Automotive 2.1 µm Full-Depth Deep Trench Isolation CMOS Image Sensor with a 120 dB Single-Exposure Dynamic Range.

An automotive 2.1 µm CMOS image sensor has been developed with a full-depth deep trench isolation and an advanced readout circuit technology. To achieve a high dynamic range, we employ a sub-pixel structure featuring a high conversion gain of a large photodiode and a lateral overflow of a small photodiode connected to an in-pixel storage capacitor. With the sensitivity ratio of 10, the expanded dynamic range could reach 120 dB at 85 °C by realizing a low random noise of 0.83 e- and a high overflow capacity of 210 ke-. An over 25 dB signal-to-noise ratio is achieved during HDR image synthesis by increasing the full-well capacity of the small photodiode up to 10,000 e- and suppressing the floating diffusion leakage current at 105 °C.

Public interest in the digital transformation accelerated by the COVID-19 pandemic and perception of its future impact.

BACKGROUND/AIMS: The coronavirus disease 2019 (COVID-19) pandemic has accelerated digital transformation (DT). We investigated the trend of the public interest in technologies regarding the DT and Koreans' experiences and their perceptions of the future impact of these technologies. METHODS: Using Google Trends, the relative search volume (RSV) for topics including "coronavirus," "artificial intelligence," "cloud," "big data," and "metaverse" were retrieved for the period from January 2020 to January 2022. A survey was conducted to assess the population's knowledge, experience, and perceptions regarding the DT. RESULTS: The RSV for "metaverse" showed an increasing trend, in contrast to those for "cloud," "big data," and "coronavirus." The RSVs for DT-related keywords had a negative correlation with the number of new weekly COVID-19 cases. In our survey, 78.1% responded that the positive impact of the DT on future lives would outweigh the negative impact. The predictors for this positive perception included experiences with the metaverse (4.0-fold) and virtual reality (VR)/augmented reality (AR) education (3.8-fold). Respondents predicted that the biggest change would occur in the healthcare sector after transportation/ communication. CONCLUSION: Koreans' search interest for "metaverse" showed an increasing trend during the COVID-19 pandemic. Koreans believe that DT will bring about big changes in the healthcare sector. Most of the survey respondents have a positive outlook about the impact of DT on future life, and the predictors for this positive perception include the experiences with the metaverse or VR/AR education. Healthcare professionals need to accelerate the adoption of DT in clinical practice, education and training.

Single-Layered Microfluidic Network-Based Combinatorial Dilution for Standard Simplex Lattice Design.

In this paper, we presented a straightforward strategy to generate 15 combinations of three samples based on an experimental simplex lattice design using a single-layer microfluidic network. First, we investigated the performances of the plain structural and the groove structural combinatorial devices by computational simulation (CFD-ACE+). The simulated output concentrations were extremely close to the desirable values within an absolute error of less than 1%. Based on the simulated designs, polydimethylsiloxane (PDMS) devices were fabricated with soft lithography and tested with fluorescent dye (sodium salt). The mixing results for 15 combinations showed good performance, with an absolute error of less than 4%. We also investigated two liquid handling methods (bottom⁻up and top⁻down) for high-throughput screening and assay. The liquid-handling methods were successfully accomplished by adding the systematic structured groove sets on the mixing channels.

Boronate-functionalized hydrogel as a novel biosensing interface for the glycated hemoglobin A1c (HbA1c) based on the competitive binding with signaling glycoprotein.

