Thin, piezoresistive silicon cantilevers are shown to provide unprecedented sensitivity for force detection in an integrated, self-sensing, readily scalable configuration. The devices realized herein are patterned from single-crystal Si epilayer membranes utilizing bulk micro- and nanomachining processes. We demonstrate an electrically transduced force sensitivity of 235 aN/Hz1/2 at room temperature and 17 aN/Hz1/2 at 10 K. Enhancement of the p+ piezoresistive gauge factor is observed at cryogenic temperatures. The results are employed to elucidate the ultimate, low-temperature sensitivity attainable from self-sensing nanoelectromechanical systems utilizing displacement transduction based upon semiconducting piezoresistors.

Microfluidic chips have been developed to generate droplets and microparticles with control over size, shape, and composition not possible using conventional methods. However, it has remained a challenge to scale-up production for practical applications due to the inherently limited throughput of micro-scale devices. To address this problem, we have developed a self-contained microchip that integrates many (N = 512) micro-scale droplet makers. This 3 × 3 cm2 PDMS microchip consists of a two-dimensional array of 32 × 16 flow-focusing droplet makers, a network of flow channels that connect them, and only two inputs and one output. The key innovation of this technology is the hybrid use of both soft-lithography and direct laser-micromachining. The microscale resolution of soft lithography is used to fabricate flow-focusing droplet makers that can produce small and precisely defined droplets. Deeply engraved (h ≈ 500 μm) laser-machined channels are utilized to supply each of the droplet makers with its oil phase, aqueous phase, and access to an output channel. The engraved channels' low hydrodynamic resistance ensures that each droplet maker is driven with the same flow rates for highly uniform droplet formation.To demonstrate the utility of this approach, water droplets (d ≈ 80 μm) were generated in hexadecane on both 8 × 1 and 32 × 16 geometries.

Local delivery of drugs offers the potential for high local drug concentration while minimizing systemic toxicity, which is often observed with oral dosing. However, local depots are typically administered less frequently and include an initial burst followed by a continuous release. To maximize efficiency of therapy, it is critical to ensure that drug is only released when needed. One of the hallmarks of rheumatoid arthritis, for example, is its variable disease activity consisting of exacerbations of inflammation punctuated by periods of remission. This presents significant challenges for matching localized drug delivery with disease activity. An optimal system would be nontoxic and only release drugs during the period of exacerbation, self-titrating in response to the level of inflammation. We report the development of an injectable self-assembled nanofibrous hydrogel, from a generally recognized as safe material, which is capable of encapsulation and release of agents in response to specific enzymes that are significantly upregulated in a diseased state including matrix metalloproteinases (MMP-2 and MMP-9) and esterases. We show that these self-assembled nanofibrous gels can withstand shear forces that may be experienced in dynamic environments such as joints, can remain stable following injection into healthy joints of mice, and can disassemble in vitro to release encapsulated agents in response to synovial fluid from arthritic patients. This novel approach represents a next-generation therapeutic strategy for localized treatment of proteolytic diseases.

A microfluidic chip is developed to selectively isolate magnetically tagged cells from heterogeneous suspensions, the track-etched magnetic micropore (TEMPO) filter. The TEMPO consists of an ion track-etched polycarbonate membrane coated with soft magnetic film (Ni20Fe80). In the presence of an applied field, provided by a small external magnet, the filter becomes magnetized and strong magnetic traps are created along the edges of the micropores. In contrast to conventional microfluidics, fluid flows vertically through the porous membrane allowing large flow rates while keeping the capture rate high and the chip compact. By utilizing track-etching instead of conventional semiconductor fabrication, TEMPOs can be fabricated with microscale pores over large areas A > 1 cm2 at little cost (< 5 ¢ cm−2). To demonstrate the utility of this platform, a TEMPO with 5 μm pore size is used to selectively and rapidly isolate immunomagnetically targeted Escherichia coli from heterogeneous suspensions, demonstrating enrichment of ζ > 500 at a flow rate of Φ = 5 mL h−1. Furthermore, the large density of micropores (ρ = 106 cm−2) allows the TEMPO to sort E. coli from unprocessed environmental and clinical samples, as the blockage of a few pores does not significantly change the behavior of the device.

