Christophoros C. Vassiliou

Mechanical loss in tantala/silica dielectric mirror coatings

Current interferometric gravitational wave detectors use test masses with mirror coatings formed from multiple layers of dielectric materials, most commonly alternating layers of SiO2 (silica) and Ta2O5 (tantala). However, mechanical loss in the Ta2O5/SiO2 coatings may limit the design sensitivity for advanced detectors. We have investigated sources of mechanical loss in the Ta2O5/SiO2 coatings, including loss associated with the coating–substrate interface, with the coating–layer interfaces and with the coating materials. Our results indicate that the loss is associated with the coating materials and that the loss of Ta2O5 is substantially larger than that of SiO2.

Implantable magnetic relaxation sensors measure cumulative exposure to cardiac biomarkers

Molecular biomarkers can be used as objective indicators of pathologic processes. Although their levels often change over time, their measurement is often constrained to a single time point. Cumulative biomarker exposure would provide a fundamentally different kind of measurement to what is available in the clinic. Magnetic resonance relaxometry can be used to noninvasively monitor changes in the relaxation properties of antibody-coated magnetic particles when they aggregate upon exposure to a biomarker of interest. We used implantable devices containing such sensors to continuously profile changes in three clinically relevant cardiac biomarkers at physiological levels for up to 72 h. Sensor response differed between experimental and control groups in a mouse model of myocardial infarction and correlated with infarct size. Our prototype for a biomarker monitoring device also detected doxorubicin-induced cardiotoxicity and can be adapted to detect other molecular biomarkers with a sensitivity as low as the pg/ml range.

Implantable diagnostic device for cancer monitoring

Biopsies provide required information to diagnose cancer but, because of their invasiveness, they are difficult to use for managing cancer therapy. The ability to repeatedly sample the local environment for tumor biomarker, chemotherapeutic agent, and tumor metabolite concentrations could improve early detection of metastasis and personalized therapy. Here we describe an implantable diagnostic device that senses the local in vivo environment. This device, which could be left behind during biopsy, uses a semi-permeable membrane to contain nanoparticle magnetic relaxation switches. A cell line secreting a model cancer biomarker produced ectopic tumors in mice. The transverse relaxation time (T(2)) of devices in tumor-bearing mice was 20+/-10% lower than devices in control mice after 1 day by magnetic resonance imaging (p<0.01). Short term applications for this device are numerous, including verification of successful tumor resection. This may represent the first continuous monitoring device for soluble cancer biomarkers in vivo.

Multi-reservoir device for detecting a soluble cancer biomarker

By combining the sensing capabilities of nanoscale magnetic relaxation switches (MRS) within multi-reservoir structures, a potentially powerful implantable multiplexed sensor has been developed. MRS are magnetic nanoparticles that decrease the transverse relaxation time (T(2)) of water in the presence of an analyte. The switches encased in polydimethylsiloxane (PDMS) devices with polycarbonate membranes (10 nm pores) have demonstrated in vitro sensing of the beta subunit of human chorionic gonadotrophin (hCG-beta), which is elevated in testicular and ovarian cancer. Devices showed transverse relaxation time (T(2)) shortening by magnetic resonance imaging (MRI) when incubated in analyte solutions of 0.5 to 5 microg hCG-beta mL(-1). The decrease in T(2) was between 9% and 27% (compared to control devices) after approximately 28 h. This prototype device is an important first step in developing an implantable sensor for detecting soluble cancer biomarkers in vivo.

Scaling of transverse nuclear magnetic relaxation due to magnetic nanoparticle aggregation

The aggregation of superparamagnetic iron oxide (SPIO) nanoparticles decreases the transverse nuclear magnetic resonance (NMR) relaxation time T2CP of adjacent water molecules measured by a Carr-Purcell-Meiboom-Gill (CPMG) pulse-echo sequence. This effect is commonly used to measure the concentrations of a variety of small molecules. We perform extensive Monte Carlo simulations of water diffusing around SPIO nanoparticle aggregates to determine the relationship between T2CP and details of the aggregate. We find that in the motional averaging regime T2CP scales as a power law with the number N of nanoparticles in an aggregate. The specific scaling is dependent on the fractal dimension d of the aggregates. We find T2CP∝N-0.44 for aggregates with d = 2.2, a value typical of diffusion limited aggregation. We also find that in two-nanoparticle systems, T2CP is strongly dependent on the orientation of the two nanoparticles relative to the external magnetic field, which implies that it may be possible to sense the orientation of a two-nanoparticle aggregate. To optimize the sensitivity of SPIO nanoparticle sensors, we propose that it is best to have aggregates with few nanoparticles, close together, measured with long pulse-echo times.

Magnetic relaxation-based platform for multiplexed assays

We explore the use of magnetic relaxation sensors as an in vitro assay platform. Functionalized magnetic nanoparticles that exhibit transverse relaxation time (T(2)) changes with the introduction of an analyte have previously been used to detect proteins, antibodies, receptor ligands, peptides, nucleic acids, oligonucleotides, and other small molecules. The standard procedure for sensitizing particles towards specific targets is, however, time-consuming and cumbersome. We report here a new approach that exploits primary-secondary antibody binding for easily derivatizing particles against specific targets. The assay is shown to be quantitative and a multiplexed assay against three target analytes is demonstrated.