According to recent increases in public healthcare costs associated with diabetes mellitus, the development of new glycemic monitoring techniques based on the biosensing of glycated hemoglobin A1c (HbA1c), a promising long-term glycemic biomarker, has become a major challenge. In the development of HbA1c biosensors for point-of-care applications, the selection of an effective biorecognition layer that provides a high reaction yield and specificity toward HbA1c is regarded as the most significant issue. To address this, we developed a novel HbA1c biosensing interfacial material by the integration of boronate hydrogel with glass fiber membrane. In the present study, a new boronate-functionalized hydrogel was designed and spatio-selectively photopolymerized on a hydrophilic glass fiber membrane by using N-hydroxyethyl acrylamide, 3-(acrylamido)phenylboronic acid, and bis(N,N'-methylene-bis-acrylamide). Using this approach, the boronic acid group, which specifically recognizes the cis-diol residue of glucose on the HbA1c molecule, can be three-dimensionally coated on the surface of the glass fiber network with a high density. Because this network structure of boronate hydrogel-grafted fibers enables capillary-driven fluid control, facile HbA1c biosensing in a lateral flow assay concept could be accomplished. On the proposed HbA1c biosensing interface, various concentrations of HbA1c (5-15%) in blood-originated samples were sensitively measured by a colorimetric assay using horseradish peroxidase, a glycoenzyme can generate chromogenic signal after the competitive binding against HbA1c to the boronic acid residues. Based on the demonstrated advantages of boronate hydrogel-modified membrane including high analytical performance, easy operation, and cost-effectiveness, we expect that the proposed biorecognition interfacial material can be applied not only to point-of-care HbA1c biosensors, but also to the quantitative analysis of other glycoprotein biomarkers.

Simultaneous detection of duplex DNA oligonucleotides using a SERS-based micro-network gradient chip.

We report the development of a programmable surface-enhanced Raman scattering (SERS)-based micro-network gradient platform to simultaneously detect two different types of DNA oligomer mixtures. The utility of this platform was demonstrated by quantitative analysis of two breast cancer-related (BRCA1) DNA oligomer mixtures. To generate on-demand concentration gradients, the microfluidic circuit was designed using an electric-hydraulic analogy. Then a multi-gradient microfluidic channel was fabricated based on the theoretical design of the concentration control module. These micro-network structures automatically produce a series of different concentration gradients by continuously mixing Cy3-labeled DNA oligomers (BRAC1-Mutation) with TAMRA-labeled DNA oligomer (BRAC1-Wild). The SERS signals for different ratios of duplex DNA oligomer mixtures, adsorbed on the surface of silver nanoparticles, were measured under flowing conditions. Total analysis time from serial mixing to SERS detection takes less than 10 min because all experimental conditions are automatically controlled inside the exquisitely designed microfluidic channel. This novel SERS-based DNA sensing technology in a micro-network gradient channel is expected to be a powerful analytical tool to simultaneously detect multiple DNA oligomer mixtures.

SERS-based immunoassay using a gold array-embedded gradient microfluidic chip.

Here we report the development of a programmable and fully automatic gold array-embedded gradient microfluidic chip that integrates a gradient microfluidic device with gold-patterned microarray wells. This device provides a convenient and reproducible surface-enhanced Raman scattering (SERS)-based immunoassay platform for cancer biomarkers. We used hollow gold nanospheres (HGNs) as SERS agents because of their highly sensitive and reproducible characteristics. The utility of this platform was demonstrated by the quantitative immunoassay of alpha-fetoprotein (AFP) model protein marker. Our proposed SERS-based immunoassay platform has many advantages over other previously reported SERS immunoassay methods. The tedious manual dilution process of repetitive pipetting and inaccurate dilution is eliminated with this process because various concentrations of biomarker are automatically generated by microfluidic gradient generators with N cascade-mixing stages. The total assay time from serial dilution to SERS detection takes less than 60 min because all of the experimental conditions for the formation and detection of immunocomplexes can be automatically controlled inside the exquisitely designed microfluidic channel. Thus, this novel SERS-based microfluidic assay technique is expected to be a powerful clinical tool for fast and sensitive cancer marker detection.

Gravity-oriented microfluidic device for uniform and massive cell spheroid formation.

