Immunoassays using high-Tc SQUIDs

The development of a system for immunoassays using highly sensitive high-Tc superconducting quantum interference devices (SQUIDs) and magnetic nanoparticles (MNPs) is described in this thesis.High-Tc SQUIDs were fabricated using pulsed laser deposition and photolithography. The sensors are planar YBa2Cu3O(7-δ) (YBCO) dc SQUID gradiometers developed for operation inside a glass fibre liquid nitrogen cryostat operating at 68-80 K. The gradiometers, with baselines of 3 mm and 4 mm, were fabricated on SrTiO3 (STO) bicrystal substrates. The flux noise of the best performing SQUID was 4.6 μФ0/√Hz and the voltage modulation 40 μV.The extremely high magnetic field resolution of SQUIDs was used in combination with MNPs for sensitive detection of biomolecules. Two different measurement modalities were used: AC-susceptometry (ACS) and magnetorelaxometry (MRX) for frequency- and time-domain measurements, respectively. ACS provides high resolution information about the size distribution of the MNP-system and the fast MRX enables studies of the reaction kinetics as a function of time.The MNPs used were multi-core particles containing single domains of magnetic material. Two different types of MNPs were used: cobalt-ferrite (CoFe2O4) and magnetite (Fe3O4). The detection limit of the present setup at the noise floor of our SQUIDs was estimated to be 50 ng of MNPs, corresponding to roughly 10^8 MNPs (of CoFe2O4) with diameter of 100 nm.The feasibility of the present system for biomolecule detection using prostate-specific antibodies/antigens is shown in this thesis. Two different assay protocols were investigated: a cluster-type assay and a one-step assay. The cluster-type assay requires more complicated preparations but the sensitivity is higher. The one-step assay is simple and fast but less sensitive. The extrapolated biomolecule sensitivity is 18 ng/ml (or about 4x10^10 molecules) using the cluster-type assay and 10 μg/ml (roughly 10^12 molecules) using the faster one-step protocol.Future development includes incorporation of microfluidic chips for manipulation of droplets of MNPs based on electrowetting-on-dielectric (EWOD). This would reduce the sample volume and facilitate sample handling

High-Tc SQUIDs for biomedical applications: immunoassays, MEG, and ULF-MRI

This thesis describes high transition temperature superconducting quantum interference devices (high-Tc SQUIDs) for magnetic immunoassays (MIAs), magnetoencephalography (MEG) and ultra-low field magnetic resonance imaging (ULF-MRI).High-Tc dc SQUID sensors were fabricated in single layers of YBa2Cu3O7−δ deposited by pulsed laser deposition and patterned using photolithography on 10 710 mm2 SrTiO3 bicrystal substrates. The best flux noise obtained was 4.6 μΦ0/√Hz and the voltage modulation of the same SQUID was 41 μV at 77 K.Planar first order gradiometers were used for MIA with magnetic nanoparticles (MNPs). The MNPs were multi-core particles containing magnetic single-domain crystals of cobalt-ferrite (CoFe2O4) or magnetite (Fe3O4). Using 2 μl droplets, the detection limit with our system was estimated to be 1.5 ng of MNPs (Fe3O4) with particle diameters of 100 nm. Biomolecule detection using prostate-specific antibodies/antigens was demonstrated. The extrapolated biomolecule sensitivity was 18 ng/ml using a cluster-type assay, and 10 μg/ml was demonstrated using a faster one-step assay.A two-channel MEG system employing high-Tc dc SQUID magnetometers was constructed. The equivalent magnetic field noise of the best SQUID was 25 fT/√Hz above 40 Hz and 43 fT/√Hz at 10 Hz. The lowest 1/f-knee achieved was below 1 Hz, which is an important feature for MEG sensors since most brain activities occur below 100 Hz.With the two-channel system, we successfully recorded the well-known (in standard MEG) α- and the μ-rhythm of human subjects. The α-rhythm was recorded with an amplitude of 800 fT/√Hz in the occipital region of the cortex and was attenuated when the subject had open eyes. The μ-rhythm was recorded in the motor cortex and was attenuated with motor activation. Furthermore, anomalous θ-band activity in the occipital region of the brain was detected which, to our knowledge, has not been reported in the MEG literature. This may indicate the usefulness of high-Tc SQUIDs for MEG where a small distance to the cortex may play a crucial role in detecting new sources.Lastly, an ULF-NMR/MRI system with a high-Tc dc SQUID magnetometer as detector was developed. We obtained the NMR signal from water in a measurement field of 81 μT. The first steps towards imaging were taken by successfully resolving two NMR peaks from two spatially separated water samples in a gradient magnetic field

