SQUIDs in biomagnetism : A roadmap towards improved healthcare

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 686865.Peer reviewedPublisher PD

Differential Magnetic Biosensor using HTS SQUID Gradiometer

A fundamental tool for containing an epidemic outbreak and mitigating its effects is early diagnostics. Currently, most of the diagnostic tests are performed by trained staff in centralized labs, which are expensive and time-consuming to establish and operate. Lack of access to such facilities could have devastating effects. The principal motivation behind point-of-care diagnostic systems is to provide a low cost, fast, sensitive, and specific test in the field which does not require highly skilled staff to operate.This thesis describes a magnetic biosensor which takes advantage of a high-Tc superconducting quantum interference device (SQUID) gradiometer sensor and magnetic nanoparticles (MNPs) to develop a diagnostic unit for point-of-care. Rolling circle amplification (RCA) is used as the primary molecular amplification method. RCA is an isothermal process with very high specificity. It is, therefore, easy to implement in a mix and measure concept of a homogeneous assay. The specific binding of the MNPs to the products of the RCA (i.e., DNA coils) changes their relaxation dynamics which is detected by sensitive ac magnetic susceptibility measurement.One of the issues with homogeneous magnetic assays, which limits their sensitivity, is the presence of excess MNP labels in the test sample solution. To mitigate this problem, a novel technique is introduced, which takes advantage of the geometry of our gradiometer sensor for a differential ac magnetic susceptibility measurement. In this technique, a negative control sample and a positive test sample are measured in a single measurement. The differential measurement virtually removes all of the unbound MNPs in the test sample and is analogous to the physical washing step typically used in conventional assays. This technique also provides better signal to noise ratio (SNR) and can detect target concentrations down to tens of femtomolar levels (45 fM).To eliminate the use of liquid nitrogen (LN2) for cooling of the SQUID sensor (as it is not abundantly available in the field) we have shown the successful operation of a SQUID gradiometer sensor on a commercially available micro-cooler platform. The operation of the SQUID on the micro-cooler and the high sensitivity of the novel differential ac susceptibility technique, realized in this work, are critical steps towards a homogeneous magnetic nucleic acid biosensor for rapid detection of diseases. The methods and instruments that are adopted and presented here are generic and could, in principle, be used for other targets such as Influenza, Ebola, and Zika. With full implementation of the molecular amplification on a disposable lab-on-a-chip, the unit would be promising for rapid and highly sensitive diagnostics at the point-of-care

Homogeneous Biosensing Based on Magnetic Particle Labels

The growing availability of biomarker panels for molecular diagnostics is leading to an increasing need for fast and sensitive biosensing technologies that are applicable to point-of-care testing. In that regard, homogeneous measurement principles are especially relevant as they usually do not require extensive sample preparation procedures, thus reducing the total analysis time and maximizing ease-of-use. In this review, we focus on homogeneous biosensors for the in vitro detection of biomarkers. Within this broad range of biosensors, we concentrate on methods that apply magnetic particle labels. The advantage of such methods lies in the added possibility to manipulate the particle labels by applied magnetic fields, which can be exploited, for example, to decrease incubation times or to enhance the signal-to-noise-ratio of the measurement signal by applying frequency-selective detection. In our review, we discriminate the corresponding methods based on the nature of the acquired measurement signal, which can either be based on magnetic or optical detection. The underlying measurement principles of the different techniques are discussed, and biosensing examples for all techniques are reported, thereby demonstrating the broad applicability of homogeneous in vitro biosensing based on magnetic particle label actuation

Studies of nanoparticles from a group of uniform materials based on organic salts (GUMBOS)

Tesfai, Aaron, B.S., B.A., University of Missouri, Columbia, 2003 Doctor of Philosophy, Spring Commencement 2010 Major: Chemistry Studies of Nanoparticles from a Group of Uniform Materials Based on Organic Salts (GUMBOS) Dissertation directed by Professor Isiah M. Warner Pages in dissertation, 101. Words in abstract, 271. Ionic liquids (ILs) are defined as organic salts composed of ions with melting points at or below 100 °C. ILs have gained considerable attention because of their desirable properties such as low volatility, high thermal stability, and tunability. GUMBOS are an emergent class of organic salts, many of which are ionic liquids (ILs). However, some have melting points above 100 °C. The synthesis and characterization of nanoparticles derived from GUMBOS (nanoGUMBOS) is investigated in the first part of this dissertation. NanoGUMBOS are more advantageous than traditional nanoparticles because they possess the inherent desirable characteristics of ILs. In addition to the attractive properties of ILs, nanoGUMBOS can be easily tuned for potential applications by altering the constituent components. The second part of this dissertation investigates the synthesis and characterization of task specific nanoGUMBOS. More specifically, magnetic and fluorescent nanoparticles derived from GUMBOS were investigated in this section. The magnetic nanoGUMBOS were synthesized using an oil-in-water (o/w) emulsion preparation method. These nanoparticles are advantageous because they are uniformly magnetic due to the magnetic functional component built into the nanoparticle. Magnetic nanoGUMBOS synthesized in this section have potential applications in the biomedical field including drug delivery and hyperthermia cancer treatment. Fluorescent nanoGUMBOS were synthesized using different particle fabrication techniques: reprecipitation, o/w emulsion, and a hydrogel preparation method. These particles that are derived from fluorophore based cations are uniformly fluorescent because the GUMBOS synthesized contain the fluorophore. Both fluorescent and magnetic nanoGUMBOS offer many advantages as compared to traditional nanoparticles because their synthetic procedures are rapid, facile, and do not require laborious steps. In addition, these novel fluorescent nanoGUMBOS have potential applications in biomedical imaging