Micro-magnetic sensing and actuation have emerged as powerful tools for the diagnosis and monitoring of cancer. These technologies can be miniaturized and integrated onto compact, microfluidic platforms, enabling molecular diagnostics to be performed in practical clinical settings. Molecular targets tagged with magnetic nanoparticles can be detected with high sensitivity directly in unprocessed clinical samples (e.g. blood, sputum) due to the inherently negligible magnetic susceptibility of biological material. As a result, magnetic microchip-based diagnostics have been applied with great success to the isolation and detection of rare cells and the measurement of sparse soluble proteins. In this paper, we review recent advances in microchip-based detection of magnetically labeled biomarkers and their translation to clinical applications in cancer.

In recent years there has been great progress harnessing the small-feature size and programmability of integrated circuits (ICs) for biological applications, by building microfluidics directly on top of ICs. However, a major hurdle to the further development of this technology is the inherent size-mismatch between ICs (~mm) and microfluidic chips (~cm). Increasing the area of the ICs to match the size of the microfluidic chip, as has often been done in previous studies, leads to a waste of valuable space on the IC and an increase in fabrication cost (>100×). To address this challenge, we have developed a three dimensional PDMS chip that can straddle multiple length scales of hybrid IC/microfluidic chips. This approach allows millimeter-scale ICs, with no post-processing, to be integrated into a centimeter-sized PDMS chip. To fabricate this PDMS chip we use a combination of soft-lithography and laser micromachining. Soft lithography was used to define micrometer-scale fluid channels directly on the surface of the IC, allowing fluid to be controlled with high accuracy and brought into close proximity to sensors for highly sensitive measurements. Laser micromachining was used to create ~50 μm vias to connect these molded PDMS channels to a larger PDMS chip, which can connect multiple ICs and house fluid connections to the outside world. To demonstrate the utility of this approach, we built and demonstrated an in-flow magnetic cytometer that consisted of a 5 × 5 cm2 microfluidic chip that incorporated a commercial 565 × 1145 μm2 IC with a GMR sensing circuit. We additionally demonstrated the modularity of this approach by building a chip that incorporated two of these GMR chips connected in series.

We use 3D confocal microscopy combined with image analysis and particle tracking techniques to study the structure and dynamics of aqueous suspensions of fluorescently labelled p(NIPAm-co-AAc) microgel particles. By adjusting the pH we can tune the interactions between the microgel particles from purely repulsive near neutral pH, to weakly attractive at low pH. This change in the interaction potential has a pronounced effect on the manner in which the suspensions solidify. We directly follow the evolution of the system after a quench from the liquid state to obtain detailed information on the route to kinetic arrest. At low pH and low concentration, dynamic arrest results mainly from crystallization driven by the attraction between particles; crystal nucleation occurs homogeneously throughout the sample and does not appear to be localized to geometric boundaries. Moreover, the growth of crystals is characterized by nucleation-limited kinetics where a rapid growth of crystal domains takes place after a long concentration-dependent lag time. At low pH and high concentration, relaxation of the suspension is constrained and it evolves only slightly, resulting in a disordered solid. At neutral pH, the dynamics are a function of the particle number concentration only; a high concentration leads to the formation of a disordered soft glassy solid.

Recent advances in microfluidics to generate and control picoliter emulsions of water in oil have enabled ultra-sensitive assays for small molecules, proteins, nucleic acids, and cells. Unfortunately, the conventional fluorescence detection used to measure the outcome of these droplet-based assays has not proven suited to match the time and space multiplexing capabilities of microfluidic systems. To address this challenge, we developed an in-flow fluorescence detection platform that enables multiple streams of droplets to be monitored using only a single photodetector and no lenses. The key innovation of our technology is the amplitude modulation of the signal from fluorescent droplets using distinct micro-patterned masks for each channel. By taking advantage of the high bandwidth of electronics, our technique enables the velocity-independent recovery of weak fluorescent signals (SNR ≪ 1) using only simple hardware, obviating the need for lasers, bulky detectors, and complex fluid control. We demonstrated a handheld-sized device that simultaneously monitors four independent channels with the capability to be scaled-up to more than sixteen, limited primarily by the droplet density.