Silicon RF NMR Biomolecular Sensor -Review (Invited Paper)

Abstract-This paper reviews our first miniature nuclear magnetic resonance (NMR) system originally reported in [1], [2], which, weighing only 2 kg, is 60 times lighter, 40 times smaller, yet 60 times more spin mass sensitive than a 120-kg state-ofthe-art commercial benchtop NMR system. The miniaturization was made possible by combining the physics of NMR with a high-performance CMOS radio-frequency integrated circuit. The system is aimed at sensing biomolecules such as cancer marker proteins, and represents a circuit designer's approach to pursue low-cost diagnostics in a portable platform. Our most recent development of even smaller NMR systems [3] will not be reviewed here, as it has yet to be exposed in full through a journal publication first

Integrated Circuit / Microfluidic Chips for Dielectric Manipulation

Engineering and Applied Science

Design of multi-channel radio-frequency front-end for 200mhz parallel magnetic resonance imaging

The increasing demands for improving magnetic resonance imaging (MRI) quality, especially reducing the imaging time have been driving the channel number of parallel magnetic resonance imaging (Parallel MRI) to increase. When the channel number increases to 64 or even 128, the traditional method of stacking the same number of radio-frequency (RF) receivers with very low level of integration becomes expensive and cumbersome. However, the cost, size, power consumption of the Parallel MRI receivers can be dramatically reduced by designing a whole receiver front-end even multiple receiver front-ends on a single chip using CMOS technology, and multiplexing the output signal of each receiver front-end into one channel so that as much hardware resource can be shared by as many channels as possible, especially the digitizer. The main object of this research is focused on the analysis and design of fully integrated multi-channel RF receiver and multiplexing technology. First, different architectures of RF receiver and different multiplexing method are analyzed. After comparing the advantages and the disadvantages of these architectures, an architecture of receiver front-end which is most suitable for fully on-chip multi-channel design is proposed and a multiplexing method is selected. According to this proposed architecture, a four-channel receiver front-end was designed and fabricated using TSMC 0.18μm technology on a single chip and methods of testing in the MRI system using parallel planar coil array and phase coil array respectively as target coils were presented. Each channel of the receiver front-end includes an ultra low noise amplifier (LNA), a quadrature image rejection down-converter, a buffer, and a low-pass filter (LPF) which also acts as a variable gain amplifier (VGA). The quadrature image rejection downconverter consists of a quadrature generator, a passive mixer with a transimpedance amplifier which converts the output current signal of the passive mixer into voltage signal while acts as a LPF, and a polyphase filter after the TIA. The receiver has an over NF of 0.935dB, variable gain from about 80dB to 90dB, power consumption of 30.8mW, and chip area of 6mm2. Next, a prototype of 4-channel RF receiver with Time Domain Multiplexing (TDM) on a single printed circuit board (PCB) was designed and bench-tested. Then Parallel MRI experiment was carried out and images were acquired using this prototype. The testing results verify the proposed concepts

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

Broadband single-chip transceivers for compact NMR probes

Nuclear magnetic resonance (NMR) is one of the most relevant spectroscopic tools in use today. However, NMR requires relatively expensive and complicated experimental settings given by the combination of high homogeneous magnetic fields and a relatively complex radio-frequency (RF) electronics. This thesis concerns the development of RF electronics hardware, specifically introducing new complementary-metal-oxide-semiconductor (CMOS) transceiver designs. This work stems from a collaboration between EPFL and Metrolab SA, and aims at pushing in two directions: first, NMR-oriented CMOS transceivers will simplify the implementation of NMR probes for both experimental and commercial applications; second, novel CMOS ultra-compact probes will deliver experimental versatility and improved sensing power at the nL and sub-nL scale. We describe broadband 1 mm^2 transceivers operating in the range from 1 MHz to 1 GHz. The microchips include a RF power amplifier, a low-noise RF preamplifier, a frequency mixer, an audio-frequency (AF) amplifier, fully integrated transmit-receive switches, IQ signal generation, and broadband quadrature detection. In this work we show multi-nuclear NMR spectroscopy in combination with excitation/detection probe-heads based on micro-solenoids, therefore validating the broadband functioning. A combination of the transceivers and Metrolab's technology is also shown to deliver state-of-art performance in prototypes of commercial probes aimed for magnetometry. We shown that custom multichannel probes employing water samples of 500 nL are capable of measurement resolutions as high as 0.06 ppb/Hz^(1/2) at 7 T, and that magnetic noise due to field fluctuations can be directly measured at this resolution level and distinguished by the electronic noise. Overall, the results of this package indicate that NMR-oriented CMOS transceivers simplify the implementation of NMR probes for both experimental and commercial applications. When CMOS transceivers are combined to external resonators the resulting NMR probe may be called "compact" in the sense that the overall probe size is dominated by the excitation/detection resonator itself. Besides the implementation of compact probes, in this thesis we introduce the concept of ultra-compact NMR probes, where a single-chip transceiver is co-integrated with a multilayer microcoil realized with the metals of the CMOS technology. We demonstrate that with a non-resonant integrated coil of about 150 µm external diameter a 1H spin sensitivity of about 1.5·10^13 spins/Hz^(1/2) is achieved at 7 T. This value of sensitivity compares well with the most sensitive inductive probes previously reported at similar volume scales, with the resulting device showing an exceptional degree of versatility. We use, for the first time, a ultra-compact CMOS probe for the NMR spectroscopy of intact, static, sub-nL single ova of 0.1 and 0.5 nL, thereby reaching the relevant volume scale where life development begins for a broad variety of organisms, humans included. Thanks to the robustness and the versatility of the probe we could deliver a first extensive study of sub-nL single ova and indicate that ultra-compact probes are promising candidates to enable NMR-based study and selection of microscopic entities at biologically relevant volume scales. Overall, the results of this study indicate that CMOS ultra-compact probes will deliver experimental versatility and improved sensing power at the nL and sub-nL scale