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Research has shown that pulse transit time (PTT), which is the time delay between the electrocardiogram (ECG) signal and the signal from a photoplethysmogram (PPG) sensor, can be used to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) without the need for a cuff. However, the LED of the PPG sensor requires the precise adjustment of both light intensity and light absorption rates according to the contact status of the light-receiving element. This results in the need for regular calibration. In this study, we propose a cuffless blood pressure monitor that measures real-time blood pressure using a microphone instead of a PPG sensor. The blood pulse wave is measured in the radial artery of the wrist using a microphone that can directly measure the sound generated by a body rather than sending energy inside the body and receiving a returning signal. Our blood pressure monitor uses the PTT between the R-peak of the ECG signal and two feature points of the blood pulse wave in the radial artery of the wrist. ECG electrodes and circuits were fabricated, and a commercial microelectromechanical system (MEMS) microphone was used as the microphone to measure blood pulses. The peak points of the blood pulse from the microphone were clear, so the estimated SBP and DBP could be obtained from each ECG pulse in real time, and the resulting estimations were similar to those made by a commercial cuff blood pressure monitor. Since neither the ECG electrodes nor the microphone requires calibration over time, the real-time cuffless blood pressure monitor does not require calibration. Using the developed device, blood pressure was measured three times daily for five days, and the mean absolute error (MAE) and standard deviation (SD) of the SBP and DBP were found to be 2.72 ± 3.42 mmHg and 2.29 ± 3.53 mmHg, respectively. As a preliminary study for proof-of-concept, these results were obtained from one subject. The next step will be a pilot study on a large number of subjects.

This paper presents a silicon−dioxide−coated capacitive electrode system for an ambulatory electrocardiogram (ECG). The electrode was coated with a nano−leveled (287 nm) silicon dioxide layer which has a very high resistance of over 200 MΩ. Due to this high resistance, the electrode can be defined as only a capacitor without a resistive characteristic. This distinct capacitive characteristic of the electrode brings a simplified circuit analysis to achieve the development of a high−quality ambulatory ECG system. The 240 um thickness electrode was composed of a stainless−steel sheet layer for sensing, a polyimide electrical insulation layer, and a copper sheet connected with the ground to block any electrical noises generated from the back side of the structure. Six different diameter electrodes were prepared to optimize ECG signals in ambulatory environment, such as the amplitude of the QRS complex, amplitude of electromagnetic interference (EMI), and baseline wandering of the ECG signals. By combining the experimental results, optimal ambulatory ECG signals were obtained with electrodes that have a diameter from 1 to 3 cm. Moreover, we achieved high−quality ECG signals in a sweating simulation environment with 2 cm electrodes.

This paper proposes to remotely estimate a human subject’s blood pressure using a millimeter-wave radar system. High blood pressure is a critical health threat that can lead to diseases including heart attacks, strokes, kidney disease, and vision loss. The commonest method of measuring blood pressure is based on a cuff that is contact-based, non-continuous, and cumbersome to wear. Continuous remote monitoring of blood pressure can facilitate early detection and treatment of heart disease. This paper investigates the possibility of using millimeter-wave frequency-modulated continuous-wave radar to measure the heart blood pressure by means of pulse wave velocity (PWV). PWV is known to be highly correlated with blood pressure, which can be measured by pulse transit time. We measured PWV using a two-millimeter wave radar focused on the subject’s chest and wrist. The measured time delay provided the PWV given the length from the chest to the wrist. In addition, we analyzed the measured radar signal from the wrist because the shape of the pulse wave purveyed information on blood pressure. We investigated the area under the curve (AUC) as a feature and found that AUC is strongly correlated with blood pressure. In the experiment, five human subjects were measured 50 times each after performing different activities intended to influence blood pressure. We used artificial neural networks to estimate systolic blood pressure (SBP) and diastolic blood pressure (SBP) with both PWV and AUC as inputs. The resulting root mean square errors of estimated blood pressure were 3.33 mmHg for SBP and 3.14 mmHg for DBP.