We propose a simple method for forming massive and uniform three-dimensional (3-D) cell spheroids in a multi-level structured microfluidic device by gravitational force. The concept of orienting the device vertically has allowed spheroid formation, long-term perfusion, and retrieval of the cultured spheroids by user-friendly standard pipetting. We have successfully formed, perfused, and retrieved uniform, size-controllable, well-conditioned spheroids of human embryonic kidney 293 cells (HEK 293) in the gravity-oriented microfluidic device. We expect the proposed method will be a useful tool to study in-vitro 3-D cell models for the proliferation, differentiation, and metabolism of embryoid bodies or tumours.

Droplet-based microfluidic device for multiple-droplet clustering.

We present a multiple-droplet clustering device that can perform sequential droplet trapping and storing. Shape-dependent droplet manipulation in forward and backward flows has been incorporated to achieve high trapping and storing efficiency in a 10 × 12 array of clustering structures (e.g., storing well, storing chamber, trapping well, and guiding track). In the forward flow, flattened droplets are trapped in each trapping well. In the backward flow, the trapped droplets are released from the trapping well and follow the guiding tracks to their corresponding storing wells. The guided droplets float up out of the confining channel to the super stratum of the storing chamber due to interfacial energy and buoyancy effects. This forward/backward flow-based trapping/storing process can be repeated several times to cluster droplets with different contents and samples in the storing chambers. We expect that the proposed platform will be a valuable tool to study complex droplet-based reactions in clustered droplets.

Design of pressure-driven microfluidic networks using electric circuit analogy.

This article reviews the application of electric circuit methods for the analysis of pressure-driven microfluidic networks with an emphasis on concentration- and flow-dependent systems. The application of circuit methods to microfluidics is based on the analogous behaviour of hydraulic and electric circuits with correlations of pressure to voltage, volumetric flow rate to current, and hydraulic to electric resistance. Circuit analysis enables rapid predictions of pressure-driven laminar flow in microchannels and is very useful for designing complex microfluidic networks in advance of fabrication. This article provides a comprehensive overview of the physics of pressure-driven laminar flow, the formal analogy between electric and hydraulic circuits, applications of circuit theory to microfluidic network-based devices, recent development and applications of concentration- and flow-dependent microfluidic networks, and promising future applications. The lab-on-a-chip (LOC) and microfluidics community will gain insightful ideas and practical design strategies for developing unique microfluidic network-based devices to address a broad range of biological, chemical, pharmaceutical, and other scientific and technical challenges.

Guiding, distribution, and storage of trains of shape-dependent droplets.

We present a simple method of guiding, distributing, and storing of a train of shape-dependent droplets by using side flows, cavity guiding tracks, and storage chambers. The squeezing flow makes a train of flattened droplets to align to one side of the wall and the pushing flow guides it to one of the designated guiding tracks. Then the guided droplets move along the guiding track due to the lowered surface energy when they flow along the track. In addition, simultaneous droplet guiding and storing process has been demonstrated. An array of storage chambers placed in each track could store each train containing differently concentrated droplets. The proposed method will be useful for distribution of droplets for further processes or storing for multiplex, large-scale, dynamic assays over time.

Parallel synchronization of two trains of droplets using a railroad-like channel network.

We present a simple method of water-in-oil droplet synchronization in a railroad-like channel network. The network consisted of a top channel, a bottom channel, and ladder-like channels interconnected between the two main channels. The presence of the pressure difference between the top and bottom channels resulted in the crossflow of carrier oil through the ladder network until the pressure in each channel was balanced automatically. The proposed model and method proved the feasibility of the parallel synchronization of two trains of droplets with up to 95% synchronization efficiency. Physical parameters that could improve the efficiency were investigated with the systematic variation of the droplet length and droplet generation frequency by controlling the flow rate in each channel. Under a subtle difference in the generation frequency, an unmatched droplet sandwiched between two matched droplets in the ladder network was switched and synchronized in turn. For perfect one-to-one droplet synchronization, the droplet length and the droplet generation frequency needed to be the same for both the top and bottom channels. In addition, one-to-multiple droplet synchronization was demonstrated by matching the product of the droplet length and the droplet generation frequency for both the top and bottom channels. The proposed method provides a simple unit operation for parallel synchronization of the trains of droplets that can be easily integrated with the conventional continuous-flow droplet-based microfluidic platform.

