem approach proposed here up the THz(ESR)/GHz(NMR) region, corresponding the strongest static magnetic fields currently available. Particularly interesting is the possibility to create arrays of such sensors for parallel DNP-enhanced NMR spectroscopy of nanoliter and subnanoliter samples

Bioagent detection using miniaturized NMR and nanoparticle amplification : final LDRD report.

This LDRD program was directed towards the development of a portable micro-nuclear magnetic resonance ({micro}-NMR) spectrometer for the detection of bioagents via induced amplification of solvent relaxation based on superparamagnetic nanoparticles. The first component of this research was the fabrication and testing of two different micro-coil ({micro}-coil) platforms: namely a planar spiral NMR {micro}-coil and a cylindrical solenoid NMR {micro}-coil. These fabrication techniques are described along with the testing of the NMR performance for the individual coils. The NMR relaxivity for a series of water soluble FeMn oxide nanoparticles was also determined to explore the influence of the nanoparticle size on the observed NMR relaxation properties. In addition, The use of commercially produced superparamagnetic iron oxide nanoparticles (SPIONs) for amplification via NMR based relaxation mechanisms was also demonstrated, with the lower detection limit in number of SPIONs per nanoliter (nL) being determined

Investigation of Cryo-Cooled Microcoils for MRI

When increasing magnetic resonance imaging (MRI) resolution into the micron scale, image signal-to-noise ratio (SNR) can be maintained by using small radiofrequency (RF) coils in close proximity to the sample being imaged. Micro-scale RF coils (microcoils) can be easily fabricated on chip and placed adjacent to a sample under test. However, the high series resistance of microcoils limits the SNR due to the thermal noise generated in the copper. Cryo-cooling is a potential technique to reduce thermal noise in microcoils, thereby recovering SNR. In this research, copper microcoils of two different geometries have been cryo-cooled using liquid nitrogen. Quality-factor (Q) measurements have been taken to quantify the reduction in resistance due to cryo-cooling. Image SNR has been compared between identical coils at room temperature and liquid nitrogen temperature. The relationship between the drop in series resistance and the increase in image SNR has been analyzed, and these measurements compared to theory. While cryo-cooling can bring about dramatic increases in SNR, the extremely low temperature of liquid nitrogen is incompatible with living tissue. In general, the useful imaging region of a coil is approximately as deep as the coil diameter, thus cryo-cooling of coils has been limited in the past to larger coils, such that the thickness of a conventional cryostat does not put the sample outside of the optimal imaging region. This research utilizes a scheme of microfluidic cooling (developed in the Texas A&M NanoBio Systems Lab), which greatly reduces the volume of liquid nitrogen required to cryo-cool the coil. Along with a small gas phase nitrogen gap, this eliminates the need for a bulky cryostat. This thesis includes a review of the existing literature on cryo-cooled coils for MRI, as well as a review of planar pair coils and spiral microcoils in MR applications. Our methods of fabricating and testing these coils are described, and the results explained and analyzed. An image SNR improvement factor of 1.47 was achieved after cryo-cooling of a single planar pair coil, and an improvement factor of 4 was achieved with spiral microcoils