We propose a new packaging process for an implantable blood pressure sensor using ultrafast laser micro-welding. The sensor is a membrane type, passive device that uses the change in the capacitance caused by the membrane deformation due to applied pressure. Components of the sensor such as inductors and capacitors were fabricated on two glass (quartz) wafers and the two wafers were bonded into a single package. Conventional bonding methods such as adhesive bonding, thermal bonding, and anodic bonding require considerable effort and cost. Therefore CO2 laser cutting was used due to its fast and easy operation providing melting and bonding of the interface at the same time. However, a severe heat process leading to a large temperature gradient by rapid heating and quenching at the interface causes microcracks in brittle glass and results in low durability and production yield. In this paper, we introduce an ultrafast laser process for glass bonding because it can optimize the heat accumulation inside the glass by a short pulse width within a few picoseconds and a high pulse repetition rate. As a result, the ultrafast laser welding provides microscale bonding for glass pressure sensor packaging. The packaging process was performed with a minimized welding seam width of 100 μm with a minute. The minimized welding seam allows a drastic reduction of the sensor size, which is a significant benefit for implantable sensors. The fabricated pressure sensor was operated with resonance frequencies corresponding to applied pressures and there was no air leakage through the welded interface. In addition, in vitro cytotoxicity tests with the sensor showed that there was no elution of inner components and the ultrafast laser packaged sensor is non-toxic. The ultrafast laser welding provides a fast and robust glass chip packaging, which has advantages in hermeticity, bio-compatibility, and cost-effectiveness in the manufacturing of compact implantable sensors.

A miniaturized pump to manipulate liquid flow in microchannels is the key component of microfluidic devices. Many researchers have demonstrated active microfluidic pumps, but most of them still required additional large peripherals to operate their micropumps. In addition, those micropumps were made of polymer materials so that their application may be limited to a variety of fields that require harsh conditions at high pressures and temperatures or organic solvents and acid/base. In this work, we present a 3D miniaturized magnetic-driven glass centrifugal pump for microfluidic devices. The pump consists of a volute structure and a 3D impeller integrated with two magnet disks of Φ1 mm. The 3D pump structure was 13 mm × 10.5 mm × 3 mm, and it was monolithically fabricated in a fused silica sheet by selective laser-induced etching (SLE) technology using a femtosecond laser. The pump operation requires only one motor rotating two magnets. It was Φ42 mm × 54 mm and powered by a battery. To align the shaft of the motor to the center of the 3D glass pump chip, a housing containing the motor and the chip was fabricated, and the overall size of the proposed micropump device was 95 mm × 70 mm × 75 mm. Compared with other miniaturized pumps, ours was more compact and portable. The output pressure of the fabricated micropump was between 215 Pa and 3104 Pa, and the volumetric flow rate range was 0.55 mL/min and 7.88 mL/min. The relationship between the motor RPM and the impeller RPM was analyzed, and the flow rate was able to be controlled by the RPM. With its portability, the proposed pump can be applied to produce an integrated and portable microfluidic device for point-of-care analysis.

We present a rapid and highly reliable glass (fused silica) microfluidic device fabrication process using various laser processes, including maskless microchannel formation and packaging. Femtosecond laser assisted selective etching was adopted to pattern microfluidic channels on a glass substrate and direct welding was applied for local melting of the glass interface in the vicinity of the microchannels. To pattern channels, a pulse energy of 10 μJ was used with a scanning speed of 100 mm/s at a pulse repetition rate of 500 kHz. After 20–30 min of etching in hydrofluoric acid (HF), the glass was welded with a pulse energy of 2.7 μJ and a speed of 20 mm/s. The developed process was as simple as drawing, but powerful enough to reduce the entire production time to an hour. To investigate the welding strength of the fabricated glass device, we increased the hydraulic pressure inside the microchannel of the glass device integrated into a custom-built pressure measurement system and monitored the internal pressure. The glass device showed extremely reliable bonding by enduring internal pressure up to at least 1.4 MPa without any leakage or breakage. The measured pressure is 3.5-fold higher than the maximum internal pressure of the conventional polydimethylsiloxane (PDMS)–glass or PDMS–PDMS bonding. The demonstrated laser process can be applied to produce a new class of glass devices with reliability in a high pressure environment, which cannot be achieved by PDMS devices or ultraviolet (UV) glued glass devices.

This study proposes a rapid and inexpensive thermocycler that enables rapid heating of samples using a thin glass chip and a cheap chip resistor to overcome the on-site diagnostic limitations of polymerase chain reaction (PCR). Microchip PCR devices have emerged to miniaturize conventional PCR systems and reduce operation time and cost. In general, PCR microchips require a thin-film heater fabricated through a semiconductor process, which is a complicated process, resulting in high costs. Therefore, this investigation substituted a general chip resistor for a thin-film heater. The proposed thermocycler consists of a compact glass microchip of 12.5 mm × 12.5 mm × 2 mm that could hold a 2 μL PCR sample and a surface-mounted chip resistor of 6432 size (6.4 mm × 3.2 mm). Improving heat transfer from the chip resistor heater to the PCR reaction chamber in the microchip was accomplished via the design and fabrication of a three-dimensional chip structure using selective laser-induced etching, a rapid prototyping technique that allowed to be embedded. The fabricated PCR microchip was combined with a thermistor temperature sensor, a blower fan, and a microcontroller. The assembled thermocycler could heat the sample at a maximum rate of 28.8 °C/s per second. When compared with a commercially available PCR apparatus running the same PCR protocol, the total PCR operating time with a DNA sample was reduced by about 20%.

