A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).

Localized Dielectric Loss Heating in Dielectrophoresis Devices.

Temperature increases during dielectrophoresis (DEP) can affect the response of biological entities, and ignoring the effect can result in misleading analysis. The heating mechanism of a DEP device is typically considered to be the result of Joule heating and is overlooked without an appropriate analysis. Our experiment and analysis indicate that the heating mechanism is due to the dielectric loss (Debye relaxation). A temperature increase between interdigitated electrodes (IDEs) has been measured with an integrated micro temperature sensor between IDEs to be as high as 70 °C at 1.5 MHz with a 30 Vpp applied voltage to our ultra-low thermal mass DEP device. Analytical and numerical analysis of the power dissipation due to the dielectric loss are in good agreement with the experiment data.

Microscale direct measurement of localized photothermal heating in tissue-mimetic hydrogels.

Photothermal hyperthermia is proven to be an effective diagnostic tool for cancer therapy. The efficacy of this method directly relies on understanding the localization of the photothermal effect in the targeted region. Realizing the safe and effective concentration of nano-particles and the irradiation intensity and time requires spatiotemporal temperature monitoring during and after laser irradiation. Due to uniformities of the nanoparticle distribution and the complexities of the microenvironment, a direct temperature measurement in micro-scale is crucial for achieving precise thermal dose control. In this study, a 50 nm thin film nickel resistive temperature sensor was fabricated on a 300 nm SiN membrane to directly measure the local temperature variations of a hydrogel-GNR mixture under laser exposure with 2 mK temperature resolution. The chip-scale approach developed here is an effective tool to investigate localization of photothermal heating for hyperthermia applications for in-vitro and ex-vivo models. Considering the connection between thermal properties, porosity and the matrix stiffness in hydrogels, we present our results using the interplay between matrix stiffness of the hydrogel and its thermal properties: the stiffer the hydrogel, the higher the thermal conductivity resulting in lower photothermal heating. We measured 8.1, 7.4, and 5.6 °C temperature changes (from the room temperature, 20 °C) in hydrogel models with stiffness levels corresponding to adipose (4 kPa), muscle (13 kPa) and osteoid (30 kPa) tissues respectively by exposing them to 2 W/cm2 laser (808 nm) intensity for 150 seconds.

A patterned single layer graphene resistance temperature sensor.

Micro-fabricated single-layer graphenes (SLGs) on a silicon dioxide (SiO2)/Si substrate, a silicon nitride (SiN) membrane, and a suspended architecture are presented for their use as temperature sensors. These graphene temperature sensors act as resistance temperature detectors, showing a quadratic dependence of resistance on the temperature in a range between 283 K and 303 K. The observed resistance change of the graphene temperature sensors are explained by the temperature dependent electron mobility relationship (~T-4) and electron-phonon scattering. By analyzing the transient response of the SLG temperature sensors on different substrates, it is found that the graphene sensor on the SiN membrane shows the highest sensitivity due to low thermal mass, while the sensor on SiO2/Si reveals the lowest one. Also, the graphene on the SiN membrane reveals not only the fastest response, but also better mechanical stability compared to the suspended graphene sensor. Therefore, the presented results show that the temperature sensors based on SLG with an extremely low thermal mass can be used in various applications requiring high sensitivity and fast operation.

On-chip detection of gel transition temperature using a novel micro-thermomechanical method.

We present a new thermomechanical method and a platform to measure the phase transition temperature at microscale. A thin film metal sensor on a membrane simultaneously measures both temperature and mechanical strain of the sample during heating and cooling cycles. This thermomechanical principle of operation is described in detail. Physical hydrogel samples are prepared as a disc-shaped gels (200 µm thick and 1 mm diameter) and placed between an on-chip heater and sensor devices. The sol-gel transition temperature of gelatin solution at various concentrations, used as a model physical hydrogel, shows less than 3% deviation from in-depth rheological results. The developed thermomechanical methodology is promising for precise characterization of phase transition temperature of thermogels at microscale.

Thermal Measurement Techniques in Analytical Microfluidic Devices.

Thermal measurement techniques have been used for many applications such as thermal characterization of materials and chemical reaction detection. Micromachining techniques allow reduction of the thermal mass of fabricated structures and introduce the possibility to perform high sensitivity thermal measurements in the micro-scale and nano-scale devices. Combining thermal measurement techniques with microfluidic devices allows performing different analytical measurements with low sample consumption and reduced measurement time by integrating the miniaturized system on a single chip. The procedures of thermal measurement techniques for particle detection, material characterization, and chemical detection are introduced in this paper.

A paper-based calorimetric microfluidics platform for bio-chemical sensing.

In this report, a paper-based micro-calorimetric biochemical detection method is presented. Calorimetric detection of biochemical reactions is demonstrated as an extension of current colorimetric and electrochemical detection mechanisms of paper-based biochemical analytical systems. Reaction and/or binding temperature of glucose/glucose oxidase, DNA/hydrogen peroxide, and biotin/streptavidin, are measured by the paper-based micro-calorimeter. Commercially available glucose calibration samples of 0.05, 0.15 and 0.3% wt/vol concentration are used for comparing the device performance with a commercially available glucose meter (electrochemical detection). The calorimetric glucose detection demonstrates a measurement error less than 2%. The calorimetric detection results of DNA concentrations from 0.9 to 7.3 mg/mL and temperature changes in biotin and streptavidin reaction are presented to demonstrate the feasibility of integrating the calorimetric detection method with paper based microfluidic devices.

Suspended and localized single nanostructure growth across a nanogap by an electric field.

Direct growth of a suspended single nanostructure (SSN) at a specific location is presented. The SSN is grown across a metallic nanoscale gap by migration in air at room temperature. The nanogap is fabricated by industrial standard optical lithography and anisotropic wet chemical silicon etching. A DC current bias, 1 nA, is applied across the metallic gap to induce nanoscale migration of Zn or ZnO. The history of the voltage drop across the gap as a function of time clearly indicates the moment when migration begins. The shape of SSNs grown across the nanogap by the migration is asymmetric at each electrode due to the asymmetric electric field distribution within the nanogap. An SSN can be used as the platform for two-terminal active or passive nanoscale electronics in optoelectronics, radio frequency (RF) resonators, and chemical/biological sensors.

Integrated freestanding single-crystal silicon nanowires: conductivity and surface treatment.

Integrated freestanding single-crystal silicon nanowires with typical dimension of 100 nm × 100 nm × 5 µm are fabricated by conventional 1:1 optical lithography and wet chemical silicon etching. The fabrication procedure can lead to wafer-scale integration of silicon nanowires in arrays. The measured electrical transport characteristics of the silicon nanowires covered with/without SiO(2) support a model of Fermi level pinning near the conduction band. The I-V curves of the nanowires reveal a current carrier polarity reversal depending on Si-SiO(2) and Si-H bonds on the nanowire surfaces.

Single microdroplet ejection using an ultrasonic longitudinal mode with a PZT/tapered glass capillary.

We have developed an ultrasonic PZT/tapered glass capillary resonant actuator that can eject a single droplet every acoustic cycle without also generating satellite droplets. The mechanism of the actuation is resonant longitudinal motion-induced squeezing of a tapered volume. The actuator is driven at 160 kHz and requires voltages less than 2 Vpp to operate. In this paper, the droplet generation of isopropanol and water mixtures, which have different densities, viscosities, and surface tensions, is investigated. It is determined that the geometrical squeezing mechanism and the ejected jet breakup makes the droplet size independent of frequency, but more a function of the ejecting orifice diameter that is much smaller than the capillary wavelength.