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In situ monitoring of bacterial growth can greatly benefit human healthcare, biomedical research, and hygiene management. Magnetic resonance imaging (MRI) offers two key advantages in tracking bacterial growth: non-invasive monitoring through opaque sample containers and no need for sample pretreatment such as labeling. However, the large size and high cost of conventional MRI systems are the roadblocks for in situ monitoring. Here, we proposed a small, portable MRI system by combining a small permanent magnet and an integrated radio-frequency (RF) electronic chip that excites and reads out nuclear spin motions in a sample, and utilize this small MRI platform for in situ imaging of bacterial growth and biofilm formation. We demonstrate that MRI images taken by the miniature--and thus broadly deployable for in situ work--MRI system provide information on the spatial distribution of bacterial density, and a sequential set of MRI images taken at different times inform the temporal change of the spatial map of bacterial density, showing bacterial growth.

The worldwide COVID-19 pandemic has changed people's lives and the diagnostic landscape. The nucleic acid amplification test (NAT) as the gold standard for SARS-CoV-2 detection has been applied in containing its transmission. However, there remains a lack of an affordable on-site detection system at resource-limited areas. In this study, a low cost "sample-in-answer-out" system incorporating nucleic acid extraction, purification, and amplification was developed on a single macrochannel-to-digital microfluidic chip. The macrochannel fluidic subsystem worked as a world-to-chip interface receiving 500-1000 μL raw samples, which then underwent bead-based extraction and purification processes before being delivered to DMF. Electrodes actuate an eluent dispensed to eight independent droplets for reverse transcription quantitative polymerase chain reaction (RT-qPCR). By reading with 4 florescence channels, the system can accommodate a maximum of 32 detection targets. To evaluate the proposed platform, a comprehensive assessment was conducted on the microfluidic chip as well as its functional components ( i.e. , extraction and amplification). The platform demonstrated a superior performance. In particular, using clinical specimens, the chip targeting SARS-CoV-2 and Flu A/B exhibited 100% agreement with off-chip diagnoses. Furthermore, the fabrication of chips is ready for scaled-up manufacturing and they are cost-effective for disposable use since they are assembled using a printed circuit board (PCB) and prefabricated blocks. Overall, the macrochannel-to-digital microfluidic platform coincides with the requirements of point-of-care testing (POCT) because of its advantages: low-cost, ease of use, comparable sensitivity and specificity, and availability for mass production.

Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm 2 chip in a device measuring 23 × 16 × 3.5 cm 3 . We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease., (© 2024. The Author(s).)

This paper presents a data-compressive neural recording IC for single-cell resolution high-bandwidth brain-computer interfaces. The IC features wired-OR lossy compression during digitization, thus preventing data deluge and massive data movement. By discarding unwanted baseline samples of the neural signals, the output data rate is reduced by 146× on average while allowing the reconstruction of spike samples. The recording array consists of pulse position modulation-based active digital pixels with a global single-slope analog-to-digital conversion scheme, which enables a low-power and compact pixel design with significantly simple routing and low array readout energy. Fabricated in a 28-nm CMOS process, the neural recording IC features 1024 channels (i.e., 32 × 32 array) with a pixel pitch of 36 μ m that can be directly matched to a high-density microelectrode array. The pixel achieves 7.4 μ V rms input-referred noise with a -3 dB bandwidth of 300-Hz to 5-kHz while consuming only 268 nW from a single 1-V supply. The IC achieves the smallest area per channel (36 × 36 μ m 2 ) and the highest energy efficiency among the state-of-the-art neural recording ICs published to date.

The MEMS microphone is a representative device among the MEMS family, which has attracted substantial research interest, and those tailored for human voice have earned distinct success in commercialization. Although sustained development persists, challenges such as residual stress, environmental noise, and structural innovation are posed. To collect and summarize the recent advances in this subject, this paper presents a concise review concerning the transduction mechanism, diverse mechanical structure topologies, and effective methods of noise reduction for high-performance MEMS microphones with a dynamic range akin to the audible spectrum, aiming to provide a comprehensive and adequate analysis of this scope.

The development of a rapid and reliable polymerase chain reaction (PCR) method for point-of-care (POC) diagnosis is crucial for the timely identification of pathogens. Microfluidics, which involves the manipulation of small volumes of fluidic samples, has been shown to be an ideal approach for POC analysis. Among the various microfluidic platforms available, digital microfluidics (DMF) offers high degree of configurability in manipulating μL/nL-scale liquid and achieving automation. However, the successful implementation of ultrafast PCR on DMF platforms presents challenges due to inherent system instability. In this study, we developed a robust and ultrafast PCR in 3.7-5 min with a detection sensitivity comparable to conventional PCR. Specifically, the implementation of the pincer heating scheme homogenises the temperature within a drop. The utilization of a μm-scale porous hydrophobic membrane suppresses the formation of bubbles under high temperatures. The design of a groove around the high-temperature zone effectively mitigates the temperature interference. The integration of a soluble sensor into the droplets provides an accurate and instant in-drop temperature sensing. We envision that the fast, robust, sensitive, and automatic DMF system will empower the POC testing for infectious diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yanwei Jia, Liang Wan, Mingzhong Li, Man-key Law, Pui-In Mak, Rui Martins have patent A DMF chip, a rapid PCR system and a PCR method pending to University of Macau., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Real-time pH control on-chip is a crucial factor for cell-based experiments in microfluidics, yet difficult to realize. In this paper, we present a flexible pH regulator on a digital microfluidic (DMF) platform. The pico-dosing technology, which can generate and transfer satellite droplets, is presented to deliver alkali/acid into the sample solution to change the pH value of the sample. An image analysis method based on ImageJ is developed to calculate the delivered volume and an on-chip colorimetric method is proposed to determine the pH value of the sample solution containing the acid-base indicator. The calculated pH values show consistency with the measured ones. Our approach makes the real-time pH control of the on-chip biological experiment more easy to control and flexible.