Rapid and accurate detection of plant pathogens in the field is crucial to prevent the proliferation of infected crops. Polymerase chain reaction (PCR) process is the most reliable and accepted method for plant pathogen diagnosis, however current conventional PCR machines are not portable and require additional post-processing steps to detect the amplified DNA (amplicon) of pathogens. Real-time PCR can directly quantify the amplicon during the DNA amplification without the need for post processing, thus more suitable for field operations, however still takes time and require large instruments that are costly and not portable. Microchip PCR systems have emerged in the past decade to miniaturize conventional PCR systems and to reduce operation time and cost. Real-time microchip PCR systems have also emerged, but unfortunately all reported portable real-time microchip PCR systems require various auxiliary instruments. Here we present a stand-alone real-time microchip PCR system composed of a PCR reaction chamber microchip with integrated thin-film heater, a compact fluorescence detector to detect amplified DNA, a microcontroller to control the entire thermocycling operation with data acquisition capability, and a battery. The entire system is 25 × 16 × 8 cm(3) in size and 843 g in weight. The disposable microchip requires only 8-µl sample volume and a single PCR run consumes 110 mAh of power. A DNA extraction protocol, notably without the use of liquid nitrogen, chemicals, and other large lab equipment, was developed for field operations. The developed real-time microchip PCR system and the DNA extraction protocol were used to successfully detect six different fungal and bacterial plant pathogens with 100% success rate to a detection limit of 5 ng/8 µl sample.

We present the selective laser-induced etching (SLE) process and design guidelines for the fabrication of three-dimensional (3D) microfluidic channels in a glass. The SLE process consisting of laser direct patterning and wet chemical etching uses different etch rates between the laser modified area and the unmodified area. The etch selectivity is an important factor for the processing speed and the fabrication resolution of the 3D structures. In order to obtain the maximum etching selectivity, we investigated the process window of the SLE process: the laser pulse energy, pulse repetition rate, and scan speed. When using potassium hydroxide (KOH) as a wet etchant, the maximum etch rate of the laser-modified glass was obtained to be 166 μm/h, exhibiting the highest selectivity about 333 respect to the pristine glass. Based on the optimized process window, a 3D microfluidic channel branching to three multilayered channels was successfully fabricated in a 4 mm-thick glass. In addition, appropriate design guidelines for preventing cracks in a glass and calibrating the position of the dimension of the hollow channels were studied.

We developed a stand-alone, real-time optical detection device capable of reading fluorescence intensities from cell samples with high sensitivity and precision, for use as a portable fluorescent sensor for sensing fluorescently labeled enterohemorrhagic Escherichia coli (EHEC) Shiga toxins (Stxs). In general, the signal intensity from the fluorescently labeled Stxs was weak due to the small number of molecules bound to each cell. To address this technical challenge, we used a highly sensitive light detector (photomultiplier tube: PMT) to measure fluorescence, and designed a portable optical housing to align optical parts precisely; the housing itself was fabricated on a 3D printer. In addition, an electric circuit that amplified PMT output was designed and integrated into the system. The system shows the toxin concentration in the sample on a liquid crystal display (LCD), and a microcontroller circuit is used to read PMT output, process data, and display results. In contrast to other portable fluorescent detectors, the system works alone, without any peripheral computer or additional apparatus; its total size is about 17 x 13 x 9 cm.sup.3, and it weighs about 770 g. The detection limit was 0.01 ppm of Alexa Fluor 488 in PBS, which is ten thousand times lower than those of other smartphone-based systems and sufficiently sensitive for use with a portable optical detector. We used the portable real-time optical sensing system to detect Alexa Fluor 488-tagged Stx2B-subunits bound to monocytic THP-1 cells expressing the toxin receptor globotriaosylceramide (Gb3). The device did not detect a signal from Gb3-negative PD36 cells, indicating that it was capable of specifically detecting Stxs bound to cells expressing the toxin receptor. Following the development of a rapid and autonomous method for fluorescently tagging cells in food samples, the optical detection system described here could be used for direct detection of Shiga toxins in food in the field.