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The commercialization of new point of care technologies holds great potential in facilitating and advancing precision medicine in heart, lung, blood, and sleep (HLBS) disorders. The delivery of individually tailored health care to a patient depends on how well that patient's health condition can be interrogated and monitored. Point of care technologies may enable access to rapid and cost-effective interrogation of a patient's health condition in near real time. Currently, physiological data are largely limited to single-time-point collection at the hospital or clinic, whereas critical information on some conditions must be collected in the home, when symptoms occur, or at regular intervals over time. A variety of HLBS disorders are highly dependent on transient variables, such as patient activity level, environment, time of day, and so on. Consequently, the National Heart Lung and Blood Institute sponsored a request for applications to support the development and commercialization of novel point-of-care technologies through small businesses (RFA-HL-14-011 and RFA-HL-14-017). Three of the supported research projects are described to highlight particular point-of-care needs for HLBS disorders and the breadth of emerging technologies. While significant obstacles remain to the commercialization of such technologies, these advancements will be required to achieve precision medicine.

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This paper reports a novel electrochemical impedance spectroscopy (EIS) biosensors that uses magnetic beads trapped in a microwell array to improve the sensitivity of conventional bead-based EIS (BEIS) biosensors. Unloading the previously measured beads by removing the magnetic bar enables the BEIS sensor to be used repeatedly by reloading it with new beads. Despite its recyclability, the sensitivity of conventional BEIS biosensors is so low that it has not attracted much attentions from the biosensor industry. We significantly improved the sensitivity of the BEIS system by introducing of a microwell array that contains two electrodes (a working electrode and a counter electrode) to concentrate the electric field on the surfaces of the beads. We confirmed that the performance of the BEIS sensor in a microwell array using an immunoassay of prostate specific antigen (PSA) in PBS buffer and human plasma. The experimental results showed that a low concentration of PSA (a few tens or hundreds of fg/mL) were detectable as a ratio of the changes in the impedance of the PBS buffer or in human plasma. Therefore, our BEIS sensor with a microwell array could be a promising platform for low cost, high-performance biosensors for applications that require high sensitivity and recyclability.

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We present a new diagnostic technique of fundamental monomeric biomaterials that do not rely on any enzyme or chemical reaction. Instead, it only uses radio frequency (RF) signal analysis. The detection and classification of basic biomaterials, such as glucose and albumin, were demonstrated. The device was designed to generate a strong resonance response with glucose solution and fabricated by simple photolithography with PDMS (Polydimethylsiloxane) well. It even was used to detect the level of glucose in mixtures of glucose and albumin and in human serum, and it operated properly and identified the glucose concentration precisely. It has a detection limit about 100µM (1.8mg/dl), and a sensitivity about 58MHz per 1mM of glucose and exhibited a good linearity in human blood glucose level. In addition, the intrinsic electrical properties of biomaterials can be investigated by a de-embedding technique and an equivalent circuit analysis. The capacitance of glucose containing samples exhibited bell-shaped Gaussian dispersion spectra around 2.4GHz. The Albumin solution did not represent a clear dispersion spectra compared to glucose, and the magnitude of resistance and inductance of albumin was higher than that of other samples. Other parameters also represented distinguishable patterns to classify those biomaterials. It leads us to expect future usage of our technique as a pattern-recognizing biosensor.

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While animal experimentations have spearheaded numerous breakthroughs in biomedicine, they also have spawned many logistical concerns in providing toxicity screening for copious new materials. Their prioritization is premised on performing cellular-level screening in vitro. Among the screening assays, secretomic assay with high sensitivity, analytical throughput, and simplicity is of prime importance. Here, we build on the over 3-decade-long progress on transistor biosensing and develop the holistic assay platform and procedure called semiconductor electronic label-free assay (SELFA). We demonstrate that SELFA, which incorporates an amplifying nanowire field-effect transistor biosensor, is able to offer superior sensitivity, similar selectivity, and shorter turnaround time compared to standard enzyme-linked immunosorbent assay (ELISA). We deploy SELFA secretomics to predict the inflammatory potential of eleven engineered nanomaterials in vitro, and validate the results with confocal microscopy in vitro and confirmatory animal experiment in vivo. This work provides a foundation for high-sensitivity label-free assay utility in predictive toxicology.