This paper proposes a 2.4-GHz fully-integrated single-frequency multi-channel RF energy harvesting (RFEH) system with increased harvested power density. The RFEH can produce an output power of ~423-μW in harvesting ambient RF energy. The front-end consists of an on-chip impedance matching network with a stacked rectifier concurrently matched to a 50 Ω input source. The circuit mitigates the "dead-zone" by enhancing the pumping efficiency, achieved through the increase of V gs drivability of the proposed internal gate boosting 6-stage low-input voltage charge pump and the 5-stage shared-auxiliary-biasing ring-voltage-controlled-oscillator (VCO) integrated to improve the start-up. The RFEH system, simulated in 180-nm complementary metal-oxide-semiconductor (CMOS), occupies an active area of 1.02 mm 2 . Post-layout simulations show a peak power conversion efficiency(PCE) of 21.15%, driving a 3.3-kΩ load at an input power of 0 dBm and sensitivity of -14.1 dBm corresponding to an output voltage, V out,RFEH of 1.25 V.

Single-nucleotide polymorphism (SNP) plays a critical role in personalized medicine, forensics, pharmacogenetics, and disease diagnostics. Among different existing SNP genotyping techniques, melting curve analysis (MCA) becomes increasingly popular due to its high accuracy and straightforward procedures in extracting the melting temperature ( T m ). Yet, its study on existing digital microfluidic (DMF) platforms has intrinsic limitations due to the temperature inhomogeneity within a thickened droplet during the on-chip rapid heating process. Although the utilization of an on-chip thermostat can regulate and monitor the dynamic melting process in real time, the limited T m accuracy resulting from the insufficient system response time to accommodate the fast-melting evolution still poses a great challenge for precise MCA with high throughput. This work proposes a one-shot MCA on a DMF platform. The tailoring of a functional substrate with hierarchical micro/nano structure enables high-resolution patterning of pL-scale droplets. Specifically, the hydrothermal and photocatalysis treatment allows the functional substrate to exhibit a superwettability contrast of >170°, facilitating passive isolation of the pL-scale DNA sample into highly-resolved pL droplets above the 200 μm superhydrophilic patterns. This high-resolution MCA technique can successfully discriminate KRAS gene targets with single-nucleotide mutations in 3 seconds. The high accuracy and consistency in the acquired T m when compared with off-chip results demonstrate its opportunities for near-patient diagnostics, precision medicines, genetic counseling, and prevention strategies on DMF platforms.

Microfluidics has been the most promising platform for drug screening with a limited number of cells. However, convenient on-chip preparation of a wide range of drug concentrations remains a large challenge and has restricted wide acceptance of microfluidics in precision medicine. In this paper, we report a digital microfluidic system with an innovative control structure and chip design for on-chip drug dispensing to generate concentrations that span three to four orders of magnitude, enabling single drug or combinatorial multi-drug screening with simple electronic control. Specifically, we utilize droplet ejection from a drug drop sitting on a special electrode, named a drug dispenser, under high-voltage pulse actuation to deliver the desired amount of drugs to be picked up by a cell suspension drop driven by low-voltage sine wave actuation. Our proof-of-principle validation for this technique as a convenient single and multi-drug screening involved testing of the drug toxicity of two chemotherapeutics, cisplatin (Cis) and epirubicin (EP), towards MDA-MB-231 breast cancer cells and MCF-10A normal breast cells. The results are consistent with those screened based on traditional 96-well plates. These findings demonstrate the reliability of the drug screening system with an on-chip drug dispenser. This system with fewer cancer cells, less drug consumption, a small footprint, and high scalability with regard to concentration could pave the way for drug screening on biopsied primary tumor cells for precision medicine or any concentration-related research.

