Quantitative, high-sensitivity measurement of liquid analytes using a smartphone compass.

Smartphone ubiquity has led to rapid developments in portable diagnostics. While successful, such platforms are predominantly optics-based, using the smartphone camera as the sensing interface. By contrast, magnetics-based modalities exploiting the smartphone compass (magnetometer) remain unexplored, despite inherent advantages in optically opaque, scattering or auto-fluorescing samples. Here we report smartphone analyte sensing utilizing the built-in magnetometer for signal transduction via analyte-responsive magnetic-hydrogel composites. As these hydrogels dilate in response to targeted stimuli, they displace attached magnetic material relative to the phone's magnetometer. Using a bilayer hydrogel geometry to amplify this motion allows for sensitive, optics-free, quantitative liquid-based analyte measurements that require neither any electronics nor power beyond that contained within the smartphone itself. We demonstrate this concept with glucose-specific and pH-responsive hydrogels, including glucose detection down to single-digit micromolar concentrations with potential for extension to nanomolar sensitivities. The platform is adaptable to numerous measurands, opening a path towards portable, inexpensive sensing of multiple analytes or biomarkers of interest.

Shaped Magnetogel Microparticles for Multispectral Magnetic Resonance Contrast and Sensing.

Multispectral magnetic resonance imaging (MRI) contrast agents are microfabricated three-dimensional magnetic structures that encode nearby water protons with discrete frequencies. The agents have a unique radiofrequency (RF) resonance that can be tuned by engineering the geometric parameters of these microstructures. Multispectral contrast agents can be used as sensors by incorporating a stimulus-driven shape-changing response into their structure. These geometrically encoded magnetic sensors (GEMS) enable MRI-based sensing via environmentally induced changes to their geometry and their corresponding RF resonance. Previously, GEMS have been made using thin-film lithography techniques in a cleanroom environment. While these approaches offer precise control of the microstructure, they can be a limitation for researchers who do not have cleanroom access or microfabrication expertise. Here, an alternative approach for GEMS fabrication based on soft lithography is introduced. The fabrication scheme uses cheap, accessible materials and simple chemistry to produce shaped magnetic hydrogel microparticles with multispectral MRI contrast properties. The microparticles can be used as sensors by fabricating them out of shape-reconfigurable, "smart" hydrogels. The change in shape causes a corresponding shift in the resonance of the GEMS, producing an MRI-addressable readout of the microenvironment. Proof-of-principle experiments showing a multispectral response to pH change with cylindrical shell-shaped magnetogel GEMS are presented.

Iron oxide nanoparticles as positive T1 contrast agents for low-field magnetic resonance imaging at 64 mT.

We have investigated the efficacy of superparamagnetic iron oxide nanoparticles (SPIONs) as positive T1 contrast agents for low-field magnetic resonance imaging (MRI) at 64 millitesla (mT). Iron oxide-based agents, such as the FDA-approved ferumoxytol, were measured using a variety of techniques to evaluate T1 contrast at 64 mT. Additionally, we characterized monodispersed carboxylic acid-coated SPIONs with a range of diameters (4.9-15.7 nm) in order to understand size-dependent properties of T1 contrast at low-field. MRI contrast properties were measured using 64 mT MRI, magnetometry, and nuclear magnetic resonance dispersion (NMRD). We also measured MRI contrast at 3 T to provide comparison to a standard clinical field strength. SPIONs have the capacity to perform well as T1 contrast agents at 64 mT, with measured longitudinal relaxivity (r1) values of up to 67 L mmol-1 s-1, more than an order of magnitude higher than corresponding r1 values at 3 T. The particles exhibit size-dependent longitudinal relaxivities and outperform a commercial Gd-based agent (gadobenate dimeglumine) by more than eight-fold at physiological temperatures. Additionally, we characterize the ratio of transverse to longitudinal relaxivity, r2/r1 and find that it is ~ 1 for the SPION based agents at 64 mT, indicating a favorable balance of relaxivities for T1-weighted contrast imaging. We also correlate the magnetic and structural properties of the particles with models of nanoparticle relaxivity to understand generation of T1 contrast. These experiments show that SPIONs, at low fields being targeted for point-of-care low-field MRI systems, have a unique combination of magnetic and structural properties that produce large T1 relaxivities.

The misunderstood meander: Redesigning MRI meander-line surface coils to reduce noise, increase uniformity, and eliminate image artifacts.

Meander-line, or zig-zag, MRI surface coils theoretically promise spatially uniform fields with optimal field localization close to the coil. In reality, they suffer poorer than expected field localizations and acquired images are often highly inhomogeneous, plagued by repeating stripe-like signal-loss artifacts. We show that both these detrimental effects arise from coil design based on the same invalid approximation in the underlying theory. Here, the conventional approximation is corrected, yielding a modified coil design that validates the new theory by rectifying the above problems. Specifically, an easily implementable coil correction, which amounts to the addition of a single extra turn of wire, is introduced and shown to increase signal uniformity by an order of magnitude, eliminate image artifacts, and reduce unwanted signal interference from deeper within the sample by tightening the coil field localization to close to the coil, as intended for zig-zag designs. With independent optimization of coil size and imaging depth possible, such corrected meander-lines surface coils may be well suited for large area, near-surface imaging and spectroscopy applications.

Observation of iron oxide nanoparticle synthesis in magnetogels using magnetic resonance imaging.