Ionic Liquids and GUMBOS for Biomedical and Sensing Applications

This dissertation is a synopsis of advancements in the field of ionic liquids and a group of uniform materials based on organic salts (GUMBOS) in biomedical applications, especially with regard to cancer research. The toxicity of chemotherapeutic agents to normal tissues and drug resistance are a major concern in cancer treatment. In this dissertation, GUMBOS and nanoGUMBOS as well as ionic liquids and nanodroplets are explored as possible chemotherapeutic agents with minimal toxicity to normal cells. In the first part of my dissertation, exploitation of ionic liquid chemistry to modulate toxicity of rhodamine 6G is reported. Rhodamine 6G-based GUMBOS with varying counter-anions that are stable under physiological conditions, display excellent fluorescence photostability, and more importantly have tunable chemotherapeutic properties were synthesized. In vitro studies indicate that the hydrophobic compounds of this series allow production of nanoGUMBOS which are non-toxic to normal cells and toxic to cancer cells. Furthermore, the anions, in combination with cations such as sodium, were observed to be non-toxic to both normal and cancer cells. Thus, we demonstrate that both the cation and anion play an extremely important and cooperative role in the anticancer properties of these compounds. In the second part, the concept of multifunctional nanoparticles is introduced and exploited for theranostic applications. Nanoparticles possessing multiple properties such as luminescence, magnetism, and cancer targeting, were synthesized and explored for use in cancer therapy. In this regard, it is demonstrated that these nanoparticles can not only be used in diagnostics and as drug delivery agents, but also as active pharmacophores. Finally, the third part of this dissertation is a report of novel ionic liquid based pH sensitive colorimetric nanosensors based on phosphonium and fluorescein. The pH dependent size changes in the nanodroplets are demonstrated and potential applications in detecting acidic environment and anticancer activity are investigated

Optimisation of superconducting thin film growth for next generation superconducting detector applications

There is a growing demand for superconducting detectors with single photon sensitivity from near- to far infrared wavelengths. Emerging application areas include imaging, remote sensing, astronomy and free space communications. Two superconducting device technologies, superconducting nanowire single-photon detectors (SSPDs/SNSPDs) and microwave kinetic inductance detectors (MKIDs) have the potential to outperform off-the-self semiconductor technologies and offer scalability to large arrays. Fabrication of high efficiency superconducting detectors strongly depends on the quality of superconducting thin films. The original work presented in this thesis has explored the growth and optimization of several superconducting thin film materials for next generation superconducting detectors. Films have been grown in an ultra-high vacuum sputter deposition system and an atomic layer deposition system. Since its initial demonstration, NbN and NbTiN have been predominantly used as the base material for SNSPDs. In this work, we have explored the optimization of both the materials with an emphasis on NbTiN. NbTiN is optimized by heating the substrates to 800 ̊C achieving a Tc of 10.4 K for a film thickness of 5.5 nm on silicon substrate. Due to their crystalline nature superconducting properties of NbN or NbTiN thin films are strongly correlated with the lattice parameters of substrate properties. This causes a restriction on the substrate choice and integration of SNSPD devices with complex circuits. Amorphous superconducting materials can be promising alternatives for this purpose. We have explored growth and optimization of amorphous MoSi and MoGe thin films. Both the materials are co-sputtered to tune the composition. For 5 nm thick MoSi film on silicon substrate we obtain Tc of 5.5 K. For MKID fabrication, TiN can be an useful base material due to its high sheet resistance and widely tuneable superconducting properties. TiN thin films have been sputtered on heated (500 ̊C) silicon substrates with a Tc of 3.9 K for a 90 nm thick film. The dielectric constants of the thin films as a function of wavelength (270-2200 nm) have been determined via variable angle spectroscopic ellipsometry (VASE). Atomic structure and stoichiometry of the films have been characterized in high resolution transmission electron microscopy (HRTEM). This study enables us to precisely control film properties and thus tailor superconducting films to the requirements of specific photon-counting applications