Evaluation of the cell health status is critical for drug screening and cell physiological activity investigations. The existing cell health assessment methods are solely devoted to the study of cell vitality or viability, leading to an incomplete evaluation. Herein, we report a convenient and robust method for the joint assessment of cell viability and vitality based on electric cell-substrate impedance sensing (ECIS) supplied with an environmental temperature control. The static value of electric cell-substrate impedance reflects the survival rate of cells, while the temperature tolerance of cells demonstrates the cell vitality. It was found that the cell vitality evaluated by the temperature tolerance of cells was independent of the initial cell numbers, rendering the proposed method easy to utilize in various applications. We compared the temperature tolerance ECIS method with the traditional trypan blue staining method, the methyl thiazolyl tetrazolium assay, and the direct impedance sensing method for joint evaluation of cell viability and vitality in drug screening. The temperature tolerance ECIS method showed comparable results but with a simpler protocol, faster results, and less dependence on the sample conditions. By providing both information on cell viability and cell vitality, the proposed temperature tolerance ECIS method would pave the way in building a simple and robust sensing system for cell health evaluation.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a zoonotic pathogen, has led to the outbreak of coronavirus disease 2019 (COVID-19) pandemic and brought serious threats to public health worldwide. The gold standard method for SARS-CoV-2 detection requires both reverse transcription (RT) of the virus RNA to cDNA and then polymerase chain reaction (PCR) for the cDNA amplification, which involves multiple enzymes, multiple reactions and a complicated assay optimization process. Here, we developed a duplex-specific nuclease (DSN)-based signal amplification method for SARS-CoV-2 detection directly from the virus RNA utilizing two specific DNA probes. These specific DNA probes can hybridize to the target RNA at different locations in the nucleocapsid protein gene (N gene) of SARS-CoV-2 to form a DNA/RNA heteroduplex. DSN cleaves the DNA probe to release fluorescence, while leaving the RNA strand intact to be bound to another available probe molecule for further cleavage and fluorescent signal amplification. The optimized DSN amount, incubation temperature and incubation time were investigated in this work. Proof-of-principle SARS-CoV-2 detection was demonstrated with a detection sensitivity of 500 pM virus RNA. This simple, rapid, and direct RNA detection method is expected to provide a complementary method for the detection of viruses mutated at the PCR primer-binding regions for a more precise detection.

Digital microfluidics has the potential to minimize and automate reactions in biochemical labs. However, the complexity of drop manipulation and sample preparation on-chip has limited its incorporation into daily workflow. In this paper, we report a novel method for flexible sample delivery on digital microfluidics in a wide volume range spanning four orders of magnitude from picoliters to nanoliters. The method is based on the phenomenon of satellite droplet ejection, triggered by a sudden change in the strength of the electric field across a drop on a hydrophobic dielectric surface. By precisely modulating the actuation signal with convenient external electric controls, satellite droplet ejection can be turned on to dispense samples or turned off to transport picking-up drops. A pico-dosing design is presented and validated in this work to demonstrate the direct and flexible on-chip sample delivery. This approach could pave the way for the acceptance of microfluidics as a common platform for daily reactions to realize lab-on-a-chip.

Due to cell heterogeneity, the differences among individual cells are averaged out in bulk analysis methods, especially in the analysis of primary tumor biopsy samples from patients. To deeply understand the cell-to-cell variation in a primary tumor, single-cell culture and analysis with limited amount of cells are in high demand. Microfluidics has been an optimum platform to address the issue given its small reaction volume requirements. Digital microfluidics, which utilizes an electric signal to manipulate individual droplets has shown promise in cell-culture with easy controls. In this work, we realize single cell trapping on digital microfluidic platform by fabricating 3D microstructures on-chip to form semi-closed micro-wells. With this design, 20% of 30 x 30 array can be occupied by isolated single cells. We also use a low evaporation silicon oil and a fluorinated surfactant to lower the droplet actuation voltage and prevent the drop from evaporation, while allowing cell respiration during the long term of culture (24 h). The main steps for single cell trapping on digital microfluidics, as illustrated in this protocol, include 3D microstructures design, 3D microstructures construction on chip and oil film with surfactant for single cell trapping on chip., Competing Interests: Competing interestsThe authors declare that they have no conflict of interest., (Copyright © 2020 The Authors; exclusive licensee Bio-protocol LLC.)

Despite its high sensitivity, low cost, and high efficiency as a DNA amplification indicator with a yes/no answer, dsDNA-binding dye encounters incompatibility when used in microfluidic systems, resulting in problems such as false negative amplification results. Besides, its inhibition of amplification at high concentrations hinders its application both on-chip and off-chip. In this study, we propose a novel DNA amplification enhancer to counteract the drawbacks of dsDNA-binding dyes. It acts as a temporary reservoir for the free-floating dyes in solution and releases them on demand during the amplification process. Through this clip-to-release on amplification mechanism, the enhancer lowered the background fluorescence of sample droplets before amplification, enhanced the signal-to-background ratio of positive samples, and eliminated the false negative signal of on-chip PCR. Moreover, the enhancer increased the off-chip polymerase chain reaction (PCR) efficiency, boosted the fluorescence signal up to 10-fold, and made less nonspecific amplification product. All the factors affecting the enhancer's performance are investigated in detail, including its structure and concentration, and the types of dsDNA-binding dye used in the reaction. Finally, we demonstrated the broad application of the proposed amplification enhancer in various DNA amplification systems, for various genes, and on various amplification platforms. It would reignite the utilization of dsDNA dyes for wider applications in DNA analysis both on-chip and off-chip.

