Ultraparamagnetic Cells Formed through Intracellular Oxidation and Chelation of Paramagnetic Iron.

Making cells magnetic is a long-standing goal of chemical biology, aiming to enable the separation of cells from complex biological samples and their visualization in vivo using magnetic resonance imaging (MRI). Previous efforts towards this goal, focused on engineering cells to biomineralize superparamagnetic or ferromagnetic iron oxides, have been largely unsuccessful due to the stringent required chemical conditions. Here, we introduce an alternative approach to making cells magnetic, focused on biochemically maximizing cellular paramagnetism. We show that a novel genetic construct combining the functions of ferroxidation and iron chelation enables engineered bacterial cells to accumulate iron in "ultraparamagnetic" macromolecular complexes, allowing these cells to be trapped with magnetic fields and imaged with MRI in vitro and in vivo. We characterize the properties of these cells and complexes using magnetometry, nuclear magnetic resonance, biochemical assays, and computational modeling to elucidate the unique mechanisms and capabilities of this paramagnetic concept.

Mitigation of Device Heterogeneity in Graphene Hall Sensor Arrays Using Per-Element Backgate Tuning.

Graphene Hall-effect magnetic field sensors (GHSs) exhibit high performance comparable to state-of-the-art commercial Hall sensors made from III-V semiconductors. Graphene is also amenable to CMOS-compatible fabrication processes, making GHSs attractive candidates for implementing magnetic sensor arrays for imaging fields in biosensing and scanning probe applications. However, their practical appeal is limited by response heterogeneity and drift, arising from the high sensitivity of two-dimensional (2D) materials to local device imperfections. To address this challenge, we designed a GHS array in which an individual backgate is added to each GHS, allowing the carrier density of each sensor to be electrostatically tuned independent of other sensors in the array. Compared to the constraints encountered when all devices are tuned with the same backgate, we expected that the flexibility afforded by individual tuning would allow for the array's sensitivity, uniformity, and reconfigurability to be enhanced. We fabricated an array of 16 GHSs, each with its own backgate terminal, and characterized the ability to modulate GHS carrier density and Hall sensitivity within CMOS-compatible voltage ranges. We then demonstrated that individual device tuning can be used to break the trade-off between device sensitivity and uniformity in the GHS array, allowing for enhancement of both objectives. Our results showed that GHS arrays exhibiting >30% variability under single-backgate operation could be compensated using individual tuning to achieve <2% variability with minimal impact on the array sensitivity.

The next generation of hybrid microfluidic/integrated circuit chips: recent and upcoming advances in high-speed, high-throughput, and multifunctional lab-on-IC systems.

Since the field's inception, pioneers in microfluidics have made significant progress towards realizing complete lab-on-chip systems capable of sophisticated sample analysis and processing. One avenue towards this goal has been to join forces with the related field of microelectronics, using integrated circuits (ICs) to perform on-chip actuation and sensing. While early demonstrations focused on using microfluidic-IC hybrid chips to miniaturize benchtop instruments, steady advancements in the field have enabled a new generation of devices that expand past miniaturization into high-performance applications that would not be possible without IC hybrid integration. In this review, we identify recent examples of labs-on-chip that use high-resolution, high-speed, and multifunctional electronic and photonic chips to expand the capabilities of conventional sample analysis. We focus on three particularly active areas: a) high-throughput integrated flow cytometers; b) large-scale microelectrode arrays for stimulation and multimodal sensing of cells over a wide field of view; c) high-speed biosensors for studying molecules with high temporal resolution. We also discuss recent advancements in IC technology, including on-chip data processing techniques and lens-free optics based on integrated photonics, that are poised to further advance microfluidic-IC hybrid chips.

Highly stable integration of graphene Hall sensors on a microfluidic platform for magnetic sensing in whole blood.

The detection and analysis of rare cells in complex media such as blood is increasingly important in biomedical research and clinical diagnostics. Micro-Hall detectors (µHD) for magnetic detection in blood have previously demonstrated ultrahigh sensitivity to rare cells. This sensitivity originates from the minimal magnetic background in blood, obviating cumbersome and detrimental sample preparation. However, the translation of this technology to clinical applications has been limited by inherently low throughput (<1 mL/h), susceptibility to clogging, and incompatibility with commercial CMOS foundry processing. To help overcome these challenges, we have developed CMOS-compatible graphene Hall sensors for integration with PDMS microfluidics for magnetic sensing in blood. We demonstrate that these graphene µHDs can match the performance of the best published µHDs, can be passivated for robust use with whole blood, and can be integrated with microfluidics and sensing electronics for in-flow detection of magnetic beads. We show a proof-of-concept validation of our system on a silicon substrate and detect magnetic agarose beads, as a model for cells, demonstrating promise for future integration in clinical applications with a custom CMOS chip.

Advancing microfluidic diagnostic chips into clinical use: a review of current challenges and opportunities.

Microfluidic diagnostic (µDX) technologies miniaturize sensors and actuators to the length-scales that are relevant to biology: the micrometer scale to interact with cells and the nanometer scale to interrogate biology's molecular machinery. This miniaturization allows measurements of biomarkers of disease (cells, nanoscale vesicles, molecules) in clinical samples that are not detectable using conventional technologies. There has been steady progress in the field over the last three decades, and a recent burst of activity catalyzed by the COVID-19 pandemic. In this time, an impressive and ever-growing set of technologies have been successfully validated in their ability to measure biomarkers in clinical samples, such as blood and urine, with sensitivity and specificity not possible using conventional tests. Despite our field's many accomplishments to date, very few of these technologies have been successfully commercialized and brought to clinical use where they can fulfill their promise to improve medical care. In this paper, we identify three major technological trends in our field that we believe will allow the next generation of µDx to have a major impact on the practice of medicine, and which present major opportunities for those entering the field from outside disciplines: 1. the combination of next generation, highly multiplexed µDx technologies with machine learning to allow complex patterns of multiple biomarkers to be decoded to inform clinical decision points, for which conventional biomarkers do not necessarily exist. 2. The use of micro/nano devices to overcome the limits of binding affinity in complex backgrounds in both the detection of sparse soluble proteins and nucleic acids in blood and rare circulating extracellular vesicles. 3. A suite of recent technologies that obviate the manual pre-processing and post-processing of samples before they are measured on a µDX chip. Additionally, we discuss economic and regulatory challenges that have stymied µDx translation to the clinic, and highlight strategies for successfully navigating this challenging space.