We show that magnetic resonance imaging (MRI) can be used to visualize the spatiotemporal dynamics of iron oxide nanoparticle growth within a hydrogel network during in situ coprecipitation. The synthesis creates a magnetic nanoparticle loaded polymer gel, or magnetogel. During in situ coprecipitation, iron oxide nanoparticles nucleate and grow due to diffusion of a precipitating agent throughout an iron precursor loaded polymer network. The creation of iron oxide particles changes the magnetic properties of the gel, allowing the synthesis to be monitored via magnetic measurements. Formation of iron oxide nanoparticles generates dark, or hypointense, contrast in gradient echo (GRE) images acquired by MRI, allowing nanoparticle nucleation to be tracked in both space and time. We show that the growth of iron oxide nanoparticles in the hydrogel scaffold is consistent with a simple reaction-diffusion model.

Patterned Surface Energy in Elastomeric Molds as a Generalized Approach to Polymer Particle Fabrication.

We present a generic fabrication scheme to produce polymer microparticles with engineerable, complex shapes. The polymer particles are made from polyethylene glycol based hydrogels using a poly(dimethylsiloxane) (PDMS) molding technique. A simple surface treatment is used to pattern the surface energy of the PDMS molds, engendering the recessed wells in the molds with a higher surface energy than that of the surface. The contrast in surface energy causes hydrogel precursor to wet only the inside of the molds, creating isolated particles after curing with UV light. This eliminates the formation of an interconnecting "scum" layer and allows for fabrication of well-defined, independent particles. We discuss resolution limits for the approach and present a simple strategy for releasing the particles. Finally, to show how the fabrication technique is inherently compatible with further particle modifications, we also demonstrate magnetic functionalization of particles.

Author Correction: Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely investigated and utilized as magnetic resonance imaging (MRI) contrast and therapy agents due to their large magnetic moments. Local field inhomogeneities caused by these high magnetic moments are used to generate T2 contrast in clinical high-field MRI, resulting in signal loss (darker contrast). Here we present strong T1 contrast enhancement (brighter contrast) from SPIONs (diameters from 11 nm to 22 nm) as observed in the ultra-low field (ULF) MRI at 0.13 mT. We have achieved a high longitudinal relaxivity for 18 nm SPION solutions, r1 = 615 s-1 mM-1, which is two orders of magnitude larger than typical commercial Gd-based T1 contrast agents operating at high fields (1.5 T and 3 T). The significantly enhanced r1 value at ultra-low fields is attributed to the coupling of proton spins with SPION magnetic fluctuations (Brownian and Néel) associated with a low frequency peak in the imaginary part of AC susceptibility (χ"). SPION-based T1-weighted ULF MRI has the advantages of enhanced signal, shorter imaging times, and iron-oxide-based nontoxic biocompatible agents. This approach shows promise to become a functional imaging technique, similar to PET, where low spatial resolution is compensated for by important functional information.

Engineering novel detectors and sensors for MRI.

Increasing detection sensitivity and image contrast have always been major topics of research in MRI. In this perspective, we summarize two engineering approaches to make detectors and sensors that have potential to extend the capability of MRI. The first approach is to integrate miniaturized detectors with a wireless powered parametric amplifier to enhance the detection sensitivity of remotely coupled detectors. The second approach is to microfabricate contrast agents with encoded multispectral frequency shifts, whose properties can be specified and fine-tuned by geometry. These two complementary approaches will benefit from the rapid development in nanotechnology and microfabrication which should enable new opportunities for MRI.

Microfabricated high-moment micrometer-sized MRI contrast agents.

While chemically synthesized superparamagnetic microparticles have enabled much new research based on MRI tracking of magnetically labeled cells, signal-to-noise levels still limit the potential range of applications. Here it is shown how, through top-down microfabrication, contrast agent relaxivity can be increased several-fold, which should extend the sensitivity of such cell-tracking studies. Microfabricated agents can benefit from both higher magnetic moments and higher uniformity than their chemically synthesized counterparts, implying increased label visibility and more quantitative image analyses. To assess the performance of microfabricated micrometer-sized contrast agent particles, analytic models and numerical simulations are developed and tested against new microfabricated agents described in this article, as well as against results of previous imaging studies of traditional chemically synthesized microparticle agents. Experimental data showing signal effects of 500-nm thick, 2-µm diameter, gold-coated iron and gold-coated nickel disks verify the simulations. Additionally, it is suggested that measures of location better than the pixel resolution can be obtained and that these are aided using well-defined contrast agent particles achievable through microfabrication techniques.

Microfabricated multispectral MRI agents: a brief overview.

This paper provides an introductory overview of recent microfabricated, as opposed to traditional chemically synthesized, magnetic resonance imaging (MRI) contrast agents. As a specific example of the enhanced agent functionality that top-down micro-engineering allows, the paper focuses on recently demonstrated magnetic microstructures that provide multispectral MRI contrast.

Micro-engineered local field control for high-sensitivity multispectral MRI.

In recent years, biotechnology and biomedical research have benefited from the introduction of a variety of specialized nanoparticles whose well-defined, optically distinguishable signatures enable simultaneous tracking of numerous biological indicators. Unfortunately, equivalent multiplexing capabilities are largely absent in the field of magnetic resonance imaging (MRI). Comparable magnetic-resonance labels have generally been limited to relatively simple chemically synthesized superparamagnetic microparticles that are, to a large extent, indistinguishable from one another. Here we show how it is instead possible to use a top-down microfabrication approach to effectively encode distinguishable spectral signatures into the geometry of magnetic microstructures. Although based on different physical principles from those of optically probed nanoparticles, these geometrically defined magnetic microstructures permit a multiplexing functionality in the magnetic resonance radio-frequency spectrum that is in many ways analogous to that permitted by quantum dots in the optical spectrum. Additionally, in situ modification of particle geometries may facilitate radio-frequency probing of various local physiological variables.