Despite the precise controllability of droplet samples in digital microfluidic (DMF) systems, their capability in isolating single cells for long-time culture is still limited: typically, only a few cells can be captured on an electrode. Although fabricating small-sized hydrophilic micropatches on an electrode aids single-cell capture, the actuation voltage for droplet transportation has to be significantly raised, resulting in a shorter lifetime for the DMF chip and a larger risk of damaging the cells. In this work, a DMF system with 3D microstructures engineered on-chip is proposed to form semi-closed micro-wells for efficient single-cell isolation and long-time culture. Our optimum results showed that approximately 20% of the micro-wells over a 30 × 30 array were occupied by isolated single cells. In addition, low-evaporation-temperature oil and surfactant aided the system in achieving a low droplet actuation voltage of 36V, which was 4 times lower than the typical 150 V, minimizing the potential damage to the cells in the droplets and to the DMF chip. To exemplify the technological advances, drug sensitivity tests were run in our DMF system to investigate the cell response of breast cancer cells (MDA-MB-231) and breast normal cells (MCF-10A) to a widely used chemotherapeutic drug, Cisplatin (Cis). The results on-chip were consistent with those screened in conventional 96-well plates. This novel, simple and robust single-cell trapping method has great potential in biological research at the single cell level., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Portable NMR combining a permanent magnet and a complementary metal-oxide-semiconductor (CMOS) integrated circuit has recently emerged to offer the long desired online, on-demand, or in situ NMR analysis of small molecules for chemistry and biology. Here we take this cutting-edge technology to the next level by introducing parallelism to a state-of-the-art portable NMR platform to accelerate its experimental throughput, where NMR is notorious for inherently low throughput. With multiple ( N ) samples inside a single magnet, we perform simultaneous NMR analyses using a single silicon electronic chip, going beyond the traditional single-sample-per-magnet paradigm. We execute the parallel analyses via either time-interleaving or magnetic resonance imaging (MRI). In the time-interleaving method, the N samples occupy N separate NMR coils: we connect these N NMR coils to the single silicon chip one after another and repeat these sequential NMR scans. This time-interleaving is an effective parallelization, given a long recovery time of a single NMR scan. To demonstrate this time-interleaved parallelism, we use N = 2 for high-resolution multidimensional spectroscopy such as J -coupling resolved free induction decay spectroscopy and correlation spectroscopy (COSY) with the field homogeneity carefully optimized (<0.16 ppm) and N = 4 for multidimensional relaxometry such as diffusion-edited T 2 mapping and T 1 - T 2 correlation mapping, expediting the throughput by 2-4 times. In the MRI technique, the N samples ( N = 18 in our demonstration) share 1 NMR coil connected to the single silicon chip and are imaged all at once multiple times, which reveals the relaxation time of all N samples simultaneously. This imaging-based approach accelerates the relaxation time measurement by 4.5 times, and it could be by 18 times if the signal-to-noise were not limited. Overall, this work demonstrates the first portable high-resolution multidimensional NMR with throughput-accelerating parallelism.

A major goal in the development of point-of-care (POC) devices is to build them as portable to provide a rapid and effective determination for disease pathogens. In nucleic acid testing, an optical detection system used to monitor the product of nucleic acid amplification has always been a bulky accessory. In this work, we developed a handheld, automatic and detection system-free thermal digital microfluidic (DMF) device for DNA detection by loop-mediated isothermal amplification (LAMP). Droplet manipulation and real-time temperature control systems were integrated into a handheld device. The control software could be installed into any tablet and communicate with the device via Bluetooth. In the experimentation, we loaded 2-μl samples with an electrowetting force into sandwich-structured DMF chips, thereby considerably reducing reagent consumptions. After an on-chip LAMP reaction, we added a highly concentrated SYBR Green I droplet and mixed it with a reaction droplet to enable product detection with the naked eye. This step prevented aerosol contamination by avoiding the exposure of the reaction droplet to the air. Using a blood parasite Trypanosoma brucei as a model system, this system showed similar results as a commercial thermal cycler and could detect 40 copies per reaction of the DNA target. This low-cost, compact device removed the bulky optical system for DNA detection, thus enabling it to be well suited for POC testing.

A digital microfluidic (DMF) system has been developed for loop-mediated isothermal amplification (LAMP)-based pathogen nucleic acid detection using specific low melting temperature (T m ) Molecular Beacon DNA probes. A positive-temperature-coefficient heater with a temperature sensor for real-time thermal regulation was integrated into the control unit, which generated actuation signals for droplet manipulation. To enhance the specificity of the LAMP reaction, low-T m Molecular Beacon probes were designed within the single-stranded loop structures on the LAMP reaction products. In the experiments, only 1 μL of LAMP reaction samples containing purified Trypanosoma brucei DNA were required, which represented over a 10x reduction of reagent consumption when comparing with the conventional off-chip LAMP. On-chip LAMP for unknown sample detection could be accomplished in 40 min with a detection limit of 10 copies/reaction. Also, we accomplished an on-chip melting curve analysis of the Molecular Beacon probe from 30 to 75 °C within 5 min, which was 3x faster than using a commercial qPCR machine. Discrimination of non-specific amplification and lower risk of aerosol contamination for on-chip LAMP also highlight the potential utilization of this system in clinical applications. The entire platform is open for further integration with sample preparation and fluorescence detection towards a total-micro-analysis system.