On-demand electrostatic droplet charging and sorting.

This study reports a droplet-based microfluidic device for on-demand electrostatic droplet charging and sorting. This device combines two independent modules: one is a hydrodynamic flow focusing structure to generate water-in-oil droplets, and the other is the two paired-electrodes for charging and sorting of the droplets. Depending on the polarity on charging electrodes, water-in-oil droplets can be electrostatically charged positively or negatively, followed by automatic real-time electric sorting. This approach will be useful when preformed droplets, with a positive, a negative, or with no charge, need to be manipulated for further on-chip droplet manipulation.

2-layer based microfluidic concentration generator by hybrid serial and volumetric dilutions.

We present a 2-layer based microfluidic concentration generator by a hybrid of a serial and a volumetric dilution for dose-response experiments in drug screening. The hybrid dilution method using 2-layer based microfluidic network significantly reduces the total number of cascaded serial dilution stages. The proposed strategy is capable of generating a large number of universal stepwise monotonic concentrations with a wide range of logarithmic and linear scales. We have studied an equivalent electrical circuit to that of the 2-layer based microfluidic network, where the only variable parameter is channel length. We have designed a microfluidic dilution generator simultaneously covering 14 doses with a combination of 4-order logarithmic and 4-point linear concentrations. The design has been verified by a commercial circuit analysis software (e.g., P-Spice) for the electrical circuit analysis and a computational fluid dynamics software (e.g., CFD-ACE+) for the microfluidic circuit analysis. As a real-life application of the proposed dilution generator, we have successfully performed a dose-response experiment using MCF-7 human breast cancer cells. We expect that the proposed dilution method will be useful to study not only high throughput drug screening but also optimization in biology, chemistry, medicine, and material sciences.

Generalized serial dilution module for monotonic and arbitrary microfluidic gradient generators.

In this paper, we propose a generalized serial dilution module for universal microfluidic concentration gradient generators including N cascaded-mixing stages in a stepwise manner. Desired concentrations were generated by means of controlled volumetric mixing ratios of two merging solutions in each stage. The flow rates were adjusted by controlling channel length, which is proportional to fluidic resistance in each channel. A generalized mathematical model for generating any complex concentration and output flow rate gradients is presented based on the fact that there is an analogy between microfluidic circuits and electrical circuits. The pressure drop corresponds to a voltage drop, the flow rate to an electrical current, and the flow resistance to an electrical resistance. A simple equivalent electrical circuit model was generalized, and in the model each channel segment was represented by an electrical resistance. As a result of the mathematical modelling, the only variable parameter in the generalized serial dilution module was the channel length. By the use of the generalized serial dilution module with N = 4, three types of microfluidic gradient generators for linear, logarithmic and Gaussian gradients were successfully designed and tested. The proposed strategy is capable of generating universal monotonic gradients with a single module or arbitrary gradients with multiple modules ranging from linear to complex non-linear shapes of concentration gradients as well as arbitrary output flow rate gradients in a stepwise manner. The simple universal gradient generation technology using the generalized serial dilution module will find widespread use in the greater chemical and biological community, and address many challenges of gradient-dependent phenomena.

Concurrent droplet charging and sorting by electrostatic actuation.

This paper presents a droplet-based microfluidic device for concurrent droplet charging and sorting by electrostatic actuation. Water-in-oil droplets can be charged on generation by synchronized electrostatic actuation. Then, simultaneously, the precharged droplets can be electrostatically steered into any designated laminar streamline, thus they can be sorted into one of multiple sorting channels one by one in a controlled fashion. In this paper, we studied the size dependence of the water droplets under various relative flow rates of water and oil. We demonstrated the concurrent charging and sorting of up to 600 dropletss by synchronized electrostatic actuation. Finally, we investigated optimized voltages for stable droplet charging and sorting. This is an essential enabling technology for fast, robust, and multiplexed sorting of microdroplets, and for the droplet-based microfluidic systems.