Immunoassays using high-Tc SQUIDs

The development of a system for immunoassays using highly sensitive high-Tc superconducting quantum interference devices (SQUIDs) and magnetic nanoparticles (MNPs) is described in this thesis.High-Tc SQUIDs were fabricated using pulsed laser deposition and photolithography. The sensors are planar YBa2Cu3O(7-δ) (YBCO) dc SQUID gradiometers developed for operation inside a glass fibre liquid nitrogen cryostat operating at 68-80 K. The gradiometers, with baselines of 3 mm and 4 mm, were fabricated on SrTiO3 (STO) bicrystal substrates. The flux noise of the best performing SQUID was 4.6 μФ0/√Hz and the voltage modulation 40 μV.The extremely high magnetic field resolution of SQUIDs was used in combination with MNPs for sensitive detection of biomolecules. Two different measurement modalities were used: AC-susceptometry (ACS) and magnetorelaxometry (MRX) for frequency- and time-domain measurements, respectively. ACS provides high resolution information about the size distribution of the MNP-system and the fast MRX enables studies of the reaction kinetics as a function of time.The MNPs used were multi-core particles containing single domains of magnetic material. Two different types of MNPs were used: cobalt-ferrite (CoFe2O4) and magnetite (Fe3O4). The detection limit of the present setup at the noise floor of our SQUIDs was estimated to be 50 ng of MNPs, corresponding to roughly 10^8 MNPs (of CoFe2O4) with diameter of 100 nm.The feasibility of the present system for biomolecule detection using prostate-specific antibodies/antigens is shown in this thesis. Two different assay protocols were investigated: a cluster-type assay and a one-step assay. The cluster-type assay requires more complicated preparations but the sensitivity is higher. The one-step assay is simple and fast but less sensitive. The extrapolated biomolecule sensitivity is 18 ng/ml (or about 4x10^10 molecules) using the cluster-type assay and 10 μg/ml (roughly 10^12 molecules) using the faster one-step protocol.Future development includes incorporation of microfluidic chips for manipulation of droplets of MNPs based on electrowetting-on-dielectric (EWOD). This would reduce the sample volume and facilitate sample handling

Noise properties of HTS flux transformers fabricated by chemical-mechanical polishing

We present on fabrication and noise properties of high-temperature superconducting (HTS) thin-film integrated multilayer flux transformers fabricated using planarization of YBCO films by chemical-mechanical polishing (CMP). The polishing allows fabrication of very shallow slope edges (less than 5\ub0) in the YBa2Cu3O7, that makes it possible to avoid formation of grain boundary junctions in crossovers and obtain very high critical current densities in the top electrode of about 2•106 A/cm2. The same planarization process is used to create interconnections between top and bottom superconducting electrodes through the SrTiO3/PrBa2Cu3O7/SrTiO3 insulating layer. HTS multilayer flip-chip flux transformer with 8x8 mm2 pickup loop and 20-turn input coil was fabricated and coupled to a bicrystal dc SQUID in a flip-chip configuration. We measured magnetic field gain of 1.2 nT/Ф0 and magnetic flux noise of the magnetometer 10 \ub5Ф0/√Hz at 1 kHz, which corresponds to magnetic field noise of 12 ft/√Hz. FLUX NOISE AT LOW FREQUENCIES! The work is supported by European FP7 project "MEGMRI" under contract number 200859

Noise properties of HTS flux transformers fabricated by chemical-mechanical polishing

We present on fabrication and noise properties of high-temperature superconducting (HTS) thin-film integrated multilayer flux transformers fabricated using planarization of YBCO films by chemical-mechanical polishing (CMP). The polishing allows fabrication of very shallow slope edges (less than 5\ub0) in the YBa2Cu3O7, that makes it possible to avoid formation of grain boundary junctions in crossovers and obtain very high critical current densities in the top electrode of about 2•106 A/cm2. The same planarization process is used to create interconnections between top and bottom superconducting electrodes through the SrTiO3/PrBa2Cu3O7/SrTiO3 insulating layer. HTS multilayer flip-chip flux transformer with 8x8 mm2 pickup loop and 20-turn input coil was fabricated and coupled to a bicrystal dc SQUID in a flip-chip configuration. We measured magnetic field gain of 1.2 nT/Ф0 and magnetic flux noise of the magnetometer 10 \ub5Ф0/√Hz at 1 kHz, which corresponds to magnetic field noise of 12 ft/√Hz. FLUX NOISE AT LOW FREQUENCIES! The work is supported by European FP7 project "MEGMRI" under contract number 200859

Development of an electrowetting-based microfluidic platform for magnetic immunoassays

We report the transport of magnetic nanoparticles (MNPs) in suspension in a 2 μl de-ionized water droplet (DIWD) using ElectroWetting-On-Dielectic (EWOD) actuation, and the detection of the MNPs by magnetic AC-susceptibility measurements using a highly sensitive high-Tc dc Superconducting Quantum Interference Device (SQUID) gradiometer. These results constitute the first development step towards a MNP-based magnetic immunoassay platform with SQUID-readout and sample droplet handling

Improvement of Ultra-Low Field Magnetic Resonance Recordings With a Multilayer Flux-Transformer-Based High-T-C SQUID Magnetometer

We have developed a multilayer flux-transformer-based high-T-C SQUID (flip-chip) magnetometer that improves signal-to-noise-ratios (SNR) in ultra-low field magnetic resonance (ulf-MR) recordings of protons in water. Direct ulf-MR-based benchmarking of the flip-chip versus a standard planar high-T-C SQUID magnetometer resulted in improvement of the SNR by a factor of 2. This gain is attributable to the improved transformation coefficient (1.9 vs 5.3 nT/Phi(0)) that increased the signal available to the flip-chip sensor and to the lower noise at the measurement frequency (15 vs 25 fT/Hz(1/2) at 4 kHz). The improved SNR can lead to better spectroscopic resolution, lower imaging times, and higher resolution in ulf-MR imaging systems based on high-T-C SQUID technology. The experimental details of the sensors, calibration, and ulf-MR benchmarking are presented in this report

High-T-c superconducting quantum interference device recordings of spontaneous brain activity: Towards high-T-c magnetoencephalography

We have performed single-and two-channel high transition temperature (high-T-c) superconducting quantum interference device (SQUID) magnetoencephalography (MEG) recordings of spontaneous brain activity in two healthy human subjects. We demonstrate modulation of two well-known brain rhythms: the occipital alpha rhythm and the mu rhythm found in the motor cortex. We further show that despite higher noise-levels compared to their low-T-c counterparts, high-T-c SQUIDs can be used to detect and record physiologically relevant brain rhythms with comparable signal-to-noise ratios. These results indicate the utility of high-T-c technology in MEG recordings of a broader range of brain activity