Precision Medicine in Oncology requires tailoring of therapeutic strategies to individual cancer patients. Due to the limited quantity of tumor samples, this proves to be difficult, especially for early stage cancer patients whose tumors are small. In this study, we exploited a 2.4 × 2.4 centimeters polydimethylsiloxane (PDMS) based microfluidic chip which employed droplet microfluidics to conduct drug screens against suspended and adherent cancer cell lines, as well as cells dissociated from primary tumor of human patients. Single cells were dispersed in aqueous droplets and imaged within 24 hours of drug treatment to assess cell viability by ethidium homodimer 1 staining. Our results showed that 5 conditions could be screened for every 80,000 cells in one channel on our chip under current circumstances. Additionally, screening conditions have been adapted to both suspended and adherent cancer cells, giving versatility to potentially all types of cancers. Hence, this study provides a powerful tool for rapid, low-input drug screening of primary cancers within 24 hours after tumor resection from cancer patients. This paves the way for further technological advancement to cutting down sample size and increasing drug screening throughput in advent to personalized cancer therapy.

Objective: The ability to record and to control action potential firing in neuronal circuits is critical to understand how the brain functions. The objective of this study is to develop a monolithic integrated circuit (IC) to record action potentials and simultaneously control action potential firing using optogenetics., Methods: A low-noise and high input impedance (or low input capacitance) neural recording amplifier is combined with a high current laser/light-emitting diode (LED) driver in a single IC., Results: The low input capacitance of the amplifier (9.7 pF) was achieved by adding a dedicated unity gain stage optimized for high impedance metal electrodes. The input referred noise of the amplifier is [Formula: see text], which is lower than the estimated thermal noise of the metal electrode. Thus, the action potentials originating from a single neuron can be recorded with a signal-to-noise ratio of at least 6.6. The LED/laser current driver delivers a maximum current of 330 mA, which is adequate for optogenetic control. The functionality of the IC was tested with an anesthetized Mongolian gerbil and auditory stimulated action potentials were recorded from the inferior colliculus. Spontaneous firings of fifth (trigeminal) nerve fibers were also inhibited using the optogenetic protein Halorhodopsin. Moreover, a noise model of the system was derived to guide the design., Significance: A single IC to measure and control action potentials using optogenetic proteins is realized so that more complicated behavioral neuroscience research and the translational neural disorder treatments become possible in the future.

Existing digital microfluidic (DMF) chips exploit the electrowetting on dielectric (EWOD) force to perform droplet splitting. However, the current splitting methods are not flexible and the volume of the droplets suffers from a large variation. Herein, we propose a DMF chip featuring a 3D microblade structure to enhance the droplet-splitting performance. By exploiting the EWOD force for shaping and manipulating the mother droplet, we obtain an average dividing error of <2% in the volume of the daughter droplets for a number of fluids such as deionized water, DNA solutions and DNA-protein mixtures. Customized droplet splitting ratios of up to 20 : 80 are achieved by positioning the blade at the appropriate position. Additionally, by fabricating multiple 3D microblades on one electrode, two to five uniform daughter droplets can be generated simultaneously. Finally, by taking synthetic DNA targets and their corresponding molecular beacon probes as a model system, multiple potential pathogens that cause sepsis are detected rapidly on the 3D-blade-equipped DMF chip, rendering it as a promising tool for parallel diagnosis of diseases.

In this paper, an ultra-compact single-chip solar energy harvesting IC using on-chip solar cell for biomedical implant applications is presented. By employing an on-chip charge pump with parallel connected photodiodes, a 3.5 × efficiency improvement can be achieved when compared with the conventional stacked photodiode approach to boost the harvested voltage while preserving a single-chip solution. A photodiode-assisted dual startup circuit (PDSC) is also proposed to improve the area efficiency and increase the startup speed by 77%. By employing an auxiliary charge pump (AQP) using zero threshold voltage (ZVT) devices in parallel with the main charge pump, a low startup voltage of 0.25 V is obtained while minimizing the reversion loss. A 4 V in gate drive voltage is utilized to reduce the conduction loss. Systematic charge pump and solar cell area optimization is also introduced to improve the energy harvesting efficiency. The proposed system is implemented in a standard 0.18- [Formula: see text] CMOS technology and occupies an active area of 1.54 [Formula: see text]. Measurement results show that the on-chip charge pump can achieve a maximum efficiency of 67%. With an incident power of 1.22 [Formula: see text] from a halogen light source, the proposed energy harvesting IC can deliver an output power of 1.65 [Formula: see text] at 64% charge pump efficiency. The chip prototype is also verified using in-vitro experiment.