A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations.

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.

Multi-well chip for forming a uniform embryoid body in a tiny droplet with mouse embryonic stem cells.

A multi-well chip (MWC) is described by which mouse embryonic carcinoma (EC) stem cells form a comparatively more rapid and uniform embryoid body (EB) over the conventional hanging drop (HD) method. The newly developed MWC consists of an array of extruded through-holes, each of which holds a droplet of the cell suspension. The study found that the small curvature radius of the droplet in the MWC improved the EB formation rate of a hanging drop from 70% to 98%. Furthermore, the EBs formed by the MWC were uniformly round in shape regardless of the number of suspended cells ranging from 0.5 x 10(3) to 20 x 10(3). The ratio of beating colonies from the MWC was over 2-fold larger than that from HD. The experiments demonstrate that the MWC will be a valuable experimental tool for robust and reproducible EB-based differentiation of a defined number of ES cells.

Novel platform for minimizing cell loss on separation process: Droplet-based magnetically activated cell separator.

To reduce the problem of cell loss due to adhesion, one of the basic phenomena in microchannel, we proposed the droplet-based magnetically activated cell separator (DMACS). Based on the platform of the DMACS-which consists of permanent magnets, a coverslip with a circle-shaped boundary, and an injection tube-we could collect magnetically (CD45)-labeled (positive) cells with high purity and minimize cell loss due to adhesion. To compare separation efficiency between the MACS and the DMACS, the total number of cells before and after separation with both the separators was counted by flow cytometry. We could find that the number (3241/59 940) of cells lost in the DMACS is much less than that (22 360/59 940) in the MACS while the efficiency of cell separation in the DMACS (96.07%) is almost the same as that in the MACS (96.72%). Practically, with fluorescent images, it was visually confirmed that the statistical data are reliable. From the viability test by using Hoechst 33 342, it was also demonstrated that there was no cell damage on a gas-liquid interface. Conclusively, DMACS will be a powerful tool to separate rare cells and applicable as a separator, key component of lab-on-a-chip.

MobileNurse: hand-held information system for point of nursing care.

Healthcare information travels with patients and clinicians and therefore the need for information to be ubiquitously available is key to reliable patient care and reliable medical systems. We have implemented MobileNurse, a prototype point-of-care system using PDA. MobileNurse has four modules each of which performs: (1) patient information management; (2) medical order check; (3) nursing recording; and (4) nursing care plan. MobileNurse provides easy input interface and various outputs for nursing records. The system consists of PDAs and a mobile support system (MSS) which supports clinical data exchange between PDAs and hospital information system. Two synchronization modules have been developed to keep the patient data consistent between PDAs and MSS. Clinical trials were performed with six volunteered nurses. They tried MobileNurse for 1-day caring-simulated patients. According to the survey after the trials, most of volunteers agreed that MobileNurse is more helpful and convenient than other non-mobile care systems to check medical orders and retrieve the results of recent clinical tests at the bedside. Through the involvement, we found out that ease-to-use interface is the most critical successful factor for mobile patient care systems.

The knowledge modeling for chronic urticaria assessment in clinical decision support system with PDA.

The benefits of a clinical information system would be enhanced by a clinical decision support system (CDSS). We have developed urticaria diagnosis knowledge model for clinical practice. In order to construct a more accurate, evidenced-based and comprehensive knowledge base for urticaria, we arranged and integrated knowledge from literatures-based knowledge, as provided by; The Korean Academy of Asthma and Allergy [1], the American Allergy Association based on an algorithm of chronic urticaria assessment. We presented this knowledge in a Boolean cross table frame and implemented these guidelines using the developed CDSS.