Low cost, portable sensors can transform health care by bringing easily available diagnostic devices to low and middle income population, particularly in developing countries. Sample preparation, analyte handling and labeling are primary cost concerns for traditional lab-based diagnostic systems. Lab-on-a-chip (LoC) platforms based on droplet-based microfluidics promise to integrate and automate these complex and expensive laboratory procedures onto a single chip; the cost will be further reduced if label-free biosensors could be integrated onto the LoC platforms. Here, we review some recent developments of label-free, droplet-based biosensors, compatible with “open” digital microfluidic systems. These low-cost droplet-based biosensors overcome some of the fundamental limitations of the classical sensors, enabling timely diagnosis. We identify the key challenges that must be addressed to make these sensors commercially viable and summarize a number of promising research directions.

Electrical detection of nucleic acid amplification through pH changes associated with nucleotide addition enables miniaturization, greater portability of testing apparatus, and reduced costs. However, current ion-sensitive field effect transistor methods for sensing nucleic acid amplification rely on establishing the fluid gate potential with a bulky, difficult to microfabricate reference electrode that limits the potential for massively parallel reaction detection. Here we demonstrate a novel method of utilizing a microfabricated solid-state quasi-reference electrode (QRE) paired with a pH-insensitive reference field effect transistor (REFET) for detection of real-time pH changes. The end result is a 0.18 μm, silicon-on-insulator, foundry-fabricated sensor that utilizes a platinum QRE to establish a pH-sensitive fluid gate potential and a PVC membrane REFET to enable pH detection of loop mediated isothermal amplification (LAMP). This technique is highly amendable to commercial scale-up, reduces the packaging and fabrication requirements for ISFET pH detection, and enables massively parallel droplet interrogation for applications, such as monitoring reaction progression in digital PCR.

The adaptation of semiconductor technologies for biological applications may lead to a new era of inexpensive, sensitive, and portable diagnostics. At the core of these developing technologies is the ion-sensitive field-effect transistor (ISFET), a biochemical to electrical transducer with seamless integration to electronic systems. We present a novel structure for a true dual-gated ISFET that is fabricated with a silicon-on-insulator (SOI) complementary metal-oxide-semiconductor process by Taiwan Semiconductor Manufacturing Company (TSMC). In contrast to conventional SOI ISFETs, each transistor has an individually addressable back-gate and a gate oxide that is directly exposed to the solution. The elimination of the commonly used floating gate architecture reduces the chance of electrostatic discharge and increases the potential achievable transistor density. We show that when operated in a "dual-gate" mode, the transistor response can exhibit sensitivities to pH changes beyond the Nernst limit. This enhancement in sensitivity was shown to increase the sensor's signal-to-noise ratio, allowing the device to resolve smaller pH changes. An improved resolution can be used to enhance small signals and increase the sensor accuracy when monitoring small pH dynamics in biological reactions. As a proof of concept, we demonstrate that the amplified sensitivity and improved resolution result in a shorter detection time and a larger output signal of a loop-mediated isothermal DNA amplification reaction (LAMP) targeting a pathogenic bacteria gene, showing benefits of the new structure for biosensing applications.

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Over one million DG-BioFETs are used for the parallel electrical detection of LAMP reactions identifying the presence of bacterial pathogens, demonstrating a miniaturized DNA-based screening platform.

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To operate an ion-sensitive field-effect transistor (ISFETs) it is necessary to set the electrolyte potential using a reference electrode. Conventional reference electrodes are bulky, fragile, and too big for applications where the electrolyte volume is small. Several researchers have proposed tackling this issue using a solid-state planar micro-reference electrode or a reference field-effect transistor. However, these approaches are limited by poor robustness, high cost, or complex integration with other microfabrication processes. Here we report a simple method to create robust on-chip quasi-reference electrodes by electrodepositing polypyrrole on micro-patterned metal leads. The electrodes were fabricated through the polymerization of pyrrole on patterned metals with a cyclic voltammetry process. Open circuit potential measurements were performed to characterize the polypyrrole electrode performance, demonstrating good stability (±1 mV), low drift (∼1 mV h(-1)), and reduced pH response (5 mV per pH). In addition, the polypyrrole deposition was repeated in microelectrodes made of different metals to test compatibility with standard complementary metal-oxide-semiconductor (CMOS) processes. Our results suggest that nickel, a metal commonly used in semiconductor foundries for silicide formation, is a good candidate to form the polypyrrole quasi-reference electrodes. Finally, the polypyrrole microelectrodes were used to operate foundry fabricated ISFETs. These experiments demonstrated that transistors biased with polypyrrole electrodes have pH sensitivity and resolution comparable to ones that are biased with standard reference electrodes. Therefore, the simple fabrication, high compatibility, and robust electrical performance make polypyrrole an ideal choice for the fabrication of outstanding microreference electrodes that enable robust and sensitive operation of multiple ISFET sensors on a chip.

This paper reports a new type of hierarchically structured surface consisting of re-entrant silicon micropillars with silicon nanowires atop for superhydrophobic surface with extremely low hysteresis. Re-entrant microstructures were fabricated on a silicon substrate through a customized one-mask microfabrication process while silicon nanopillars were created on the entire surface of microstructures, including sidewalls, by a metal-assisted-chemical etching process. The strategy of constructing hierarchical surfaces aims to reduce the actual contact area between liquid and top part of solid surface, thereby increasing the contact angle and reducing the sliding angle. The strategy of using re-entrant profile of the microstructure aims to prevent a liquid droplet from falling into cavities of roughened structures and decrease the actual contact area between the liquid droplet and sidewalls of solid structures, therefore reducing adhesion forces acting on the liquid droplet. Our measurement shows that the surface incorporating both hierarchical and re-entrant strategies exhibits a sliding angle as low as 0.5°, much lower than sliding angles of surfaces only incorporating either one of the strategies.