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.

SOI mixed-mode design techniques and case studies

Marija Blagojevic

Since the emergence of Silicon On Insulator (SOI) technology the research activities have been concentrated on a detailed analysis of SOI devices and their use in different application fields (low-voltage, low-power circuits, high temperature electronics, digital circuits, etc.). The present thesis deals with low-voltage, low-power mixed-mode design using a SOI technology. The goal is to establish the concepts that allow one to design SOI mixed-mode circuits, and to apply these concepts to the design of fully depleted (FD) and partially depleted (PD) SOI circuits and systems. Two studies have been realized in the scope of this work: a Hall sensor based microsystem design using an experimental FD SOI technology a DRAM design using capacitor-less 1T floating-body PD SOI memory cells. At the beginning of this thesis, two major types of SOI devices are introduced, namely FD and PD devices. The most important properties of these devices are then presented and compared to those of CMOS bulk devices. A design methodology based on design retargeting from bulk to SOI technology is further proposed. This methodology is developed with the aim of being implemented for the design of FD SOI circuits. It consists in using the same device dimensions and bias currents for the bulk and the corresponding FD SOI design. The analysis performed proves that such an approach permits one to obtain better circuit performances using the FD SOI technology. The EKV model is chosen for Spice simulations. For that purpose the extraction of the EKV intrinsic parameters has been performed for the experimental 0.5 μm FD SOI technology. The EKV model card obtained from transistor measurements is implemented straightforwardly for circuit simulations. The first study presented in this thesis is an FD SOI Hall sensor front-end for energy measurement. The mixed-mode microsystem design is completely based on the proposed design methodology. The system level solutions are also included, such as the spinning-current method that serves for reduction of the offset and low frequency noise of the analog front-end, and a high resolution analog-to-digital conversion technique. The integrated microsystem is entirely functional. Furthermore, according to the existing literature, this integrated circuit is the first microsystem completely realized using FD SOI technology. The overall system error that is obtained is less than 1.5 %. During the second part of this work, a novel sensing scheme that exploits an automatic reference generation based on successive approximations has been developed for the PD SOI capacitor-less 1T DRAM. The 1T DRAM reference current is generated by an adjustable current source. The electrical calibration of the reference current is performed using a digital-to-analog converter and successive approximations algorithm. The proposed scheme is evaluated in a 2 kb test chip. The circuit integrated using PD SOI technology contains a 2 kb 1T memory array, as well as automatic reference generators and peripheral circuits. The automatic reference generator comprises current mode sense amplifier, M/3M converter, and successive approximations register. All blocks implemented in the test chip are described in detail, and PD SOI design issues are discussed. A number of experimental results demonstrate the potential of the PD SOI 1T DRAM for future embedded DRAM applications. The measured retention time under holding conditions is higher than 1s. In the continuous read mode, a few hundreds of the read cycles can be performed without a refresh operation. The test chip has a measured access time of 25 ns with a read cycle time of 70 ns.

EPFL2005

Methods for Molecular Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy using Hyperpolarized Nuclei

Riccardo Balzan

Since the introduction 10 years ago of the dissolution method, Dynamic Nuclear Polarization (DNP) became a widely applied and powerful technique to enhance nuclear magnetic resonance (NMR) signals of low naturally abundant, insensitive nuclear spins for analytical chemistry and biomedical research. The aim of DNP is to obtain a very high degree of polarization on the nuclei of interest in cryogenic conditions (i.e. 1 K ), a hundred or more times higher than the thermal polarization. Then, trough a fast dissolution process the molecules hosting the nuclear spins are mixed in a room temperature solution and, since their polarization is conserved if their relaxation times are long enough, they can be used for in vitro or in vivo experiments with a SNR enhanced by 104 times or more. Although the DNP technique was established about 60 years ago, the hardware and cryogenic equipment needed to perform DNP and the subsequent dissolution, still are a technological challenge. In this thesis we will cover different DNP aspects, ranging from hardware installation, software development, solid state measurement, in vitro and in vivo experiments and a possible application of DNP to MRI studies of granular materials. A new DNP cryostat was developed and tested to determine its cryogenic performances and then optimized for fast cooldown, helium holdtime and overall minimal operational consumption. We will show the characteristics of the cryostat and the performances on standard operations like cooling and DNP at 1 K . Another important aspect the development tackled was automation. The management of the system was condensed in a single electronic box capabile to handle the interface with all the cryostat instruments. This box is driven by a single common USB port trough a custom made software interface we developed. Although a few manual operations are still needed, we achieved a high degree of automation. The solid state polarization enhancement ε is defined as the ratio between the DNP enhanced and the thermal polarization signals. It can be determined by measuring the DNP enhanced signal after the system stabilizes in the polarized state (i.e. after about 5 buildup time) and thermal polarization signal after the spins have fully relaxed to equilibrium (i.e. after about 5T1). As a first application of the new system, we present a method that exploits the behavior of steady states magnetization produced with trains of evenly spaced pulses, at constant flip angle. This method allows to precisely determine the thermally polarized signal of a sample with known T1 and a given flip angle in a small fraction (as low as half of a T1 or less depending on the requested accuracy) of the time needed in the usual "wait 5 T1 and pulse" scheme. The main drawback of the dissolution DNP is that the large polarization achieved will ineluctably relax towards its thermal equilibrium value in a few times T1, that for typical 13C labeled molecules is shorter than a minute. On the other hand some nuclei as 6Li and quaternary 15N show a very long T1 on the order of few minutes in biological conditions, allowing measurements as long as several minutes. 6Li is very sensitive to contrast agents such as Gd-doped contrast agents, O2 and de-oxygenated hemoglobin. We studied the effect of the oxygenation of human and rat blood on the 6Li T1, showing clear changes between oxygenated and de-oxygenated samples. Thus we showed that 6Li could be used to map blood oxygenation levels in vitro, and suggest possible in vivo applications, even in brain due to its capability to easily pass the blood brain barrier. 15N labeled choline has a very long 15N T1 and can be used to probe rate of transport or metabolism in brain. Although it has a long T1, the spectral dispersion between the precursor, choline, and its metabolites is very small. The spectral dispersion is much larger for 1 H spins and thus being able to partially transfer repeatedly the 15N to 1H before detection would greatly increase the spectral separation between metabolites while still being able to measure the time course of the metabolic process, which is not the case with a full transfer like with INEPT. We demonstrate that a Hartmann–Hahn polarization transfer can be used to partially transfer the hyperpolarization of 15N to surrounding 1H before detection on 1H. This method can then be applied to in vivo DNP experiments. Even with a very high signal it is very difficult to quantify metabolites that are very close in the NMR spectrum, compared to the actual in vivo linewidth. To improve the spectral resolution it is worth performing the experiments in high magnetic fields. We show the first in vivo rat muscle DNP measurement of acetate at 14.1 T , to resolve e.g. the glutamate peak from acetate substrate. Finally we discuss a segmentation algorithm used to precisely reconstruct granular samples composed of up to 104 spheres. We used a standard Gradient Echo imaging sequence on a Siemens 7 T MRI human scanner to obtain high resolution images of a phantom composed of a cylinder filled with Cu2+ doped water and plastic spheres. Then the 3D images where segmented trough a thresholded Hugh transform method and the beads centers determined. The datasets were studied to extract structural and geometrical information.

EPFL2013

SOI mixed-mode design techniques and case studies

Marija Blagojevic

EPFL2005

Methods for Molecular Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy using Hyperpolarized Nuclei

Riccardo Balzan

EPFL2013