Solid MRI contrast agents for long-term, quantitative in vivo oxygen sensing.

Significance Information on tissue oxygen tension is critical to the successful treatment of many human diseases. Clinical decisions for diseases such as cancer benefit from knowing how oxygen tension changes in response to treatment. Acquiring this knowledge obviously requires a series of measurements and is limited currently by the use of invasive oxygen electrodes. We have developed an oxygen-sensitive MRI contrast agent for chronic oxygen tension measurements. This contrast agent can be delivered with a small-gauge needle that is minimally invasive, and subsequent measurements are entirely noninvasive. The material is stable in the body for at least 1 mo, and we envision that other types of responsive contrast agents can be used with this technology to detect different metabolites. Targeted MRI contrast agents have proven useful in research and clinical studies for highlighting specific metabolites and biomarkers [Davies GL, et al. (2013) Chem Commun (Camb) 49(84):9704–9721] but their applicability in serial imaging is limited owing to a changing concentration postinjection. Solid enclosures have previously been used to keep the local concentration of contrast agent constant, but the need to surgically implant these devices limits their use [Daniel K, et al. (2009) Biosens Bioelectron 24(11):3252–3257]. This paper describes a novel class of contrast agent that comprises a responsive material for contrast generation and an injectable polymeric matrix for structural support. Using this principle, we have designed a contrast agent sensitive to oxygen, which is composed of dodecamethylpentasiloxane as the responsive material and polydimethylsiloxane as the matrix material. A rodent inspired-gas model demonstrated that these materials are functionally stable in vivo for at least 1 mo, which represents an order of magnitude improvement over an injection of liquid siloxane [Kodibagkar VD, et al. (2006) Magn Reson Med 55(4):743–748]. We also observed minimal adverse tissue reactions or migration of contrast agents from the initial injection site. This class of contrast agents, thus, represented a new and complementary method to monitor chronic diseases by MRI.

Effects of electrical charging on the mechanical Q of a fused silica disk

We report on the effects of an electrical charge on mechanical loss of a fused silica disk. A degradation of Q was seen that correlated with charge on the surface of the sample. We examine a number of models for charge damping, including eddy current damping, and loss due to polarization. We conclude that rubbing friction between the sample and a piece of dust attracted by the charged sample is the most likely explanation for the observed loss.

1H nuclear magnetic resonance (NMR) as a tool to measure dehydration in mice

Dehydration is a prevalent pathology, where loss of bodily water can result in variable symptoms. Symptoms can range from simple thirst to dire scenarios involving loss of consciousness. Clinical methods exist that assess dehydration from qualitative weight changes to more quantitative osmolality measurements. These methods are imprecise, invasive, and/or easily confounded, despite being practiced clinically. We investigate a non‐invasive, non‐imaging 1H NMR method of assessing dehydration that attempts to address issues with existing clinical methods. Dehydration was achieved by exposing mice (n = 16) to a thermally elevated environment (37 °C) for up to 7.5 h (0.11–13% weight loss). Whole body NMR measurements were made using a Bruker LF50 BCA‐Analyzer before and after dehydration. Physical lean tissue, adipose, and free water compartment approximations had NMR values extracted from relaxation data through a multi‐exponential fitting method. Changes in before/after NMR values were compared with clinically practiced metrics of weight loss (percent dehydration) as well as blood and urine osmolality. A linear correlation between tissue relaxometry and both animal percent dehydration and urine osmolality was observed in lean tissue, but not adipose or free fluids. Calculated R2 values for percent dehydration were 0.8619 (lean, P < 0.0001), 0.5609 (adipose, P = 0.0008), and 0.0644 (free fluids, P = 0.3445). R2 values for urine osmolality were 0.7760 (lean, P < 0.0001), 0.5005 (adipose, P = 0.0022), and 0.0568 (free fluids, P = 0.3739). These results suggest that non‐imaging 1H NMR methods are capable of non‐invasively assessing dehydration in live animals. Copyright

A Novel Magnetic Relaxation-Based Platform for Hydration Monitoring

Hydration state has long been of interest to the military due to its importance in the relationship between physiological indexes and heat exhaustion. The need for hydration monitoring and assessment exists for civilian applications as well. An accurate evaluation of the hydration state in congestive heart failure patients is essential for the correct dose of the diuretic to be prescribed. Current hydration monitoring methods, however, are either unreliable, or require invasive and costly measurement techniques. We investigate in this paper a novel method with the potential for noninvasive and rapid determination of the hydration state of an individual based on nuclear magnetic resonance relaxation measurements. Feasibility studies are performed based on murine models of dehydration and specific tissues of interest for noninvasive screening are determined. The established platform can be employed for developing a portable hydration sensor for accurate and real-time monitoring of the hydration state.