Complementary metal oxide semiconductor (CMOS) technology enables low-cost and large-scale integration of transistors and physical sensing materials on tiny chips (e.g., <1 cm 2 ), seamlessly combining the two key functions of biosensors: transducing and signal processing. Recent CMOS biosensors unified different transducing mechanisms (impedance, fluorescence, and nuclear spin) and readout electronics have demonstrated competitive sensitivity for in vitro diagnosis, such as detection of DNA (down to 10 aM), protein (down to 10 fM), or bacteria/cells (single cell). Herein, we detail the recent advances in CMOS biosensors, centering on their key principles, requisites, and applications. Together, these may contribute to the advancement of our healthcare system, which should be decentralized by broadly utilizing point-of-care diagnostic tools.

Unlabelled: Atomistic molecular dynamics simulation is a promising technique to investigate the energetics and dynamics in the protein-surface adsorption process which is of high relevance to modern biotechnological applications. To increase the chance of success in simulating the adsorption process, favorable orientations of the protein at the surface must be determined. Here, we present ProtPOS which is a lightweight and easy-to-use python package that can predict low-energy protein orientations on a surface of interest. It combines a fast conformational sampling algorithm with the energy calculation of GROMACS. The advantage of ProtPOS is it allows users to select any force fields suitable for the system at hand and provide structural output readily available for further simulation studies., Availability and Implementation: ProtPOS is freely available for academic and non-profit uses at http://cbbio.cis.umac.mo/software/protpos, Supplementary Information: Supplementary data are available at Bioinformatics online., Contact: shirleysiu@umac.mo., (© The Author 2016. Published by Oxford University Press.)

Capacitive micromachined ultrasonic transducers (CMUTs) have emerged as a competitive alternative to piezoelectric ultrasonic transducers, especially in medical ultrasound imaging and therapeutic ultrasound applications, which require high output pressure. However, as compared with piezoelectric ultrasonic transducers, the output pressure capability of CMUTs remains to be improved. In this paper, a novel structure is proposed by forming an embossed vibrating membrane on a CMUT cell operating in the collapse mode to increase the maximum output pressure. By using a beam model in undamped conditions and finite-element analysis simulations, the proposed embossed structure showed improvement on the maximum output pressure of the CMUT cell when the embossed pattern was placed on the estimated location of the peak deflection. As compared with a uniform membrane CMUT cell worked in the collapse mode, the proposed CMUT cell can yield the maximum output pressure by 51.1% and 88.1% enhancement with a single embossed pattern made of Si3N4 and nickel, respectively. The maximum output pressures were improved by 34.9% (a single Si3N4 embossed pattern) and 46.7% (a single nickel embossed pattern) with the uniform membrane when the center frequencies of both original and embossed CMUT designs were similar.

We developed a thermal digital microfluidic (T-DMF) device enabling ultrafast DNA melting curve analysis (MCA). Within 7 seconds, the T-DMF device succeeded in differentiating a melting point difference down to 1.6 °C with a variation of 0.3 °C in a tiny droplet sample (1.2 μL), which was 300 times faster and with 20 times less sample spending than the standard MCA (35 minutes, 25 μL) run in a commercial qPCR machine. Such a performance makes it possible for a rapid discrimination of single-nucleotide mutation relevant to prompt clinical decision-making. Also, aided by electronic intelligent control, the T-DMF device facilitates sample handling and pipelining in an automatic serial manner. An optimized oval-shaped thermal electrode is introduced to achieve high thermal uniformity. A device-sealing technique averts sample contamination and permits uninterrupted chemical/biological reactions. Simple fabrication using a single chromium layer fulfills both the thermal and typical transport electrode requirements. Capable of thermally modulating DNA samples with ultrafast MCA, this T-DMF device has the potential for a wide variety of life science analyses, especially for disease diagnosis and prognosis.

Herein, we describe a micro-nuclear magnetic resonance (μNMR) relaxometer miniaturized to palm-size and electronically automated for multi-step and multi-sample chemical/biological diagnosis. The co-integration of microfluidic and microelectronic technologies enables an association between the droplet managements and μNMR assays inside a portable sub-Tesla magnet (1.2 kg, 0.46 Tesla). Targets in unprocessed biological samples, captured by specific probe-decorated magnetic nanoparticles (NPs), can be sequentially quantified by their spin-spin relaxation time (T2) via multiplexed μNMR screening. Distinct droplet samples are operated by a digital microfluidic device that electronically manages the electrowetting-on-dielectric effects over an electrode array. Each electrode (3.5 × 3.5 mm(2)) is scanned with capacitive sensing to locate the distinct droplet samples in real time. A cross-domain-optimized butterfly-coil-input semiconductor transceiver transduces between magnetic and electrical signals to/from a sub-10 μL droplet sample for high-sensitivity μNMR screening. A temperature logger senses the ambient temperature (0 to 40 °C) and a backend processor calibrates the working frequency for the transmitter to precisely excite the protons. In our experiments, the μNMR relaxometer quantifies avidin using biotinylated Iron NPs (Φ: 30 nm, [Fe]: 0.5 mM) with a sensitivity of 0.2 μM. Auto-handling and identification of two targets (avidin and water) are demonstrated and completed within 2.2 min. This μNMR relaxometer holds promise for combinatorial chemical/biological diagnostic protocols using closed-loop electronic automation.

