A handheld high-sensitivity micro-NMR CMOS platform with B-field stabilization for multi-type biological/chemical assays

We report a micro-nuclear magnetic resonance (NMR) system compatible with multi-type biological/chemical lab-on-a-chip assays. Unified in a handheld scale (dimension: 14 x 6 x 11 cm³, weight: 1.4 kg), the system is capable to detect<100 pM of Enterococcus faecalis derived DNA from a 2.5 μL sample. The key components are a portable magnet (0.46 T, 1.25 kg) for nucleus magnetization, a system PCB for I/O interface, an FPGA for system control, a current driver for trimming the magnetic (B) field, and a silicon chip fabricated in 0.18 μm CMOS. The latter, integrated with a current-mode vertical Hall sensor and a low-noise readout circuit, facilitates closed-loop B-field stabilization (2 mT → 0.15 mT), which otherwise fluctuates with temperature or sample displacement. Together with a dynamic-B-field transceiver with a planar coil for micro-NMR assay and thermal control, the system demonstrates: 1) selective biological target pinpointing; 2) protein state analysis; and 3) solvent-polymer dynamics, suitable for healthcare, food and colloidal applications, respectively. Compared to a commercial NMR-assay product (Bruker mq-20), this platform greatly reduces the sample consumption (120x), hardware volume (175x), and weight (96x)

Giant Magnetoresistive Biosensors for Time-Domain Magnetorelaxometry: A Theoretical Investigation and Progress Toward an Immunoassay.

Magnetorelaxometry (MRX) is a promising new biosensing technique for point-of-care diagnostics. Historically, magnetic sensors have been primarily used to monitor the stray field of magnetic nanoparticles bound to analytes of interest for immunoassays and flow cytometers. In MRX, the magnetic nanoparticles (MNPs) are first magnetized and then the temporal response is monitored after removing the magnetic field. This new sensing modality is insensitive to the magnetic field homogeneity making it more amenable to low-power portable applications. In this work, we systematically investigated time-domain MRX by measuring the signal dependence on the applied field, magnetization time, and magnetic core size. The extracted characteristic times varied for different magnetic MNPs, exhibiting unique magnetic signatures. We also measured the signal contribution based on the MNP location and correlated the coverage with measured signal amplitude. Lastly, we demonstrated, for the first time, a GMR-based time-domain MRX bioassay. This approach validates the feasibility of immunoassays using GMR-based MRX and provides an alternative platform for point-of-care diagnostics

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

Room temperature "optical nanodiamond hyperpolarizer": Physics, design, and operation.

Dynamic Nuclear Polarization (DNP) is a powerful suite of techniques that deliver multifold signal enhancements in nuclear magnetic resonance (NMR) and MRI. The generated athermal spin states can also be exploited for quantum sensing and as probes for many-body physics. Typical DNP methods require the use of cryogens, large magnetic fields, and high power microwave excitation, which are expensive and unwieldy. Nanodiamond particles, rich in Nitrogen-Vacancy (NV) centers, have attracted attention as alternative DNP agents because they can potentially be optically hyperpolarized at room temperature. Here, unraveling new physics underlying an optical DNP mechanism first introduced by Ajoy et al. [Sci. Adv. 4, eaar5492 (2018)], we report the realization of a miniature "optical nanodiamond hyperpolarizer," where 13C nuclei within the diamond particles are hyperpolarized via the NV centers. The device occupies a compact footprint and operates at room temperature. Instrumental requirements are very modest: low polarizing fields, low optical and microwave irradiation powers, and convenient frequency ranges that enable miniaturization. We obtain the best reported optical 13C hyperpolarization in diamond particles exceeding 720 times of the thermal 7 T value (0.86% bulk polarization), corresponding to a ten-million-fold gain in averaging time to detect them by NMR. In addition, the hyperpolarization signal can be background-suppressed by over two-orders of magnitude, retained for multiple-minute long periods at low fields, and deployed efficiently even to 13C enriched particles. Besides applications in quantum sensing and bright-contrast MRI imaging, this work opens possibilities for low-cost room-temperature DNP platforms that relay the 13C polarization to liquids in contact with the high surface-area particles

Magnetic Nanoparticles and microNMR for Diagnostic Applications

Sensitive and quantitative measurements of clinically relevant protein biomarkers, pathogens and cells in biological samples would be invaluable for disease diagnosis, monitoring of malignancy, and for evaluating therapy efficacy. Biosensing strategies using magnetic nanoparticles (MNPs) have recently received considerable attention, since they offer unique advantages over traditional detection methods. Specifically, because biological samples have negligible magnetic background, MNPs can be used to obtain highly sensitive measurements in minimally processed samples. This review focuses on the use of MNPs for in vitro detection of cellular biomarkers based on nuclear magnetic resonance (NMR) effects. This detection platform, termed diagnostic magnetic resonance (DMR), exploits MNPs as proximity sensors to modulate the spin-spin relaxation time of water molecules surrounding the molecularly-targeted nanoparticles. With new developments such as more effective MNP biosensors, advanced conjugational strategies, and highly sensitive miniaturized NMR systems, the DMR detection capabilities have been considerably improved. These developments have also enabled parallel and rapid measurements from small sample volumes and on a wide range of targets, including whole cells, proteins, DNA/mRNA, metabolites, drugs, viruses and bacteria. The DMR platform thus makes a robust and easy-to-use sensor system with broad applications in biomedicine, as well as clinical utility in point-of-care settings

Towards CMOS Nuclear Magnetic Resonance Spectroscopy: Design, Implementation and Experimental Results

Nuclear Magnetic Resonance (NMR) Spectroscopy is used intensively along with other ancillary spectroscopic and characterization techniques. The design and implementation of High Throughput NMR Spectroscopy is a key challenge to accelerate the drug discovery process. On the other hand, the current conventional NMR technologies are expensive and bulky. The development of novel handheld NMR spectroscopy is a key challenge towards NMR spectroscopy for Point-of-Care (PoC) diagnostics applications. This thesis addresses the above-mentioned challenges of High Throughput NMR Spectroscopy and Handheld NMR spectroscopy by developing new integrated circuits dedicated to NMR spectroscopy using Complementary Metal Oxide Semiconductor (CMOS) technology. Simulation and characterization results were also used to prove the functionality and applicability of the proposed techniques. We have designed two CMOS chips using 0.13-m technology, first chip includes number of new vertical microcoils and LNA with 780 pV/Hz at 300 MHz and the second one is a new dual-path NMR receiver

Generation and characterisation of graphite and bio-oil from the pyrolysis of woody biomass

The thermal conversion of biomass to biochar has been studied for over 100 years (Laboratory et al., 1978). Over the past two decades it has gained momentum in environmental and energy research (Stavi & Lal, 2013). Concerns over climate change, poverty, declining agricultural production, fertiliser shortage, and fuel generation are all topics that biochar and bio-oils have aimed to address. Optimisation of biochar and bio-oils production, however, has received relatively little attention from a whole-of-system approach. The work undertaken in this thesis aims to address these limitations and provide a system that maximises the conversion of woody biomass to biochar and bio-oils

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