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Optoelectronic tweezers (OET) has advanced within the past decade to become a promising tool for cell and microparticle manipulation. Its incompatibility with high conductivity media and limited throughput remain two major technical challenges. Here a novel manipulation concept and corresponding platform called Self-Locking Optoelectronic Tweezers (SLOT) are proposed and demonstrated to tackle these challenges concurrently. The SLOT platform comprises a periodic array of optically tunable phototransistor traps above which randomly dispersed single cells and microparticles are self-aligned to and retained without light illumination. Light beam illumination on a phototransistor turns off the trap and releases the trapped cell, which is then transported downstream via a background flow. The cell trapping and releasing functions in SLOT are decoupled, which is a unique feature that enables SLOT's stepper-mode function to overcome the small field-of-view issue that all prior OET technologies encountered in manipulation with single-cell resolution across a large area. Massively parallel trapping of more than 100,000 microparticles has been demonstrated in high conductivity media. Even larger scale trapping and manipulation can be achieved by linearly scaling up the number of phototransistors and device area. Cells after manipulation on the SLOT platform maintain high cell viability and normal multi-day divisibility.

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We have demonstrated, for the first time, a novel three-dimensional (3D) memory chip architecture of stacked-memory-devices-on-logic (SMOL) achieving up to 95% of cell-area efficiency by directly building up memory devices on top of front-end CMOS devices. In order to realize the SMOL, a unique 3D Flash memory device and vertical integration structure have been successfully developed. The SMOL architecture has great potential to achieve tera-bit level memory density by stacking memory devices vertically and maximizing cell-area efficiency. Furthermore, various emerging devices could replace the 3D memory device to develop new 3D chip architectures.

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In this paper, we propose a serial dilution microfluidic chip which is able to generate logarithmic or linear step-wise concentrations. These concentrations were generated via adjustments in the flow rate of two converging fluids at the channel junctions of the ladder network. The desired dilution ratios are almost independent of the flow rate or diffusion length of molecules, as the dilution device is influenced only by the ratio of volumetric flow rates. Given a set of necessary dilution ratios, whether linear or logarithmic, a serial dilution chip can be constructed via the modification of a microfluidic resistance network. The design principle was suggested and both the logarithmic and linear dilution chips were fabricated in order to verify their performance in accordance with the fluorescence intensity. The diluted concentrations of a fluorescein solution in the microfluidic device evidenced relatively high linearity, and the cytotoxicity test of MCF-7 breast cancer cells via the logarithmic dilution chip was generally consistent with the results generated with manual dilution.

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This paper reports the pre-concentration of C-reactive protein (CRP) antigen with packed beads in a microfluidic chamber to enhance the sensitivity of the miniaturized fluorescence detection system for portable point-of-care testing devices. Although integrated optical systems in microfluidic chips have been demonstrated by many groups to replace bulky optical systems, the problem of low sensitivity is a hurdle for on-site clinical applications. Hence we integrated the pre-concentration module with miniaturized detection in microfluidic chips (MDMC) to improve analytical sensitivity. Cheap silicon-based photodiodes with optical filter were packaged in PDMS microfluidic chips and beads were packed by a frit structure for pre-concentration. The beads were coated with CRP antibodies to capture antigens and the concentrated antigens were eluted by an acid buffer. The pre-concentration amplified the fluorescence intensity by about 20-fold and the fluorescence signal was linearly proportional to the concentration of antigens. Then the CRP antigen was analyzed by competitive immunoassay with an MDMC. The experimental result demonstrated that the analytical sensitivity was enhanced up to 1.4 nM owing to the higher signal-to-noise ratio. The amplification of fluorescence by pre-concentration of bead-based immunoassay is expected to be one of the methods for portable fluorescence detection system.

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This paper reports a miniaturized fluorescence detection chip for capillary electrophoresis immunoassay of atrazine, which effectively reduces the size of fluorescence detection system. The photodiode with fluorescence filter was embedded in PDMS (polydimethylsiloxane) microfluidic chip and was placed just below the microfluidic channel. This detection chip is only few mm thick without loss of fluorescence due to the proximity of photodiode and channel. To investigate the feasibility of in situ detection of agricultural herbicide, atrazine was detected using capillary electrophoresis immunoassay in microfluidic chip. Mixture of 570 nM fluorescence-labeled atrazine (Ag*) and 700 nM anti-atrazine antibody (Ab) was injected and separated in 25 mm long microfluidic channel. The separated peaks of Ab-Ag* immunocomplex and Ag* were detected by the miniaturized detector and the change of peak magnitude was also observed with the variation of Ab concentration. The result was verified with those of external PMT (photomultiplier tube) and commercial capillary electrophoresis system. Hence, we have demonstrated the feasibility of portable CE immunoassay of atrazine with on-chip fluorescence detector.