Neurofeedback training (NFT) has shown positive effects on cognition and behavior enhancement as well as clinical treatment. However, little is known about the training effects in brain activity besides training location which is crucial for understanding the mechanism of neurofeedback and enhancing training efficiency. This study aimed to investigate beta/theta ratio (BTR) NFT effects on the spectral topography of electroencephalogram (EEG). Eleven healthy volunteers completed 25 sessions of NFT in consecutive five days with 5 sessions per day. The results showed that BTR NFT in occipital region did have significant effect on parietal, central and frontal regions, and the changes of BTR and theta amplitude detected in these regions were consistent with the changes at the training location. Moreover, the percentage changes of BTR and theta amplitude in parietal region were significantly greater than those in frontal region probably due to the shorter distance to the training location.

We present a modular nuclear magnetic resonance-digital microfluidics (NMR-DMF) system as a portable diagnostic platform for miniaturized biological assays. With increasing number of combinations between designed probes and a specific target, NMR has become an accurate and rapid assay tool, which is capable of detecting particular kinds of proteins, DNAs, bacteria and cells with a customized probe quantitatively. Traditional sample operation (e.g., manipulation and mixing) relied heavily on human efforts. We herein propose a modular NMR-DMF system to allow the electronic automation of multi-step reaction-screening protocols. A figure-8 shaped coil is proposed to enlarge the usable inner space of a portable magnet by 4.16 times, generating a radio frequency (RF) excitation field in the planar direction. By electronically managing the electro-wetting-on-dielectric (EWOD) effects over an electrode array, preloaded droplets with the inclusion of biological constituents and targets can be programmed to mix and be guided to the detection site (3.5 × 3.5 mm(2)) for high-sensitivity NMR screening (static B field: 0.46 T, RF field: 1.43 mT per ampere), with the result (voltage signal) displayed in real-time. To show the system's utility, automated real-time identification of 100 pM of avidin in a 14 μL droplet was achieved. The system shows promise as a robust and portable diagnostic device for a wide variety of biological analyses and screening applications.

LATE-PCR is an advanced form of non-symmetric PCR that efficiently generates single-stranded DNA which can readily be characterized at the end of amplification by hybridization to low-temperature fluorescent probes. We demonstrate here for the first time that monoplex and duplex LATE-PCR amplification and probe target hybridization can be carried out in double layered PDMS microfluidics chips containing dried reagents. Addition of a set of reagents during dry down overcomes the common problem of single-stranded oligonucleotide binding to PDMS. These proof-of-principle results open the way to construction of inexpensive point-of-care devices that take full advantage of the analytical power of assays built using LATE-PCR and low-temperature probes.

Most biopotential readout front-ends rely on the g m- C lowpass filter (LPF) for forefront signal conditioning. A small g m realizes a large time constant ( τ = C / g m) suitable for ultra-low-cutoff filtering, saving both power and area. Yet, the noise and linearity can be compromised, given that each g m cell can involve one or several noisy and nonlinear V- I conversions originated from the active devices. This paper proposes the subthreshold-source-follower (SSF) Biquad as a prospective alternative. It features: 1) a very small number of active devices reducing the noise and nonlinearity footsteps; 2) No explicit feedback in differential implementation, and 3) extension of filter order by cascading. This paper presents an in-depth treatment of SSF Biquad in the nW-power regime, analyzing its power and area tradeoffs with gain, linearity and noise. A gain-compensation (GC) scheme addressing the gain-loss problem of NMOS-based SSF Biquad due to the body effect is also proposed. Two 100-Hz 4th-order Butterworth LPFs using the SSF Biquads with and without GC were fabricated in 0.35- μm CMOS. Measurement results show that the non-GC (GC) LPF can achieve a DC gain of -3.7 dB (0 dB), an input-referred noise of 36 μV rms (29 μV rms ), a HD3@60 Hz of -55.2 dB ( - 60.7 dB) and a die size of 0.11 mm² (0.08 mm²). Both LPFs draw 15 nW at 3 V. The achieved figure-of-merits (FoMs) are favorably comparable with the state-of-the-art.

The complexity of droplet hydrodynamics on a digital microfluidic (DMF) system eventually weakens its potential for application in large-scale chemical/biological micro-reactors. We describe here an intelligent DMF technology to address that intricacy. A wide variety of control-engaged droplet manageability is proposed and demonstrated through the operation of our modular DMF prototype, which comprises: (i) rigid profiling ability of different droplet's hydrodynamics under a real-time trajectory track of droplet-derived capacitance, permitting accurate and autonomous multi-droplet positioning without visual setup and heavy image signal processing; (ii) fuzzy-enhanced controllability saving up to 21% charging time when compared with the classical approach, enhancing the throughput, fidelity and lifetime of the DMF chip, while identifying and renouncing those weakened electrodes deteriorated over time, and (iii) expert manipulability of multi-droplet routings under countermeasure decisions in real time, preventing droplet-to-droplet or task-to-task interference. Altogether, this work exhibits the first modular DMF system with built-in electronic-control software-defined intelligence to enhance the fidelity and reliability of each droplet operation, allowing future manufacturability of a wide range of life science analyses and combinatorial chemical screening applications.

Portable/Implantable biomedical applications usually exhibit stringent power budgets for prolonging battery life time, but loose operating frequency requirements due to small bio-signal bandwidths, typically below a few kHz. The use of sub-threshold digital circuits is ideal in such scenario to achieve optimized power/speed tradeoffs. This paper discusses the design of a sub-threshold standard cell library using a standard 0.18-µm CMOS technology. A complete library of 56 standard cells is designed and the methodology is ensured through schematic design, transistor width scaling and layout design, as well as timing, power and functionality characterization. Performance comparison between our sub-threshold standard cell library and a commercial standard cell library using a 5-stage ring oscillator and an ECG designated FIR filter is performed. Simulation results show that our library achieves a total power saving of 95.62% and a leakage power reduction of 97.54% when compared with the same design implemented by the commercial standard cell library (SCL).

Healthcare electronics count on the effectiveness of the on-patient signal preprocessing unit to moderate the wireless data transfer for better power efficiency. In order to reduce the system power in long-time ECG acquisition, this work describes an on-patient QRS detection processor for arrhythmia monitoring. It extracts the concerned ECG part, i.e., the RR-interval between the QRS complex for evaluating the heart rate variability. The processor is structured by a scale-3 quadratic spline wavelet transform followed by a maxima modulus recognition stage. The former is implemented via a symmetric FIR filter, whereas the latter includes a number of feature extraction steps: zero-crossing detection, peak (zero-derivative) detection, threshold adjustment and two finite state machines for executing the decision rules. Fabricated in 0.35-μm CMOS the 300-Hz processor draws only 0.83 μW, which is favorably comparable with the prior arts. In the system tests, the input data is placed via an on-chip 10-bit SAR analog-to-digital converter, while the output data is emitted via an off-the-shelf wireless transmitter (TI CC2500) that is configurable by the processor for different data transmission modes: 1) QRS detection result, 2) raw ECG data or 3) both. Validated with all recordings from the MIT-BIH arrhythmia database, 99.31% sensitivity and 99.70% predictivity are achieved. Mode 1 with solely the result of QRS detection exhibits 6× reduction of system power over modes 2 and 3.

Memory performance has been reported to be associated with electroencephalogram (EEG) alpha activity. This study aimed to improve short term memory performance by individual alpha neurofeedback training (NFT). With appropriate protocol designed for NFT, the experimental results showed that the participants were able to learn to increase the relative amplitude in individual alpha band during NFT and short term memory performance was significantly enhanced by 20 sessions of NFT. More importantly, further analysis revealed that the improvement of short term memory was positively correlated with the increase of the relative amplitude in the individual upper alpha band during training. In addition, effective strategies for individual alpha training varied among individuals and the most successful mental strategies were related to positive thinking., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A critical problem in using steady-state visual evoked potential (SSVEP) based brain-computer interfaces (BCIs) for clinical and commercial use is the visual fatigue the user may suffer when staring at flashing stimuli. Aiming at the design of user-friendly BCIs with satisfactory performance, this work is to preliminarily investigate how different colors influence the SSVEP (i.e. frequency or phase) and system performance. The results show that white stimuli can lead to the highest performance, followed by gray, red, green and blue stimuli.

This paper describes an ultra-low-power filtering technique for biomedical applications designated as T-wave sensing in heart-activities detection systems. The topology is based on a source-follower-based Biquad operating in the sub-threshold region. With the intrinsic advantages of simplicity and high linearity of the source-follower, ultra-low-cutoff filtering can be achieved, simultaneously with ultra low power and good linearity. An 8(th)-order 2.4-Hz lowpass filter design example optimized in a 0.35-μm CMOS process was designed achieving over 85-dB dynamic range, 74-dB stopband attenuation and consuming only 0.36 nW at a 3-V supply.

Due to the artifacts in electroencephalography (EEG) data, the performance of brain-computer interface (BCI) is degraded. On the other hand, in the motor imagery based BCI system, EEG signals are usually contaminated by the misleading trials caused by improper imagination of a movement. In this paper, we present a novel algorithm to detect the abnormal EEG data using genetic algorithm (GA). After trial pruning, a subset of the EEG data are selected, on which common spatial pattern (CSP) and Gaussian classifier are trained. The performance of the proposed method is tested on Data set IIa of BCI Competition IV, and the simulation result demonstrates a significant improvement for six out of nine subjects.